Article

Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp

Authors:
  • Clinic Augustinum
  • Ortenau Klinikum Offenburg Germany
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Abstract

Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation. To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension. Randomized, double-blind, placebo-controlled crossover study. University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest. 14 healthy mountaineers and trekkers. Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp). Oral sildenafil, 50 mg, or placebo. At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants. The study did not examine the effects of sildenafil on normoxic exercise tolerance. Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.

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... However, these values decrease in chronic hypoxia [3] as a consequence of acclimation; a phenomenon known as the "lactate paradox" [9,25] and to enhanced lactate utilization during exercise [18]. Exercise in hypoxia also exacerbates the reduction in oxygen arterial saturation, which reduces arterial oxygen content due to higher extraction at peripheral level and lower uptake during the exchange in the lungs [16,28], and increases the risk of pulmonary edema [2,30], especially in people with higher susceptibility to acute mountain sickness [13]. Sildenafil use was originally prescribed for the treatment of erectile dysfunction [12,26,33]. ...
... Sildenafil does not Improve … Int J Sports Med reduction of pulmonary arterial hypertension (PAH) in mild or severe hypoxia in healthy people. Previous research has shown that sildenafil diminishes pulmonary arterial hypertension during medium or high altitude exposure and under similar experimental hypoxic conditions [31,41], and may improve exercise performance [14,16]. Furthermore, it has been shown that sildenafil can improve oxygen saturation during several days of exposure to high altitude [32]. ...
... However, we observed remarkable differences in comparison with previous reported effects of sildenafil on physical performance. Most of the previous performance improvements after sildenafil administration were found in acclimatized subjects at altitudes usually reserved for mountaineering activities [16,17]. However, most sports competitions are held at much lower altitudes. ...
Article
The increase in pulmonary arterial pressure (PAP) due to hypoxic pulmonary vasoconstriction (HPV) could be a limiting factor for physical performance during hypoxic exposure. Sildenafil has been shown to reduce PAP in situations of moderate or severe hypoxia, and consequently its role as an ergogenic aid and even a possible doping substance must be considered. We performed a double-blind crossover study to determine the effects of sildenafil on cardiovascular, respiratory and metabolic parameters in normoxia and during acute exposure to hypobaric hypoxia (4 000 m) at rest and during maximal and submaximal (60% VO2 max) exercise tests. One hour before testing started, sildenafil (100 mg) or a placebo was orally administered to 11 volunteers. In normoxic conditions, sildenafil did not affect performance. Similarly, no significant differences were found in cardiovascular and respiratory parameters in hypoxic conditions at rest or during exercise. The use of sildenafil to improve physical performance in non-acclimatized subjects is not supported by our data. © Georg Thieme Verlag KG Stuttgart · New York.
... Previous research has been inconclusive on the effectiveness of sildenafil to reduce HPV and improve exercise performance during acute moderate-and high-altitude exposure. Several studies have shown a strong effect of sildenafil in reducing PAP at rest [7][8][9] and during exercise [7,9,10]. However, only two [7,11] of the five studies that measured CO [7,[10][11][12][13] showed an increase in PAP because of sildenafil use during exercise in hypoxia. ...
... Previous research has been inconclusive on the effectiveness of sildenafil to reduce HPV and improve exercise performance during acute moderate-and high-altitude exposure. Several studies have shown a strong effect of sildenafil in reducing PAP at rest [7][8][9] and during exercise [7,9,10]. However, only two [7,11] of the five studies that measured CO [7,[10][11][12][13] showed an increase in PAP because of sildenafil use during exercise in hypoxia. ...
... Several studies have shown a strong effect of sildenafil in reducing PAP at rest [7][8][9] and during exercise [7,9,10]. However, only two [7,11] of the five studies that measured CO [7,[10][11][12][13] showed an increase in PAP because of sildenafil use during exercise in hypoxia. Only three [7,10,11] of six studies that measured performance outcomes [7,8,[10][11][12][13] showed an increase with sildenafil use. ...
Article
Full-text available
Sildenafil is a pulmonary vasodilator that has potential to mitigate the decrement in endurance performance caused by hypoxic pulmonary vasoconstriction. The purpose of this study was to determine the effects of sildenafil on pulmonary artery pressure, cardiac output, pulse oxygen saturation, and exercise performance at moderate simulated altitude. We hypothesized that sildenafil would reduce the decline in exercise performance in hypoxia by blunting the rise in pulmonary artery pressure and causing a relative increase in cardiac output and oxygen saturation. Twelve endurance trained men performed three experimental cycling trials at sea level and simulated moderate altitude of 3,000m (FIO2 = 0.147) after ingesting either a placebo or sildenafil 50 mg capsule in a double blinded fashion. Each test consisted of a warmup period, a 15-minute steady state period at 60% of peak power output, and a 16.1 km time-trial. All subjects experienced a decline in maximal exercise capacity in hypoxia that ranged from 6% to 24%. This decline was correlated with the reduction in pulse oxygen saturation in hypoxic maximal exercise. Sildenafil had no effect on pulmonary artery pressure, cardiac output, or pulse oxygen saturation measured during steady state exercise. There was no effect of sildenafil on mean power output during the time-trial. During high intensity cycle exercise in acute, moderate hypoxia pulmonary artery pressure is unaffected by sildenafil and does not appear to influence cardiovascular function or exercise performance.
... Several randomized double-blind placebo-controlled cross-over studies clearly demonstrated attenuation of hypoxic PAP elevation in healthy volunteers at rest and during exercise by a single dose of the phosphodiestherase-5 inhibitor sildenafil [20,[114][115][116]. Moreover, in randomized double-blind placebo-controlled studies, sildenafil reduced systolic PAP at rest and during exercise in healthy individuals at high altitude [114,116,117]. ...
... Several randomized double-blind placebo-controlled cross-over studies clearly demonstrated attenuation of hypoxic PAP elevation in healthy volunteers at rest and during exercise by a single dose of the phosphodiestherase-5 inhibitor sildenafil [20,[114][115][116]. Moreover, in randomized double-blind placebo-controlled studies, sildenafil reduced systolic PAP at rest and during exercise in healthy individuals at high altitude [114,116,117]. ...
... Inhaled NO Soluble guanylate cyclase stimulator decreases sPAP and improves oxygenation in HAPE-prone subjects at HA [112] reduces mPAP and PVR in HAPE patients at HA [113] decreases PAP and PVR in hypoxia-breathing healthy subjects [112] Sildenafil Phosphodiesterase 5 inhibitor prevents an increase in PAP and PVR in hypoxia-breathing healthy subjects [20,151] decreases sPAP and improves exercise capacity under hypoxic breathing and at HA in healthy subjects [114] decreases sPAP and improves blood oxygenation upon acute HA exposure in healthy subjects [117] attenuates sPAP increase and RV dysfunction upon acute HA exposure in healthy subjects [22] Tadalafil Phosphodiesterase 5 inhibitor attenuates an increase in PAP and prevents HAPE development [64] Bosentan Endothelin receptor receptor A/B antagonist prevents an increase in sPAP and PVR in hypoxia breathing healthy subjects [125][126][127] prevents an increase in sPAP and improves arterial oxygen saturation in healthy subjects exposed to HA [122] Sitaxentan Endothelin receptor antagonist prevents an increase of PAP and PVR and exercise capacity decline in hypoxia-breathing healthy subjects [129] reduces PVR and improves lung diffusion capacity and exercise capacity in healthy subjects exposed to HA [152] reduces PAP and PVR and improves exercise capacity in healthy subjects exposed to HA [129] Nifedipine Calcium channel blocker reduces PAP and improves HAPE symptoms [66] attenuates an increase in PAP and prevents HAPE development [63] Dexamethasone Anti-inflammatory and immunosuppressive agent attenuates an increase in PAP and prevents HAPE development [64] attenuates an increase in TRG and PVR and improves oxygenation in COPD patients at HA [153] attenuates an increase in TRG and improves exercise capacity [154] Acetazolamide Carbonic anhydrase inhibitor prevents an increase in TRG in hypoxia-breathing healthy subjects [136] HA, high altitude; PAP, pulmonary artery pressure; sPAP, systolic pulmonary artery pressure; RVSP, right ventricular systolic pressure; TRG, tricuspid regurgitation gradient; PVR, pulmonary vascular resistance; HAPE, high altitude pulmonary edema; COPD, chronic obstructive pulmonary disease; NOS, nitric oxide synthase; PAEC, pulmonary artery endothelial cell; PASMC, pulmonary artery smooth muscle cell. ...
Article
Full-text available
Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.
... However, more recently, robust and growing studies suggest that the right ventricle (RV) might also be an important determinant of maximal cardiac output and VO 2 max [3,4]. More broadly, the RV-pulmonary circulation unit, including the capillary network, has been identified as a potential factor modulating the aerobic exercise capacity in normoxia [5][6][7][8] and in hypoxia [7][8][9][10]. Indeed, pulmonary vascular reserve, or the ability of the pulmonary circulation to extend, recruit, and vasodilate to smooth an intravascular pressure increase, is critical in minimizing RV afterload and maximizing peak cardiac output at exercise [5,6]. ...
... Increased PAP during exercise is known to limit exercise capacity in pulmonary hypertension patients through a decreased maximum cardiac output by an overloaded right ventricle [11]. Recently it has also been suggested that the same phenomenon could appear in healthy individuals exercising at high workloads at sea level [5][6][7][8] but even more at altitude [7][8][9][10]. ...
... Indeed, specific pulmonary vasodilating interventions have been reported to improve the decreased aerobic exercise capacity in hypoxia with little or no effect on normoxic exercise performance. Primary studies described an increase in maximal workload and VO 2 max after intake of sildenafil, a phosphodiesterase-5 inhibitor used to treat erectile dysfunction in healthy hypoxic subjects [9,[67][68][69]. It has been suggested that the underlying mechanism was an increase maximal Q due to a reduced RV afterload after HPV inhibition or pulmonary vasodilation. ...
... Dans les premiers temps de l'exposition à l'altitude, le Q̇c au repos ne semble pas affecté (Hopkins et al., 2003;Reeves et al., 1987;Wolfel et al., 1991) ou est légèrement augmenté . A l'exercice sous maximal, pour une intensité donnée, le Q̇c serait augmenté par rapport au niveau de la mer (Stenberg et al., 1966;Wagner, 2000) tandis qu'à l'exercice maximal, plusieurs auteurs observent une diminution du Qċ max Ghofrani et al., 2004;Hopkins et al., 2003). A 5300 m, Calbet et al. (2003a) ont mesuré une diminution de 17% de Qċ max . ...
... Plusieurs études ont ensuite confirmé que l'hypertension pulmonaire à l'effort contribue à la limitation de la V̇O 2max en haute altitude Naeije et Dedobbeleer, 2013;Pavelescu et al., 2013). En effet lorsque les RVP sont diminuées par prise de sildénafil (vasodilatateur pulmonaire), le Q̇c max et la V̇O 2max sont améliorés (Faoro et al., 2007;Ghofrani et al., 2004;Richalet et al., 2005). De plus l'inhibition de la VPH par prise de bosentan (vasodilatateur pulmonaire) a montré une amélioration d'environ 25% du déficit de V̇O 2max engendré par l'hypoxie (Faoro et al., 2009 ...
... En haute altitude, plusieurs études récentes suggèrent une limitation du Q̇c max , en partie liée à une élévation de la postcharge du ventricule droit consécutive à une augmentation de la Pap induite par la VPH (Faoro et al., 2007;Ghofrani et al., 2004;Naeije et al., 2010). En général, pour une altitude modérée comme à ̴ 2000 mètres, le Qċ max varie peu en comparaison du niveau de la mer (Mollard et al., 2007b 1,8 ± 0,3 1,9 ± 0,2 1,8 ± 0,2 max 2,1 ± 0,2 1,8 ± 0,1 1,7 ± 0,1 Pcap début 13 ± 0,5 12 ± 0,6 14 ± 0,4 mmHg max 27 ± 0,7 ⁰ Ψ 25 ± 0,7 ⁰ * 28 ± 1,4 ⁰ Qc début 6,0 ± 0,4 5,3 ± 0,3 5,3 ± 0,3 l.min −1 max 18 ± 1,1 ⁰ * 18 ± 1,2 ⁰ * 15 ± 1,0 ⁰ VES début 0,09 ± 0,01 * 0,09 ± 0,01 * 0,08 ± 0,003 l max 0,12 ± 0,01 ⁰ * 0,12 ± 0,01 ⁰ * 0,10 ± 0,01 ⁰ FC début 62 ± 2,7 * 63 ± 4,1 * 77 ± 5,7 bpm max 168 ± 4,2 ⁰ 163 ± 6,1 ⁰ 165 ± 5,4 ⁰ Pente Pap/̇ mmHg.l ...
Thesis
En plaine, la moitié des athlètes entrainés en endurance sont susceptibles de développer une hypoxémie induite par l’exercice (HIE). Actuellement, la pratique des sports d’endurance de montagne est en plein essor. Dans ces disciplines, les athlètes très entrainés en endurance et donc susceptibles de développer une HIE, évoluent régulièrement en altitude modérée. Ce travail s’est intéressé à l’évolution de la HIE en altitude modérée, ainsi qu’à ses conséquences et sa relation avec la modification des composantes cardio-respiratoires à l’exercice. Nos résultats indiquent que : 1) la désaturation artérielle n’est pas potentialisée en altitude aiguë chez les athlètes HIE par rapport à des athlètes non-HIE alors que les athlètes HIE ont une chute de consommation maximale d’oxygène et de fréquence cardiaque maximale plus importante, 2) les athlètes HIE développent un stress hémodynamique important associé à des réponses vasculaires pulmonaires spécifiques à l’exercice en plaine, 3) tous les athlètes présentent une limitation de la diffusion pulmonaire à l’exercice maximal en altitude aiguë et nos résultats ne permettent pas d’affirmer une limitation cardiaque plus importante chez les athlètes HIE, 4) en hypoxie chronique, la désaturation artérielle est influencée par les modalités de pratique sportive. Notre travail a permis d’établir des recommandations pour les athlètes entrainés en endurance, de plus en plus nombreux, désirant performer en altitude modérée.
... D'autres auteurs ont mis en évidence que le Q cmax serait diminué en altitude par rapport à la plaine, quel que soit le niveau d'altitude (Calbet et al. 2008;Ghofrani et al. 2004;Hopkins et al. 2003;Peltonen et al. 2001 ...
... De plus, Louie et al. (1992) L'élévation du degré d'hypoxémie pendant l'effort stimule la VPH et contribue donc à l'intensification de l'hypertension pulmonaire. A 5 000 m, les valeurs de pressions artérielles pulmonaires s'élevaient de 30 mmHg au repos à 43 mmHg à l'exercice maximal (Ghofrani et al. 2004). Plusieurs études ont montré que la prise de médicaments (Bosentan et Sildénafil qui sont utilisés comme vasodilatateur pulmonaire), permettant de limiter l'hypertension pulmonaire hypoxique, améliorait le Q cmax et la V O 2 max en haute altitude (Faoro et al. 2007(Faoro et al. , 2009Ghofrani et al. 2004). ...
... A 5 000 m, les valeurs de pressions artérielles pulmonaires s'élevaient de 30 mmHg au repos à 43 mmHg à l'exercice maximal (Ghofrani et al. 2004). Plusieurs études ont montré que la prise de médicaments (Bosentan et Sildénafil qui sont utilisés comme vasodilatateur pulmonaire), permettant de limiter l'hypertension pulmonaire hypoxique, améliorait le Q cmax et la V O 2 max en haute altitude (Faoro et al. 2007(Faoro et al. , 2009Ghofrani et al. 2004). Des améliorations d'environ 25% du déficit de VO 2max engendré par l'hypoxie ont été observées dans ces études. ...
Thesis
A l’heure actuelle aucun consensus n’existe sur l’utilisation des substrats énergétiques lors d’un exercice en altitude. Certaines études ont montré une utilisation accrue des glucides en altitude comparée à la plaine mais les intensités d’exercices utilisées sont discutables et l’utilisation de méthodes biochimiques traditionnelles ont permis de doser qu’un nombre restreint de molécules. Aujourd’hui grâce à la métabolomique, il est possible d’analyser les variations d’un grand nombre de métabolites simultanément. Le but de cette thèse est d’étudier l’incidence de l’altitude modérée sur l’utilisation des substrats énergétiques à l’effort à l’aide de la métabolomique par résonnance magnétique nucléaire du proton. Des échantillons de plasmas et d’urines ont été collectés lors d’exercices d’endurance en plaine et en altitude modérée chez des sujets non acclimatés. Nos premiers résultats, dans les plasmas, ont montré une baisse de la glycémie et une utilisation accrue des acides aminés ramifiés entre avant et après un exercice d’endurance en altitude, ce qui n’a pas été observé en plaine. Ces résultats ont ensuite été confirmé lors d’un exercice d’endurance jusqu’à épuisement. De plus, nous avons montré que l’utilisation des urines permet de mettre en avant les résultats obtenus dans les plasmas, ce qui est très encourageant pour la compréhension des adaptations métaboliques en altitude par des méthodes non invasives. Pour finir, nous avons utilisé une méthode statistique innovante appelée « analyse en composantes communes et poids spécifiques ». Les résultats ont permis d’observer les variabilités communes entre les paramètres physiologiques mesurés et les variations des métabolites plasmatiques.
... Su papel como posible factor para aumentar el rendimiento en el ejercicio en condiciones de hipoxia está por demostrar, pero el uso de sildenafilo ha aumentado entre los montañeros, no como un fármaco preventivo del edema pulmonar de gran altitud, sino en la creencia de que podría ayudar a mejorar el rendimiento físico a gran altura geográfica. Varios estudios han tratado de abordar este tema, con resultados Since the work of Ghofrani et al. 1 about the improvement of physical capacity during exercise in hypoxia conditions due to the use of sildenafil, 1 several studies have attempted to reproduce their findings. However, to date, there is still controversy over whether phosphodiesterase type 5 inhibitor is a substance that can actually improve performance under hypoxic conditions. ...
... 14---16 VO 2max tends to diminish in direct proportion to the decrease in CaO 2 , which occurs as hypoxia increases. 17,18 Exercise exacerbates CaO 2 reduction due to the lower uptake of O 2 during gas exchanging in the lungs, 1,19 which may increase the risk of pulmonary edema, 11,20 especially in people predisposed to suffer this complications associated to rapid ascent. 21 Considering that the increase in PAP could be an important factor limiting performance during exercise in hypoxia, 22 sildenafil has been proposed as a potential ergogenic aid for physical activity in hypoxic conditions due to its possible benefits for athletic performance, and has been widely used. ...
... The first published study concerning the relationship between sildenafil, exercise and hypoxia was that of Ghofrani et al. 1 These authors studied a group of 14 people (12 men and 2 women) who had previous experience in altitude exposure. Data from the participants were recorded at rest and during maximum incremental exercise tests (W peak ) in two different situations: (1) at an altitude of 171 m breathing through a mask of a hypoxic gas mixture with 10% fraction of oxygen for 2 h and (2) at an altitude of 5245 m after 8 days of ascent until Everest base camp. ...
Article
Sildenafil has proven to efficiently reduce the increase in pulmonary artery pressure provoked by hypoxic pulmonary vasoconstriction. However, its role as a possible factor in increasing exercise performance under hypoxic conditions remains to be demonstrated. The use of sildenafil has increased among mountaineers, not as a high altitude pulmonary edema preventive drug, but as a means that could help to improve performance. Several studies have attempted to address this issue, with conflicting results. Currently, despite the inconclusive data at simulated or real altitude, and with the clear evidence that, in normoxia, sildenafil does not improve performance, this drug is being used (and sometimes overused) by people who climb high peaks. However, such potential performance improvement would depend on the degree of hypoxemia (altitude) and the individual responsiveness to this drug. This paper reviews the current knowledge on this matter.
... To avoid altitude related illnesses and/or exhaustion, and ultimately to increase their chance of reaching the summit, climbers may use medications, with or without prescription. Several categories of drugs may be relevant to this purpose: first, since the rapid altitude gain increases the risk of acute mountain sickness, prophylactic treatments with acetazolamide [3] or glucocorticoids [4] may be considered; second, the potential risk of exhaustion may also incite some climbers to take stimulants [5]; third, the performance-enhancing effect of phosphodiesterase 5 (PDE-5) inhibitors at high altitude may prompt people to use these drugs to optimize their ascent [6]; and fourth, high-altitude sleep disturbances that may otherwise compromise the summit push can be alleviated by specific hypnotic drugs [7,8]. ...
... It may be worthwhile to highlight that, with the exception of hypnotics, all the drugs mentioned above possess a favorable effect at altitude [6,9,10]; acetazolamide, glucocorticoids and stimulants are indeed banned in sports, being included in the list of prohibited substances of the World Anti-Doping Agency (WADA) [11]. As alpinism is not subject to anti-doping rules, any objections to the use of medications are based on ethical or safety concerns. ...
Article
Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance.
... They noted much smaller increases in mean PA pressure with exposure to hypobaric hypoxia following the extended period at moderate elevation (25 + 4 vs. 37 + 8 mmHg, P < 0.001). Ghofrani et al. (Ghofrani et al., 2006) noted This article is protected by copyright. All rights reserved. ...
... We did not measure cardiac output, but data from many other studies show at rest that acclimatized volunteers have very little change (5-7% fall) in cardiac output up to altitudes of 6000 m and over the changes in inspired oxygen fraction we tested. (Groves et al., 1987;Ghofrani et al., 2006) The impact on TVPG and, therefore, pulmonary artery systolic pressure (PASP) with these small changes in cardiac output would be to reduce PASP by about 2% (Grant & Canty, 1989) and thus would not likely to have influenced our conclusions. ...
Article
Full-text available
We sought to determine whether changes in pulmonary artery pressure responses to hypoxia suggestive of vascular remodeling occur during progressive exposure to high altitude and whether such alterations are related to changes in concentrations of circulating biomarkers with known or suspected actions on the pulmonary vasculature during ascent. We measured tricuspid valve transvalvular pressure gradients (TVPG) in healthy volunteers breathing air at sea level (London, UK) and under hypoxic conditions simulating the PI O2 at two locations in Nepal, Namche Bazaar (NB, elevation 3,500 m) and Everest Base Camp (EBC, elevation 5,300 m). During a subsequent thirteen day trek, TVPG was measured at NB and EBC while volunteers breathed air and hyperoxic or hypoxic mixtures simulating the PI O2 at the other locations. For each location, we determined the slope of the relationship between TVPG and arterial oxygen saturation (Sa O2 ) to estimate the pulmonary vascular response to hypoxia. Mean TVPG breathing air was higher at any Sa O2 at EBC than at sea level or NB, but there was no change in the slope of the relationship between Sa O2 and TVPG between locations. Nitric oxide availability remained unchanged despite increases in oxidative stress (elevated 8-isoprostane). Erythropoietin, pro-ANP and IL-18 levels progressively increased on ascent. Associations with TVPG were only observed with erythropoietin, 8-isoprostane, nitrite and cGMP. While the increased TVPG for any given Sa O2 at EBC suggests pulmonary vascular remodeling may occur during 2 weeks of progressive hypoxia, the lack of change in the slope of the relationship between TVPG and Sa O2 indicates that the acute pulmonary vascular responsiveness to changes in oxygenation does not vary within this time frame. This article is protected by copyright. All rights reserved.
... Hypoxic pulmonary vasoconstriction, combined with a decreased pulmonary vascular distensibility, results in a steep pressure/flow relationship during exercise, which, combined with hypoxemia, contributes to limitations in performance at altitude (50,51). Studies showing that reduction of pulmonary vascular resistance by phosphodiesterase inhibitors or endothelin-receptor antagonists is associated with an increased V O 2 and exercise capacity at altitude and in normobaric hypoxia support the notion that an increased right ventricular afterload contributes to exercise limitation at altitude (13,15,19). ...
... The reduced exercise capacity in healthy individuals exposed to hypoxia can be increased by acclimatization (26), presumably by supplemental oxygen and, according to randomized-controlled trials, by pulmonary vasodilator drugs, such as endothelin receptor antagonists or phosphodiesterase-5 inhibitors or (in subjects susceptible to high-altitude pulmonary edema) by dexamethasone (19,38,40). Conversely, acetazolamide seems to reduce exercise capacity at altitude, despite a higher Sp O 2 at rest, although these data are not conclusive (5). ...
Article
Exercise performance is determined by oxygen supply to working muscles and vital organs. In healthy individuals, exercise performance is limited in the hypoxic environment at altitude, when oxygen delivery is diminished due to the reduced alveolar and arterial oxygen partial pressures. In patients with pulmonary hypertension, exercise performance is already reduced near sea level due to impairments of the pulmonary circulation and gas exchange and, presumably, these limitations are more pronounced at altitude. In studies performed near sea level in healthy subjects as well as in patients with pulmonary hypertension (PH) maximal performance during progressive ramp exercise and endurance of submaximal constant load exercise were substantially enhanced by breathing oxygen-enriched air. Both in healthy individuals and in PH-patients these improvements were mediated by a better arterial, muscular and cerebral oxygenation along with a reduced sympathetic excitation, as suggested by the reduced heart rate and alveolar ventilation at submaximal isoloads, and an improved pulmonary gas exchange efficiency, especially in patients with PH. In summary, in healthy individuals and in patients with pulmonary hypertension, alterations in the inspiratory PO2 by exposure to hypobaric hypoxia or normobaric hyperoxia reduce or enhance exercise performance, respectively, by modifying oxygen delivery to the muscles and the brain, by effects on cardiovascular and respiratory control and by alterations in pulmonary gas exchange. The understanding of these physiologic mechanisms helps counselling individuals planning altitude or air travel and prescribing oxygen therapy to patients with pulmonary hypertension.
... PDE5-I is not effective in preventing AMS (Maggiorini, 2006;Jouanin et al., 2009). In some susceptible individuals, PDE5-I may possibly exacerbate AMS by an unknown mechanism (Ghofrani et al., 2004). ...
... On the contrary, Xu et al. (2014) showed that shortterm treatment attenuated the pulmonary systolic arterial pressure, but had no significant beneficial effects on SaO 2 , heart rate, and AMS. Other studies have investigated the effects of PDE5-I on exercise performance at altitude (Zhao et al., 2001;Ghofrani et al., 2004;Aldashev et al., 2005;Perimenis, 2005;Ricart et al., 2005;Richalet et al., 2005;Hsu et al., 2006;Reichenberger et al., 2007) and these studies showed that certain individuals can benefit from Sildenafil use during acute hypoxia, but not normoxia, in terms of cardiac output, arterial saturation, and exercise performance (Di Luigi et al., 2008). ...
Article
Kurdziel, Marta, Jarosław Wasilewski, Karolina Gierszewska, Anna Kazik, Gracjan Pytel, Jacek Wacławski, Adam Krajewski, Anna Kurek, Lech Poloński, and Mariusz Gąsior. Echocardiographic assessment of right ventricle dimensions and function after exposure to extreme altitude: Is an expedition to 8000 m hazardous for right ventricular function? High Alt Med Biol 00:000-000, 2017.-Although the right ventricle (RV) is under great hypoxic stress at altitude, still little is known what happens to the RV after descent. The aim of this study was to evaluate RV dimensions and function after exposure to extreme altitude. Therefore, echocardiographic examination was performed according to a protocol that focused on the RV in 11 healthy subjects participating in an expedition to K2 (8611 m) or Broad Peak (BP, 8051 m). In comparison to measurements before the expedition, after 7-8 weeks of sojourn above 2300 meters with the aim of climbing K2 and BP, the RV Tei index increased (0.5 ± 0.1 vs. 0.4 ± 0.1; p = 0.028), and RV free wall longitudinal systolic strain (RVFWLSS) decreased (-23.1% ± 2.7% vs. -25.9% ± 2.4%; p = 0.043). Decrease in peak systolic strain and strain rate was observed in the basal and mid segments of the RV free wall (respectively: -24.4% ± 4.4% vs. -30.9% ± 6.5%; -1.4 ± 0.3 s(-1) vs. -1.8 ± 0.3 s(-1); -28.7% ± 3.9% vs. -34% ± 3.3%; -1.5 ± 0.2 s(-1) vs. -1.9 ± 0.3 s(-1); p for all <0.05). The linear RV dimensions, the proximal and distal RV outflow tracks, increased (respectively: 31.3 ± 4 mm vs. 29.2 ± 3 mm, p = 0.025; 27 ± 2.7 mm vs. 24.8 ± 3 mm, p = 0.012). We found that exposure to extreme altitude may cause RV dilatation and a decrease in RV performance. The Tei index and RVFWLSS are sensitive performance indices to detect changes in RV function after the exposure to hypoxic stress. The observed alterations seem to be a manifestation of physiological adaptation to high-altitude condition in healthy individuals.
... Despite the well-established effects of sildenafil on erectile dysfunction [23], several experiments have tested the effects of this drug on the physical performance and arterial oxygen saturation of healthy subjects [13,16,24,32,35,40]. In this sense, numerous experiments have demonstrated that sildenafil may increase arterial oxygen saturation, reduce systolic pulmonary arterial pressure, which can occur in response of an improved pulmonary diffusion, and restore exercise tolerance under artificial and natural hypoxia environments in healthy subjects [13,33,34]; as well as arterial oxygen saturation and time-trial performance in endurance trained athletes at moderate altitude [16]. ...
... Despite the well-established effects of sildenafil on erectile dysfunction [23], several experiments have tested the effects of this drug on the physical performance and arterial oxygen saturation of healthy subjects [13,16,24,32,35,40]. In this sense, numerous experiments have demonstrated that sildenafil may increase arterial oxygen saturation, reduce systolic pulmonary arterial pressure, which can occur in response of an improved pulmonary diffusion, and restore exercise tolerance under artificial and natural hypoxia environments in healthy subjects [13,33,34]; as well as arterial oxygen saturation and time-trial performance in endurance trained athletes at moderate altitude [16]. On the other hand, the potential benefits of sildenafil treatment on exercise performance has been clearly discarded during acute hypoxia exposure [16,20,43]. ...
Article
The current study aimed to determine the effects of sildenafil-associated aerobic exercise training (ET) on the physical performance, hemodynamic, autonomic and inflammatory parameters of rats. Male Wistar rats were randomly assigned to: sedentary rats placebo-treated (SP); sedentary rats sildenafil-treated (SS); trained rats placebo-treated (TP); and trained rats sildenafil-treated (TS). Sildenafil treatment consisted of 8 weeks of daily oral gavage (1.5 mg/kg), one hour before the session of ET (60–75% of maximal running speed, 5 days/week, for 8 weeks). After ET period, physical capacity, hemodynamic, autonomic and skeletal muscle inflammatory profile were assessed. Chronic sildenafil treatment causes an additional increase of physical capacity in aerobically trained rats. However, these beneficial effects were accompanied by unwanted alterations, as increased of arterial pressure and peripheral sympathetic modulation, as well as exacerbated inflammatory status on skeletal muscle of rats. Taken together, these data suggest the positive and negative effects of sildenafil chronic administration, associated to aerobic ET, at doses used in clinical practice. This report stresses the importance of paying greater attention to the indiscriminate use of this substance in high-performance sports.
... Second, the data from our study highlight opportunities to provide adequate counseling to climbers about the utility of these medications at high altitude and their safety and potential side effects, particularly when used in unstudied combinations. Although data demonstrate that the medications included in our survey are useful for preventing and treating altitude illness (Luks et al., 2014), only a few of the medications, including sildenafil (Ghofrani et al., 2006) and dexamethasone (Siebenmann et al., 2011), have been shown to increase exercise capacity in hypoxia and, therefore, might affect climbing performance. Acetazolamide, on the other hand, has been shown to have either no effect (Hackett et al., 1985;Faoro et al., 2007) or an adverse effect on exercise performance in healthy individuals at 3450-6900 m (Gonzales and Scheuermann, 2013;Bradwell et al., 2014). ...
... To address this concern, we examined reported medication use according to the time period in which survey respondents attempted to climb the mountain. The trends in usage for each medication are displayed in Figure 2. In examining these data, it should be noted that no climbers reported using salmeterol, sildenafil, or tadalafil before 2006, which is not surprising given that the study showing the effects of long-acting beta agonists in individuals susceptible to high altitude pulmonary edema was only published in 2002 (Sartori et al., 2002), whereas evidence regarding the effects of phosphodiesterase inhibitors on maximum exercise capacity was published in 2006 (Ghofrani et al., 2006). This is in contrast to the situation with acetazolamide, dexamethasone, and nifedipine, as data regarding their utility were available in the literature much earlier. ...
Article
Full-text available
Luks, Andrew M., Colin Grissom, Luanne Freer, and Peter Hackett. Medication use among mount Everest climbers: practice and attitudes. High Alt Med Biol. 00:000-000, 2016.-The lay public, media, and medical experts have expressed concern about the ethics of climbers using medications to improve performance and increase the odds of summit success while climbing at high altitude, but the true incidence of this practice remains unclear. We conducted an anonymous survey of climbers who have attempted to climb Mt. Everest to gather information about medication use and attitudes toward medication and supplemental oxygen use while climbing the mountain. One hundred eighty-seven individuals completed the survey, providing information about medication and oxygen use for 262 expeditions to Mt. Everest between 1963 and 2015, the majority of which occurred after the year 2000. The majority of respondents were male (82%) and from English-speaking countries (75%). Medications were used on 43% of climbs, with acetazolamide being the most commonly used medication. Reported use of dexamethasone, nifedipine, sildenafil, or tadalafil was uncommon as was use of multiple medications at the same time. The majority of respondents indicated that it was acceptable for climbers to use medications and supplemental oxygen to prevent altitude illness while climbing Mt. Everest. Opinions were more mixed regarding whether summiting without the use of medications or oxygen carried the same value as reaching the summit using those interventions. Our data suggest that less than one-half of Mt. Everest climbers use medications during their expedition, with the primary medication used being acetazolamide, for prevention of altitude illness. Given the limitations of the study design and preliminary nature of these data, further research is warranted to further clarify these issues.
... PDE5-I is not effective in preventing AMS (Maggiorini, 2006;Jouanin et al., 2009). In some susceptible individuals, PDE5-I may possibly exacerbate AMS by an unknown mechanism (Ghofrani et al., 2004). ...
... On the contrary, Xu et al. (2014) showed that shortterm treatment attenuated the pulmonary systolic arterial pressure, but had no significant beneficial effects on SaO 2 , heart rate, and AMS. Other studies have investigated the effects of PDE5-I on exercise performance at altitude (Zhao et al., 2001;Ghofrani et al., 2004;Aldashev et al., 2005;Perimenis, 2005;Ricart et al., 2005;Richalet et al., 2005;Hsu et al., 2006;Reichenberger et al., 2007) and these studies showed that certain individuals can benefit from Sildenafil use during acute hypoxia, but not normoxia, in terms of cardiac output, arterial saturation, and exercise performance (Di Luigi et al., 2008). ...
Article
Results: Prophylactic, therapeutic, and recreational uses of drugs relevant to mountaineering are presented with an assessment of their risks and benefits. Conclusions: If using drugs not regulated by the World Anti-Doping Agency (WADA), individuals have to determine their own personal standards for enjoyment, challenge, acceptable risk, and ethics. No system of drug testing could ever, or should ever, be policed for recreational climbers. Sponsored climbers or those who climb for status need to carefully consider both the medical and ethical implications if using drugs to aid performance. In some countries (e.g., Switzerland and Germany), administrative systems for mountaineering or medication control dictate a specific stance, but for most recreational mountaineers, any rules would be unenforceable and have to be a personal decision, but should take into account the current best evidence for risk, benefit, and sporting ethics.
... Nonetheless, some authors did not find a relationship between the degree of hypoxemia and the occurrence of AMS (33,37,45). At rest in healthy individuals, the magnitude of arterial O 2 desaturation is largely regulated by the inspired PO 2 (19,47). However, the degree of hypoxemia resulting from a given reduction of inspired PO 2 is exaggerated by exercise, because the contraction-induced rate of muscular O 2 extraction often exceeds the capacity for pulmonary O 2 diffusion (12,19,25,39,46). ...
... At rest in healthy individuals, the magnitude of arterial O 2 desaturation is largely regulated by the inspired PO 2 (19,47). However, the degree of hypoxemia resulting from a given reduction of inspired PO 2 is exaggerated by exercise, because the contraction-induced rate of muscular O 2 extraction often exceeds the capacity for pulmonary O 2 diffusion (12,19,25,39,46). Other mechanisms impairing the efficiency of pulmonary gas exchange, such as a patent foramen ovale or intrapulmonary arteriovenous anastomoses (IPAVA), may also be involved. ...
Article
High rate of muscular oxygen utilization facilitates the development of hypoxemia during exercise at altitude. Because endurance training stimulates oxygen extraction capacity, we investigated whether endurance athletes are at higher risk to developing hypoxemia and thereby acute mountain sickness (AMS) symptoms during exercise at simulated high altitude. Elite athletes (ATL, n=8) and fit controls (CON, n=7) cycled for 20 min @100 Watt (EX100w) as well as performed an incremental VO2max test (EXMAX) in normobaric hypoxia (0.107 FIO2) or normoxia (0.209 FIO2). Cardiorespiratory responses, arterial PO2 (PaO2), and oxygenation status in m. vastus lateralis (TOIM) and frontal cortex (TOIC) by near-infrared spectroscopy, were measured. Muscle O2-uptake rate was estimated from Δ[O2Hb] during a 10-min arterial occlusion in m. gastrocnemius. VO2max in normoxia was 70±2 ml.min(-1).kg(-1) in ATL versus 43±2 in CON, and in hypoxia decreased more in ATL (- 41%) than in CON (-25%, p<0.05). Both in normoxia at PaO2 of ~95 mmHg, and in hypoxia at PaO2 of ~35 mmHg, muscle O2-uptake was 2-fold higher in ATL than in CON (0.12 vs. 0.06 ml.min(-1).100g(-1); p<0.05). During EX100W in hypoxia PaO2 dropped to lower (p<0.05) values in ATL (27.6±0.7 mmHg) than in CON (33.5±1.0 mmHg). During EXMAX, but not during EX100W, TOIM was ~15% lower in ATL than in CON (p<0.05). TOIC was similar between the groups at any time. This study shows that maintenance of high muscular oxygen extraction rate at very low circulating PaO2 stimulates the development of hypoxemia during submaximal exercise in hypoxia in endurance-trained individuals. This effect may predispose to premature development of AMS symptoms during exercise at altitude.
... Lovering et al. (2008) have shown that this type of shunting increases with inspired hypoxia and exercise. The presence of pulmonary hypertension and its speculated effect on her poor exercise tolerance and increased intrapulmonary shunting led to a phosphodiesterase (PDE)-5 inhibitor as a rational choice to blunt this effect (Ghofrani et al., 2004;Richalet et al., 2005). Sildenafil, a PDE-5 inhibitor, has been shown to protect against the development of altitude-induced pulmonary hypertension and improve gas exchange (Richalet et al., 2005). ...
... Sildenafil, a PDE-5 inhibitor, has been shown to protect against the development of altitude-induced pulmonary hypertension and improve gas exchange (Richalet et al., 2005). It is also notable that although sildenafil had no effect on the arterial oxygen saturation at rest or during exercise, sildenafil did reduce the PASP during exercise and increased maximal workload and cardiac output in a case series of trekkers (Ghofrani et al., 2004). This effect was seen in our patient when she climbed in the Sierra Nevada while taking tadalafil, a longer acting PDE-5 inhibitor. ...
Article
High-altitude pulmonary edema (HAPE) is a common presumptive diagnosis for a patient who experiences significant dyspnea and cyanosis at altitude. In this study, we present a case of a 58-year-old woman who was initially diagnosed with HAPE, although further evaluation revealed the presence of two underlying contributors to her significant hypoxemia at altitude. We discuss the medical workup for causes of greater than expected hypoxemia at altitude and the role some relevant medical comorbidities may play.
... Several studies have addressed the hypotheses that pulmonary artery pressure during exercise can be lowered by pulmonary vasodilators, and that this can lead to an increase in cardiac output and in exercise capacity. In 2004, Ghofrani et al. showed that sildenafil reduced pulmonary artery pressure, and increased cardiac output and peak work rate, both whilst volunteers at low altitude breathed 10% oxygen and whilst at Everest Base Camp at an altitude of 5400 m (Ghofrani et al. 2004). Their volunteers had a median age of 36.5 years. ...
... This study was conducted in iron-replete healthy participants of a similar age; nevertheless its finding of a reduction in pulmonary artery pressure during moderate cycling exercise tentatively suggests a mechanism whereby exercise capacity may have been improved in the patients in clinical studies. If this turns out to be the case, it would be analogous to the enhancement of exercise achieved in some studies of healthy human volunteers exposed to hypoxia, such as that using sildenafil at Everest Base Camp (Ghofrani et al. 2004). It may be the case that, whilst the small fall in pulmonary artery pressure measured in this study has no impact on maximal exercise capacity in our healthy volunteers, it could be sufficient to affect exercise capacity in a patient with impaired myocardial function. ...
Article
Full-text available
In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V ˙ O 2 m a x ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V ˙ O 2 m a x remained unaffected in the iron-replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.
... In addition to the lack of significant changes in oxygen uptake, there was no difference in work rate between nitrite infusion and saline control in our study. Although the limitations described above also apply to these parameters, this finding is inconsistent with the effect of other NO modulating drugs such as sildenafil, which improved aerobic exercise capacity during experimental hypoxic stress (low inspired oxygen fraction) (13) or agents that impair NO generation (20). Furthermore, exercise performance was improved with peak V O 2 and ⌬V O 2 /⌬W significantly increased in patients with pre-and postcapillary pulmonary hypertension receiving NO inhalation and sildenafil, respectively (15,16). ...
Article
This study investigated the effects of aerobic-to-anaerobic exercise on nitrite stores in the human circulation and evaluated the effects of systemic nitrite infusion on aerobic and anaerobic exercise capacity and hemodynamics. Six healthy volunteers were randomized to receive sodium nitrite or saline for 70 minutes in two separate occasions in an exercise study. Subjects cycled on an upright electronically-braked cycle ergometer 30 minutes into the infusion according to a ramp protocol designed to attain exhaustion in 10 minutes. They were allowed to recover for 30 minutes thereafter. The changes of whole blood nitrite concentrations over the 70-minute study period were analyzed by pharmacokinetic modeling. Longitudinal measurements of hemodynamic and clinical variables were analyzed by fitting nonparametric regression spline models. During exercise, nitrite consumption/elimination rate was increased by approximately 137%. Cardiac output (CO), mean arterial pressure (MAP), and pulmonary artery pressure (PAP) were increased, but smaller elevation of MAP and larger increases of CO and PAP were found during nitrite infusion compared to placebo control. The higher CO and lower MAP during nitrite infusion were likely attributed to vasodilation and a decrease in SVR. In contrast, there were no significant changes in mean pulmonary artery pressures and pulmonary vascular resistance. These findings, together with the increased consumption of nitrite during exercise, support the notion of nitrite conversion to release NO resulting in systemic vasodilatation. However, at the dosing used in this protocol achieving uM plasma concentrations of nitrite, exercise capacity was not enhanced as opposed to other reports using lower dosing.
... PH lowers exercise capacity due to reduced O2 delivery to the blood (Rubin, 1997;Weitzenblum, 2003). One particular study of healthy mountaineers found that Viagra reduced PH at sea level and at an altitude of 5400m during both exercise and rest (Ghofrani et al., 2004). Furthermore, O2 saturation may be improved after several days of high altitude exposure (Richalet et al., 2005). ...
Article
Full-text available
div class="page" title="Page 38"> Article Source: http://www.popsci.com/science/article/2012-11/fyi-can- viagra-make-you-a-better-athlete Introduction : Athletes have started taking Viagra to gain a competitive edge. Viagra’s use might be expanding into the athletic world for its alleged boost to one’s physical capability. This paper will discuss Viagra’s impact on society, its users, athletic organisations, and whether its purported performance enhance- ment uses are valid and safe. Pharmacology : Viagra works by relaxing smooth muscle cells through the in- hibition of PDE5, thus, increasing the bioavailability of cGMP. Results : Subjects had a higher VO2 max and recovered faster from pulmonary hypertension when given Viagra. Other results are mixed and not well estab- lished. Barriers : Allowing Viagra into the athletic community may cause concern from sports organisations but will conversely and unequally burden those who require Viagra for healthy sexual function. Conclusion : These findings do not directly correlate to an improvement in ath- letic performance. Furthermore, taking Viagra may pose as a risk to one’s health. Viagra should only be taken upon consultation with a health care professional. </div
... Again, these findings mirror studies in healthy mountaineers in which sildenafil reduced systolic pulmonary artery pressure at rest and during exercise at both low and high altitude. 8 Given the communalities in pathology and response to sildenafil in SIPE and HAPE, it is tempting to speculate on similar parallels regarding 2 manifest questions: (1) If HAPE and SIPE are forms of hydrostatic lung edema, then why is the edema fluid rich in high-molecular-weight protein and red blood cells? (2) What mechanisms underlie the observed changes in pulmonary (micro)vascular pressures? ...
Article
With reported incidences typically around 1%(1), swimming-induced pulmonary edema (SIPE) is increasingly recognized as a not uncommon syndrome that is triggered by strenuous swimming and characterized by dyspnea, cough, and hemoptysis. Interestingly, SIPE shares common features with another form of pulmonary edema that is caused by strenuous exercise in an evolutionary non-physiological habitat, namely high-altitude pulmonary edema (HAPE): Both SIPE and HAPE typically affect young healthy individuals, are triggered by strenuous exercise in a cold environment, resolve spontaneously after return to "physiological" conditions, yet will recur upon re-exposure in prone individuals(2,3). At the pathological level, edema fluid in both SIPE and HAPE patients contains considerable amounts of red blood cells and high molecular weight proteins in the absence of markedly elevated inflammatory markers(4,5). The pathophysiology of both diseases has long puzzled the field, and hampered the development of effective counterstrategies, as their features tend to evade the traditional classification of pulmonary edema.
... 575 However, tadalafil was associated with severe acute mountain sickness in 2 subjects, as has been reported with sildenafil. 576 Sildenafil has been suggested for HAPE prophylaxis in adults. 577 Immediate descent to lower altitude and administration of supplemental O 2 are the primary therapies for adults and children with HAPE. ...
Article
Full-text available
Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.
... Accordingly, it was hypothesized that HPV would account, in part, for the detrimental effect of hypoxia on aerobic capacity (Naeije, 2011). In support, pharmacological attenuation of HPV in hypoxia using selective vasodilators, such as sitaxsentan, sildenafil, or bosentan, elevates arterial O 2 saturation (SaO 2 ) and improves exercise tolerance, partly restoring aerobic capacity toward normoxic values (Ghofrani et al., 2004; Richalet et al., 2005; Naeije et al., 2010; Olfert et al., 2011; Pham et al., 2012). However, the increase in arterial oxygenation per se reported by these studies can also account for the improved exercise performance (Anholm and Foster, 2011). ...
Article
Full-text available
Background: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. Methods: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. Results: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). Conclusion: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.
... Treatment with sildenafil citrate d improves these patients' PH severity, pulmonary edema and adverse clinical signs. 18 The occurrence of pulmonary alveolar infiltrates associated with PH in dogs is not well described in the scientific literature and may be an under-recognized clinical feature of PH. The purpose of this study was to describe a series of dogs with naturally occurring PH and radiographic alveolar infiltrates before and after treatment with sildenafil. ...
Article
Full-text available
To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. Ten client-owned dogs. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002). A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil. Copyright © 2015 Elsevier B.V. All rights reserved.
... Therefore, sildenafil acts in various different disorders. It reduces, for example, pulmonary and systemic pressure (30,31,81,82), relaxes saphenous veins and pectoral arteries (16), and increases flowmediated forearm circulation in patients with chronic heart failure (38), type 2 diabetes (17), and coronary artery disease (36). The effects of sildenafil on microvascular disorders such as Raynaud's phenomenon have not been subject of controlled studies. ...
... **Denotes highly significantly different from baseline (normoxia) P < 0.001. on the most visible effect of PDE inhibitors on HPV ( Ghofrani et al. 2004, Kjaergaard et al. 2007, Reichenberger et al. 2007), the present framework provides a large number of parameters at multiple time points in non-acclimatized subjects and because of this it constitutes an accurate overview about feasibility of using this methods of hypoxic testing. Similar to other studies, we report an increase in RV dimensions. ...
Article
Aim: Acute hypoxia produces acute vasoconstriction in the pulmonary circulation with consequences on right ventricular (RV) structure and function. Previous investigations in healthy humans have been restricted to measurements after altitude acclimatization or were interrupted by normoxia. We hypothesized that immediate changes in RV dimensions in healthy subjects in response to normobaric hypoxia differ without the aforementioned constraints. Methods: Transthoracic echocardiography was performed in 35 young, healthy subjects exposed to 11% oxygen, as well as 6 controls under sham hypoxia (20.6% oxygen, single blind) first at normoxia and after 30, 60, 100, 150 minutes of hypoxia or normoxia, respectively. A subgroup of 15 subjects continued with 3-min cycling exercise in hypoxia with subsequent evaluation followed by an assessment one minute at rest while breathing 4l/min oxygen. Results: During hypoxia, there was a significant linear increase of all RV dimensions (RVD1 +29mm, RVD2 +42mm, RVD3 +41mm, RVOT +13mm, RVEDA +18mm, p<0.01) in the exposure group vs. the control group. In response to hypoxia, right ventricular systolic pressure RVSP showed a modest increase in hypoxia at rest (+7.3mmHg, p<0.01) and increased further with physical effort (+11.8mmHg, p<0.01). After one minute of oxygen at rest it fell by 50% of the maximum increase. Conclusion: Acute changes in RV morphology occur quickly after exposure to normobaric hypoxia. The changes were out of proportion to a relatively low estimated increase in pulmonary pressure, indicating direct effects on RV structure. The results in healthy subjects are basis for future clinically oriented interventional studies in normobaric hypoxia. This article is protected by copyright. All rights reserved.
... Moreover, the authors reported that the high altitude related decrease in V O 2max was inversely related to the increase in resting PVR observed at high altitude (Pavelescu et al. 2013). In addition, a number of previous studies have demonstrated that pharmacologic reduction of pulmonary artery pressure and pulmonary vascular resistance secondary to dilation of the pulmonary vascular resistance vessels is associated with an improvement in exercise capacity and an increase in the membrane component of lung diffusion in humans exposed to hypoxia and/or high altitude (de Bisschop et al. 2012;Faoro et al. 2009;Faoro et al. 2007;Ghofrani et al. 2004;Naeije et al. 2010). For example, Naeije et al. (2010) reported that administration of sitaxsentan, a selective endothelin-A receptor blocker, decreased PVR with a concomitant partial restoration in V O 2max in subjects exposed to both acute normobaric hypoxia and chronic hypobaric hypoxia. ...
Article
Full-text available
Purpose: We determined whether well-acclimatized humans have a reserve to recruit pulmonary capillaries in response to exercise at high altitude. Methods: At sea level, lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary capillary blood volume (V c) were measured at rest before maximal oxygen consumption ([Formula: see text]) was determined in seven adults. Then, DLCO, DmCO and V c were measured pre- and post-exhaustive incremental exercise at 5150 m after ~40 days of acclimatization. Results: Immediately after exercise at high altitude, there was an increase in group mean DmCO (14 ± 10 %, P = 0.040) with no pre- to post-exercise change in group mean DLCO (46.9 ± 5.8 vs. 50.6 ± 9.6 ml/min/mmHg, P = 0.213) or V c (151 ± 28 vs. 158 ± 37 ml, P = 0.693). There was, however, a ~20 % increase in DLCO from pre- to post-exercise at high altitude (51.2 ± 0.2 vs. 61.1 ± 0.2 ml/min/mmHg) with a concomitant increase in DmCO (123 ± 2 vs. 156 ± 4 ml/min/mmHg) and V c (157 ± 3 vs. 180 ± 8 ml) in 2 of the 7 participants. There was a significant positive relationship between the decrease in [Formula: see text] from sea level to high altitude and the change in DLCO and lung diffusing capacity for nitric oxide (DLNO) from rest to end-exercise at high altitude. Conclusion: These data suggest that recruitment of the pulmonary capillaries in response to exercise at high altitude is limited in most well-acclimatized humans but that any such a reserve may be associated with better exercise capacity.
... • Ghofrani et al. 95 documented improvements in exercise capacity in a randomized, double-blind placebo-controlled trial in 14 healthy subjects during normobaric hypoxia (10% O 2 ) and at altitude (Mount Everest base camp, 5245 m above sea level). ...
Article
The use of substances and medications with potential cardiovascular effects among those practicing sports and physical activity has progressively increased in recent years. This is also connected to the promotion of physical activity and exercise as core aspects of a healthy lifestyle, which has led also to an increase in sport participation across all ages. In this context, three main users' categories can be identified, (i) professional and amateur athletes using substances to enhance their performance, (ii) people with chronic conditions, which include physical activity and sport in their therapeutic plan, in association with prescribed medications, and (iii) athletes and young individuals using supplements or ergogenic aids to integrate their diet or obtaining a cognitive enhancement effect. All the substances used for these purposes have been reported to have side effects, among whom the cardiovascular consequences are the most dangerous and could lead to cardiac events. The cardiovascular effect depends on the type of substance, the amount, the duration of use, and the individual response to the substances, considering the great variability in responses. This Position Paper reviews the recent literature and represents an update to the previously published Position Paper published in 2006. The objective is to inform physicians, athletes, coaches, and those participating in sport for a health enhancement purpose, about the adverse cardiovascular effects of doping substances, commonly prescribed medications and ergogenic aids, when associated with sport and exercise.
... Oral sildenafil reduced pulmonary hypertension both at rest and during exercise while maintaining gas exchange and systemic arterial pressure. 226 In further analysis, the 14 members of a Mount Everest expedition were monitored during an acute hypoxic challenge at sea level, and further environmental hypoxia exposure at altitudes of 3440 m and 5245 m and 2 weeks after return to sea level. They received either placebo or 50 mg sildenafil in a double-blind randomized cross-over design. ...
Article
Phosphodiesterase inhibitors (PDE) can be used as therapeutic agents for various diseases such as dementia, depression, schizophrenia and erectile dysfunction in men, as well as congestive heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, other inflammatory diseases, diabetes and various other conditions. In this review we will concentrate on one type of PDE, mainly PDE5 and its role in pulmonary vascular diseases.
... Stembridge et al. suggest that improved exercise performance with sildenafil may be seen at more extreme altitudes (i.e. above 4500-5000 m), and there is evidence to support this proposition (Ghofrani et al. 2004). Wagner's modelling work would suggest that improvements in cardiac output at Everest (8848 m, Pb 253 mmHg) would have virtually no improvement inV O2 max (Wagner, 1996). ...
... Even though this phenomenon likely played a major role in the strength of the relationship between V O 2max SL and exercise SpO 2 at high altitude, its contribution should be slightly reduced. Indeed, some studies have reported that, compared with sea level, the maximal cardiac output could decrease or be blunted during exercise in hypoxia (Calbet and Lundby 2009), possibly due to a reduction in heart rate (Fukuda et al. 2010;Peltonen et al. 2001) or impaired right ventricular function as a consequence of hypoxia-induced pulmonary vasoconstriction (Ghofrani et al. 2004). ...
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Purpose: The aim of this study was to establish a model to estimate the level of arterial oxygen saturation (SpO2) and help determine the appropriate hypoxic dose in humans exercising in acute hypoxia. Methods: SpO2 values were collected in seven untrained (UTS) and seven endurance-trained male subjects (ETS) who performed six cycle incremental and maximal tests at sea level and at simulated altitudes of 1000m, 1500m, 2500m, 3500m and 4500m. Oxygen uptake was continuously measured and maximal oxygen uptake (V ̇O_2max) was determined in each subject and at each altitude. Intensity was expressed as percentage of V ̇O_2max. Results: There were strong non-linear relationships between altitude and SpO2 at low, moderate and high intensity both in ETS and UTS (r=0.97, p<0.001). SpO2 was significantly correlated to exercise intensity at sea level and at all simulated altitudes in ETS but only from 2500m in UTS. There were inverse correlations between SpO2 and sea-level V ̇O_2max at all altitudes, which were stronger from 2500m and with the increase in exercise intensity. The three-variable model we established predicts (p<0.001) the SpO2 level of individuals exercising in acute hypoxia based on their sea-level V ̇O_2max, the intensity of exercise and the altitude level. Conclusion: The model demonstrates that the drop of SpO2 during exercise in acute hypoxia is larger with the increase in both sea-level V ̇O_2max and exercise intensity. The model also highlights that the pivotal altitude from which the fall in SpO2 is exacerbated is between 2000 and 2500m, depending on both sea-level V ̇O_2max and exercise intensity.
... Patients with liver diseases are at hazard of emerging pulmonary vascular complications [43]. Sildenafil has also been reported to increase arterial Po2 [44] and recover bodily performance in numerous circumstances of severe pulmonary hypertension, but no education has explored the consequence of a numerous daytime action by sildenafil on these variables in usual focusses bare to elevation circumstances [45,46,47]. Approximately medical doctor have initiated by sildenafil as another to, and in mixture with, in the initial organisation of PAH, but its residence is inaccurate [48]. ...
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In today’s world main problem adolescence consumption of drugs are increasing day by day. Sildenafil is the sexual drug. Sildenafil is the drug which to increase sexual power and improves flow of blood to the phallus (male reproductive part). It’s most commonly found in the form of brand names are Viagra and Revatio. It can be administrated orally or injected directly into the veins. Sildenafil is an effective inhibitor of recurring guanosine monophosphate in the corpus cavernosum and consequently rises the penile reaction to sexual stimulus. Sildenafil also causes some side effect like headache, heartburn, flushed skin, visual disturbance, and dyspepsia. Sildenafil does not protect with sexually transmitted diseases like HIV, hepatitis B, AIDS etc. Sildenafil may effect severe organ like cardiovascular system, reproductive system, pulmonary hypertension, retinal dysfunction etc. Due to overdose of the sildenafil the person get heart attack, stroke, irregular heartbeats and death may also occur in rare cases. This paper aims about the detailed study of the sexual drug and the poisonous effects which is caused to the humans.
... pulmonary hypertension or chronic heart failure), iNO has been shown to increase V O 2peak (Matsumoto et al. 1997). Previous work using sildenafil to induce pulmonary vasodilation under hypoxic conditions has been shown to increase V O 2max in healthy (mostly male) subjects (Ghofrani et al. 2004;Hsu et al. 2006;Faoro et al. 2007). While the RV and pulmonary circulation appear to limit exercise capacity in some clinical populations, no study to date has examined the impact of acutely reducing pulmonary artery pressure on V O 2max in healthy individuals. ...
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Purpose: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]O2max). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved [Formula: see text]O2max, particularly in untrained individuals. The purpose of the study was to examine whether iNO improved [Formula: see text]O2max in endurance trained and untrained individuals. Methods: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO. Results: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]O2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min-1; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group. Conclusion: Despite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O2max with iNO suggests that the pulmonary vasculature does not limit [Formula: see text]O2max in young healthy individuals, regardless of fitness level.
... An additional factor might be a limitation in right ventricular flow output secondary to hypoxic pulmonary hypertension. Actually, an improvement in maximal workload and maximal oxygen uptake (VO 2max ) together with a decrease in pulmonary artery pressure (PAP) was reported after the intake of medication as sildenafil or dexamethasone in hypoxic healthy volunteers ( Ghofrani et al., 2004). However, improved exercise capacity in these studies could not unequivocally be ascribed to associated inhibition of hypoxic pulmonary vasoconstriction, because of additional effects including a variable improvement in arterial oxygen content ( Richalet et al., 2005). ...
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Respiratory/inspiratory muscle training (RMT/IMT) has been proposed to improve the endurance performance of athletes in normoxia. In recent years, due to the increased use of hypoxic training method among athletes, the RMT applicability has also been tested as a method to minimize adverse effects since hyperventilation may cause respiratory muscle fatigue during prolonged exercise in hypoxia. We performed a review in order to determine factors potentially affecting the change in endurance performance in hypoxia after RMT in healthy subjects. A comprehensive search was done in the electronic databases MEDLINE and Google Scholar including keywords: “RMT/IMT”, and/or “endurance performance”, and/or “altitude” and/or “hypoxia”. Seven appropriate studies were found until April 2018. Analysis of the studies showed that two RMT methods were used in the protocols: respiratory muscle endurance (RME) (isocapnic hyperpnea: commonly 10-30’, 3-5d/week) in three of the seven studies, and respiratory muscle strength (RMS) (Powerbreathe device: commonly 2x30 reps at 50% MIP (maximal inspiratory pressure), 5-7d/week) in the remaining four studies. The duration of the protocols ranged from four to eight weeks, and it was found in synthesis that during exercise in hypoxia, RMT promoted 1) reduced respiratory muscle fatigue, 2) delayed respiratory muscle metaboreflex activation, 3) better maintenance of SaO2 and blood flow to locomotor muscles. In general, no increases of maximal oxygen uptake (VO2max) were described. Ventilatory function improvements (maximal inspiratory pressure) achieved by using RMT fostered the capacity to adapt to hypoxia and minimized the impact of respiratory stress during the acclimatization stage in comparison with placebo/sham. In conclusion, RMT was found to elicit general positive effects mainly on respiratory efficiency and breathing patterns, lower dyspneic perceptions and improved physical performance in conditions of hypoxia. Thus, this method is recommended to be used as a pre-exposure tool for strengthening respiratory muscles and minimizing the adverse effects caused by hypoxia related hyperventilation. Future studies will assess these effects in elite athletes.
... Compared to placebo, neither iloprost nor furosemide influenced maximum heart rate in the Han. In (Ghofrani et al., 2004;Naeije & Dedobbeleer, 2013). Since iloprost had no effect in the Tibetans, our results would then suggest that HPV is not a limiting factor for exercise performance in the Tibetan population. ...
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A B S T R AC T Background: Tibetans lose less aerobic exercise capacity in hypoxia compared to lowland Han. We tested if inhalation of iloprost (to counter hypoxic pulmonary vasoconstriction) and furosemide (to decrease afferent vagal traffic from pulmonary receptors) improve performance in hypoxia in Han compared to Tibetans. Methods: 8 Tibetans and 8 Han, living at 2,260 m, did incremental uphill treadmill running to exhaustion at ambient pressure on day 1, followed by three runs at 5,000 m (hypobaric chamber) after inhalation of iloprost (ILO), furosemide (FUR) or placebo (PLA), on different days in a counterbalanced order. Results: In Han the performance decrement from 2,260 m to 5,000 m was greater than in Tibetans (p<0.05). In Han iloprost improved performance at 5,000 m compared to placebo (p<0.05 vs. PLA); furosemide had no effects. In Tibetans there were no treatment effects. Peripheral O 2 saturations at peak exercise at 5,000 m, were higher by ~8 % in the Tibetans (p<0.05 vs. Han). Maximum heart rate was lowered by 13±6 bpm in Han at 5,000 m regardless of treatment compared to 2,260 m (p<0.05). Tibetans reached similar maximum heart rates ~200 bpm at 5,000 m and 2,260 m, independent of treatment. Conclusions: The blunting of the exercise impairment in severe hypoxia in Han during maximal exercise after inhalation of iloprost suggests that hypoxic pulmonary vasoconstriction and right ventricular function are potential performance limiting factors in Han in hypoxia.
... В рандомизированном двойном слепом плацебо-контролируемом перекрестном исследовании, проведенном более 10 лет назад нашими сотрудниками совместно с учеными из имперского колледжа Лондона, было показано, что с помощью ингибитора фосфодиэстеразы-5 силденафила можно уменьшить ответ легочного сосудистого русла на острое гипоксическое воздействие [173]. В другом рандомизированном двойном слепом плацебоконтролируемом перекрестном исследовании впервые удалось показать, что воздействуя с помощью фармакологических препаратов на легочное сосудистое сопротивление, можно добиться увеличения максимальной физической работоспособности [174]. Ингибирующее влияние однократного приема силденафила на гипоксическую легочную гипертонию в покое и при физической нагрузке было подтверждено позднее в другом рандомизированном двойном слепом перекрестном исследовании [175]. ...
... First, Sanchez del Rio et al. [29] found that nitric oxide (NO) can irritate and discharge the nerve fibers constituting the trigeminovascular system, resulting in high-altitude headaches. Moreover, NO increases blood-brain barrier permeability, which may also cause headaches [30]. Studies have shown that endothelial function can be impaired by small amounts of oxygen free radicals in smokers, resulting in decreased NO synthesis and increased NO decomposition Fig. 2 Forest plot of the relationship between AMS and smoking. ...
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Background People rapidly ascending to high altitudes (>2500 m) may suffer from acute mountain sickness (AMS). The association between smoking and AMS risk remains unclear. Therefore, we performed a meta-analysis to evaluate the association between smoking and AMS risk. Methods The association between smoking and AMS risk was determined according to predefined criteria established by our team. Meta-analysis was conducted according to the PRISMA guidelines. We included all relevant studies listed in the PubMed and Embase databases as of September 2015 in this meta-analysis and performed systemic searches using the terms “smoking”, “acute mountain sickness” and “risk factor”. The included studies were required to provide clear explanations regarding their definitions of smoking, the final altitudes reached by their participants and the diagnostic criteria used to diagnose AMS. Odds ratios (ORs) were used to evaluate the association between smoking and AMS risk across the studies, and the Q statistic was used to test OR heterogeneity, which was considered significant when P < 0.05. We also computed 95% confidence intervals (CIs). Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). ResultsWe used seven case-control studies including 694 smoking patients and 1986 non-smoking controls to analyze the association between smoking and AMS risk. We observed a significant association between AMS and smoking (OR = 0.71, 95% CI 0.52–0.96, P = 0.03). Conclusions We determined that smoking may protect against AMS development. However, we do not advise smoking to prevent AMS. More studies are necessary to confirm the role of smoking in AMS risk.
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Key points: We sought to determine the isolated and combined influence of hypovolaemia and hypoxic pulmonary vasoconstriction on the decrease in left ventricular (LV) function and maximal exercise capacity observed under hypobaric hypoxia. We performed echocardiography and maximal exercise tests at sea level (344 m), and following 5-10 days at the Barcroft Laboratory (3800 m; White Mountain, California) with and without (i) plasma volume expansion to sea level values and (ii) administration of the pulmonary vasodilatator sildenafil in a double-blinded and placebo-controlled trial. The high altitude-induced reduction in LV filling and ejection was abolished by plasma volume expansion but to a lesser extent by sildenafil administration; however, neither intervention had a positive effect on maximal exercise capacity. Both hypovolaemia and hypoxic pulmonary vasoconstriction play a role in the reduction of LV filling at 3800 m, but the increase in LV filling does not influence exercise capacity at this moderate altitude. Abstract: We aimed to determine the isolated and combined contribution of hypovolaemia and hypoxic pulmonary vasoconstriction in limiting left ventricular (LV) function and exercise capacity under chronic hypoxaemia at high altitude. In a double-blinded, randomised and placebo-controlled design, 12 healthy participants underwent echocardiography at rest and during submaximal exercise before completing a maximal test to exhaustion at sea level (SL; 344 m) and after 5-10 days at 3800 m. Plasma volume was normalised to SL values, and hypoxic pulmonary vasoconstriction was reversed by administration of sildenafil (50 mg) to create four unique experimental conditions that were compared with SL values: high altitude (HA), Plasma Volume Expansion (HA-PVX), Sildenafil (HA-SIL) and Plasma Volume Expansion with Sildenafil (HA-PVX-SIL). High altitude exposure reduced plasma volume by 11% (P < 0.01) and increased pulmonary artery systolic pressure (19.6 ± 4.3 vs. 26.0 ± 5.4, P < 0.001); these differences were abolished by PVX and SIL respectively. LV end-diastolic volume (EDV) and stroke volume (SV) were decreased upon ascent to high altitude, but were comparable to sea level in the HA-PVX trial. LV EDV and SV were also elevated in the HA-SIL and HA-PVX-SIL trials compared to HA, but to a lesser extent. Neither PVX nor SIL had a significant effect on the LV EDV and SV response to exercise, or the maximal oxygen consumption or peak power output. In summary, at 3800 m both hypovolaemia and hypoxic pulmonary vasoconstriction contribute to the decrease in LV filling, but restoring LV filling does not confer an improvement in maximal exercise performance.
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Background: Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. Methods: This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10-6 M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. Results: The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10-5 M or above elicited a significant relaxation response to 10-6 M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. Conclusion: High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle.
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Erectile dysfunction (ED) is a prevalent form of male sexual dysfunction. Phosphodiesterase type 5 (PDE5) inhibitor is the first-line treatment for ED. Numerous well-designed and -conducted clinical trials and postmarketing studies have established the safety and efficacy of PDE5 inhibitors for the treatment of ED. Ever since the first approval of sildenafil in 1998, PDE5 inhibitors have had several advances in their clinical use. More new agents with different pharmacokinetic profiles and new formulations were marketed. Conventional on-demand administration expanded to daily dosing. These advances provide more flexibility in clinical treatment of ED for patients and physicians. Moreover, clinical indications of PDE5 inhibitors extend from treatment of ED to pulmonary arterial hypertension and signs and symptoms of benign prostatic hyperplasia because of the distribution of PDE5 enzyme in human organs and tissues. The evolution of PDE5 inhibitors heralds a remarkable medical history from bench to clinical practice.
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Exercise and competitive sports should be associated with a wide range of health benefits with the potential to inspire a positive community health legacy. However, the reputation of sports is being threatened by an ever-expanding armamentarium of agents with real or perceived benefits in performance enhancement. In addition to the injustice of unfair advantage for dishonest athletes, significant potential health risks are associated with performance-enhancing drugs. Performance-enhancing drugs may have an effect on the cardiovascular system by means of directly altering the myocardium, vasculature, and metabolism. However, less frequently considered is the potential for indirect effects caused through enabling athletes to push beyond normal physiological limits with the potential consequence of exercise-induced arrhythmias. This review will summarize the known health effects of PEDs but will also focus on the potentially greater health threat posed by the covert search for performance-enhancing agents that have yet to be recognized by the World Anti-Doping Agency. History has taught us that athletes are subjected to unmonitored trials with experimental drugs that have little or no established efficacy or safety data. One approach to decrease drug abuse in sports would be to accept that there is a delay from when athletes start experimenting with novel agents to the time when authorities become aware of these drugs. This provides a window of opportunity for athletes to exploit with relative immunity. It could be argued that all off-label use of any agent should be deemed illegal.
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This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective.
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L Sylvester JT, Shimoda LA, Aaronson PI, Ward JPT. Hypoxic Pulmonary Vasoconstric-tion. Physiol Rev 92: 367–520, 2012; doi:10.1152/physrev.00041.2010.—It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophys-iological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.
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A defect of nitric oxide (NO) synthesis in the lung of high-altitude pulmonary edema (HAPE) has been suggested to contribute to its exaggerated pulmonary hypertension. Several polymorphisms have been identified in the gene encoding endothelial nitric oxide synthase (eNOS), which is a key enzyme responsible for NO synthesis, some of which were reported to be associated with vascular disorders. We studied 41 HAPE-susceptible subjects (HAPE-s) and 51 healthy climbers (control group) in a Japanese population. We examined 2 polymorphisms of the eNOS gene, including the Glu298Asp variant and 27-base pair (bp) variable numbers of tandem repeats using polymerase chain reaction followed by restriction fragment length polymorphism. The Asp allelic frequency of the Glu298Asp variant was 25.6% in the HAPE-s and 9.8% in the controls, which was significantly different between the two groups (P=0.0044). The eNOS4a allelic frequency of 27-bp variable numbers of tandem repeats was 23.2% in the HAPE-s, significantly higher than that of 6.9% in the controls (P=0.0016). In HAPE-s group, 11 of 41 (26.8%) subjects possessed simultaneously both of the two significant alleles, but among the controls, none did, which showed a high statistical difference between the two groups (P=0.000059). Both polymorphisms of the eNOS gene were significantly associated with HAPE. A genetic background may underlie the impaired NO synthesis in the pulmonary circulation of HAPE-s. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.
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Objective: This prospective single-blinded study was performed to quantitate noninvasive pulmonary artery systolic pressure (PASP) responses to prolonged acute hypoxia and normoxic exercise. Background: Hypoxia-induced excessive rise in pulmonary artery pressure is a key factor in high-altitude pulmonary edema (HAPE). We hypothesized that subjects susceptible to HAPE (HAPE-S) have increased pulmonary artery pressure response not only to hypoxia but also to exercise. Methods: PASP was estimated at 45, 90 and 240 min of hypoxia (FiO2 = 12%) and during supine bicycle exercise in normoxia using Doppler-echocardiography in nine HAPE-S and in 11 control subjects. Results: In the control group, mean PASP increased from 26+/-2 to 37+/-4 mm Hg (deltaPASP 10.3+/-2 mm Hg) after 90 min of hypoxia and from 27+/-4 to 36+/-3 mm Hg (deltaPASP 8+/-2 mm Hg) during exercise. In contrast, all HAPE-S subjects revealed significantly greater increases (p = 0.002 vs. controls) in mean PASP both during hypoxia (from 28+/-4 to 57+/-10 mm Hg, deltaPASP 28.7+/-6 mm Hg) and during exercise (from 28+/-4 to 55+/-11 mm Hg, deltaPASP 27+/-8 mm Hg) than did control subjects. Stress echocardiography allowed discrimination between groups without overlap using a cut off PASP value of 45 mm Hg at work rates less than 150 W. Conclusions: These data indicate that HAPE-S subjects may have abnormal pulmonary vascular responses not only to hypoxia but also to supine bicycle exercise under normoxic conditions. Thus, Doppler echocardiography during supine bicycle exercise or after 90 min of hypoxia may be useful noninvasive screening methods to identify subjects susceptible to HAPE.
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CBF increases with acute hypoxia despite the opposing vasoconstrictor effects of the drop in pCO2 caused by hyperventilation. Maintaining normocapnia by adding CO2 the hypoxic CBF responsiveness about doubles. As we have shown recently by this test, the hypoxic CBF response is not blunted but rather somewhat sharpened over five days at almost 4000 meters of altitude. This, along with other evidence, shows that CBF does not in itself adapt to chronic hypoxia. Nevertheless, a decrease in CBF is seen over days at constant altitude primarily due to increase in the hematocrit. The cerebral vasodilatation cannot explain the usual (mild) form of AMS. But it may well be involved in the pathogenesis of the rare but severe cerebral form of AMS, as prolonged increased capillary pressure in vasodilated areas could lead to vasogenic cerebral edema.
To verify the abnormal pulmonary vascular response implicated in the pathogenesis of high altitude pulmonary edema (HAPE), we examined the hemodynamic responses to hypoxia in HAPE-susceptible subjects (HAPE-S) by means of both right heart catheterization and pulsed Doppler echocardiography. The HAPE-S were seven men and one woman with a history of HAPE. Six healthy volunteers who had repeated experiences of mountain climbing without any history of altitude-related problems served as control subjects. The HAPE-S showed much greater increase in pulmonary vascular resistance (PVR) than did the control subjects, resulting in a much higher level of pulmonary arterial pressure (Ppa) under acute hypoxia both of 15% O2 and 10% O2. We then evaluated the usefulness of pulsed Doppler echocardiography in the prediction of pulmonary hypertension. Acceleration time (AcT) and right ventricular ejection time (RVET) were measured from the flow velocity pattern in the right ventricular outflow tract. The ratio of AcT to RVET was correlated to invasively determined mean Ppa (Ppa) and PVR. The results were as follows: (1) AcT/RVET = 0.52 to 0.0047 (Ppa), r = -0.93, SEE = 0.017, p less than 0.001 (HAPE-S); (2) AcT/RVET = 0.55 to 0.0055 (Ppa), r = -0.70, SEE = 0.030, p less than 0.001 (HAPE-S); (4) AcT/RVET = 0.52 to 0.00077 (PVR), r = -0.91, SEE = 0.016, p less than 0.001 (control subjects). We conclude that HAPE-S have a constitutional abnormality in the pulmonary vascular response to hypoxia, which is a possible causative factor of HAPE, and that pulsed Doppler echocardiography may be supportive to assess the pulmonary vascular pressor response in the HAPE-S.
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42 patients with chronic obstructive lung disease underwent right heart hemodynamics (Swan-Ganz catheter) and M mode echocardiography. Echocardiographic study showed that right ventricular index (RVI) and right ventricular anterior wall thickness (RVAWT) were increased in most patients, while septal thickness and motion were nearly always normal. The finding of impaired RVI and normal RVAWT in several patients, while no one showed normal RVI and increased RVAWT, suggests that arterial pulmonary hypertension results in initial dilatation and only later in hypertrophy of the right ventricle. Echocardiographic parameters were well correlated with hemodynamic and pulmonary function parameters. The good correlations between echocardiographic and hemodynamic data suggest that echocardiography may be a useful technique in the noninvasive assessment of the effects of pulmonary hypertension on the right heart in COLD.
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1. Cyclic guanosine 3'-5'-monophosphate (cyclic GMP) is the second messenger of important physiologically active mediators controlling the pulmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertension. 2. Levels of cyclic GMP measured during baseline conditions at 5 and 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with time. Pretreatment with DMPPO (1 microM) induced a larger increase in cyclic GMP concentration in the perfusate from chronically hypoxic rat lungs (31+/-36 at 5 min to 1821+/-83 pmol ml(-1) at 60 min) than in normoxic rat lungs (329+/-20 to 1281+/-127 pmol ml(-1), P<0.05). 3. In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 microM) potentiated the vasodilator effects of atrial natriuretic peptide (100 pM-10 nM) and sodium nitroprusside (1 pM 10 nM), but did not alter vasodilation to isoproterenol. 4. In conscious rats previously exposed to 15 days hypoxia and studied under 10% O2, DMPPO (0.01, 0.05 and 0.1 mg kg(-1), i.v. bolus) caused a dose-dependent decrease in pulmonary arterial pressure (Pap) with no change in systemic artery pressure (Sap) and cardiac output. 5. Continuous infusion of DMPPO (0.1 mg kg(-1) h(-1) i.v. by osmotic pumps) in rats exposed to 10% O2 during 2-weeks reduced the Pap (P<0.05) and the degree of muscularization of pulmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrophy. 6. These results suggest that cyclic GMP phosphodiesterase inhibition may selectively dilate pulmonary circulation during chronic hypoxia.
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To describe the course of changes in perfusion lung scintigraphy (LS) after acute pulmonary embolism (PE) and test the hypothesis that patients with persistent pulmonary hypertension (PH)/right ventricle (RV) dysfunction after acute PE can be differentiated from those without through larger perfusion defects (PDf) on LS. Design. Prospective, one-year follow-up study with repeated LS and echocardiography-Doppler investigations. Single centre, University Hospital. Patients with clinical suspicion of acute PE with a diagnosis confirmed by LS and/or pulmonary angiography and able to undergo repeated investigations. Of the 78 patients included, a six-week follow-up was completed in 67 and a one-year follow-up in 64. Time course of PDf in relation to time course of pulmonary artery systolic pressure (PAsP) and RV function. Initially, PDf decreased exponentially, until the beginning of a stable phase, which was achieved within 54 days for 90% of the patients and within 148 days for all. The temporal relation for the regress of PDf and decrease in PAsP was loose. Patients with persistent PDf suffered PH/RV dysfunction more often than those without. However, the variability in the degree of haemodynamic changes for a given extent of PDf was large. After acute PE, LS is of use for the identification of the group of patients that may have persistent PH/RV dysfunction. However. since the identification of individual patients is uncertain, LS cannot replace echocardiography-Doppler in the identification of persistent PH/RV dysfunction after acute PE.
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Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.
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The most reliable prediction of high altitude tolerance can be derived from the clinical history of previous comparable exposures. Unfortunately, there are no reliable tests for prediction prior to first-time ascents. Although susceptibility to AMS is usually associated with a low hypoxic ventilatory response (HVR), there is too much overlap with the range of normal values, which precludes measuring HVR or O(2) saturation during brief hypoxia for reliable identification of susceptibility to AMS. A low HVR and an exaggerated rise in pulmonary artery pressure with (prolonged) hypoxia, or exercise in normoxia, are markers of susceptibility to high altitude pulmonary edema (HAPE). These tests can not be recommended for routinely determining high altitude tolerance because the prevalence of susceptibility to HAPE is low and because specificity and sensitivity of these tests are not sufficiently established. On the other hand, HAPE may be avoided in susceptible individuals by ascent rates of 300 m per day above an altitude of 2000 m. Since prediction of risk of mountain sickness is difficult, it is important during the physician consultation prior to ascent to consider the altitude profile, the type of ascent, the performance capacity, the history of previous exposures, and the medical infrastructure of the area.
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This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling. Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.
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The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors. The short-term effects of 8.4 to 10.5 microgram of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4+/-1.3 versus 6.4+/-1.1 mm Hg; P<0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8+/-1.4 versus 9.4+/-1.3 mm Hg; P<0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects. Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.
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Almost every second hiker or climber develops two to three symptoms of the high altitude illness after a rapid ascent (>300 m/h) to an altitude above 4000 m. We distinguish two forms of high altitude illness, a cerebral form called acute mountain sickness and a pulmonary form called high altitude pulmonary edema. Acute mountain sickness presents during its early and benign stage with mild to moderate headache, loss of appetite, nausea, vomiting, dizziness and insomnia. Rarely, acute mountain sickness progresses into its life-threatening severe form called high altitude cerebral edema. The pathophysiologic mechanism of this high altitude associated cerebral dysfunction is not fully understood. In contrast to the acute mountain sickness, the clinical presentation of high altitude pulmonary edema is that of a cardiopulmonary disease. Symptoms associated with high altitude pulmonary edema are incapacitating fatigue, chest tightness, dyspnoe at the minimal effort that advances to dyspnoe at rest and orthopnoe, and a dry non-productive cough that progresses to cough with pink frothy sputum due to hemoptysis. The hallmark of high altitude pulmonary edema is a severe pulmonary hypertension with mean pulmonary artery pressure between 35 and 55 mmHg. An elevated vascular pressure in the pulmonary capillary has recently been identified as the major contributor of alveolar fluid flooding. Pulmonary capillary hypertension is caused by an excessive hypoxic vasoconstriction of the small pulmonary arteries and veins (50-900 μm). The present review aims at epidemiology, clinics, pathophysiology and the management of high altitude pulmonary edema.
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Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis. We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat. Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.
Article
Clinical studies have demonstrated that sildenafil citrate (Viagra) is an effective and well-tolerated oral treatment for erectile dysfunction. Despite its established safety profile, concern about its cardiovascular safety persists among some physicians and the general public. This concern has stemmed primarily from sporadic reports of adverse events published in the literature and sensationalized by the media. However, the only absolute contraindication for sildenafil is concurrent use of nitrates. Because sildenafil has been on the market for 4 years and under clinical investigation for even longer, we can now evaluate its long-term safety in men who have been taking the drug for several years. We review this issue from 3 perspectives. First, we reassess the overall safety profile of sildenafil by reviewing the initial controlled clinical trials and open-label studies. We present new data from patients who have been exposed to sildenafil for up to 4.5 years. We also evaluate the results from independent postmarketing studies. Second, we review the cardiovascular-specific results from the clinical trials, long-term extension, and postmarketing studies. Lastly, we review the specific effects on the visual system based on findings from studies conducted during drug development and post marketing.
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Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange. Chronic alveolar hypoxia results in vascular remodeling and pulmonary hypertension. Previous studies have reported conflicting results of the effect of chronic alveolar hypoxia on pulmonary vasoreactivity and the contribution of nitric oxide (NO), which may be related to species and strain differences as well as to the duration of chronic hypoxia. Therefore, we investigated the impact of chronic hypoxia on HPV in rabbits, with a focus on lung NO synthesis. After exposure of the animals to normobaric hypoxia (10% O(2)) for 1 day to 10 wk, vascular reactivity was investigated in ex vivo perfused normoxic ventilated lungs. Chronic hypoxia induced right heart hypertrophy and increased normoxic vascular tone within weeks. The vasoconstrictor response to an acute hypoxic challenge was strongly downregulated within 5 days, whereas the vasoconstrictor response to the thromboxane mimetic U-46619 was maintained. The rapid downregulation of HPV was apparently not linked to changes in the lung vascular NO system, detectable in the exhaled gas and by pharmacological blockage of NO synthesis. Treatment of the animals with long-term inhaled NO reduced right heart hypertrophy and partially maintained the reactivity to acute hypoxia, without any impact on the endogenous NO system being noted. We conclude that chronic hypoxia causes rapid downregulation of acute HPV as a specific event, preceding the development of major pulmonary hypertension and being independent of the lung vascular NO system. Long-term NO inhalation partially maintains the strength of the hypoxic vasoconstrictor response.
Article
The absence (deletion allele [D]) of a 287 base-pair fragment in the ACE gene is associated with higher ACE tissue activity than its presence (insertion allele [I]) and, as such, may enhance vasoconstriction and fluid retention through increased levels of angiotensin II and aldosterone. Because fluid retention is found in acute mountain sickness (AMS) and exaggerated pulmonary hypertension is essential in the pathophysiology of high-altitude pulmonary edema (HAPE), we hypothesized that the DD genotype is associated with increased susceptibility to these illnesses. ACE genotype was thus determined in 83 mountaineers staying over night at 4559 m and related to AMS symptoms. Genotype was similarly determined in 76 mountaineers who had participated in previous studies at 4559 m; 38 of the latter group had a history of HAPE, and 25 had developed HAPE again during these studies. The allele frequency was in Hardy-Weinberg equilibrium in both investigations. Neither the history nor the observed episodes of HAPE nor the prevalence of AMS defined as an AMS-C score >/= 0.70 (environmental symptom questionnaire) in the first study or in both studies taken together were significantly different between the genotypes DD, ID, and II. We conclude that I/D-ACE gene polymorphism has no important effect on susceptibility to AMS or HAPE.
Article
The term "cor pulmonale" is still very popular in the medical literature, but its definition varies and there is presently no consensual definition. Forty years ago an expert committee of the World Health Organization 1 defined cot pulmonale as "hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs...". This pathological definition is in fact of limited value in clinical practice. It has been proposed to replace the term "hypertrophy" by "alteration in the structure and function of the right ventricle". It has also been proposed to define clinically cor pulmonale by the presence of oedema in patients with respiratory failure. Finally, as pulmonary arterial hypertension is "the sine qua non" of cor pulmonale, 2 we believe that the best definition of cot pulmonale is :pulmonary arterial hypertension resulting from diseases affecting the structure and/or the function of the lungs; pulmonary arterial hypertension results in right ventricular enlargement (hypertrophy and/or dilatation) and may lead with time to right heart failure. A new diagnostic classification of pulmonary hypertension was developed by a group of experts in 1998 3 and is presented on table 1. In our opinion cor pulmonale corresponds to the third part of this classification (pulmonary hypertension associated with disorders of the respiratory system and/or hypoxaemia) and must be distinguished from pulmonary venous hypertension (part 2), and also from primary pulmonary hypertension (part 1) and from thromboembolic pulmonary hypertension (part 4). This article reviews the current state of knowledge about pulmonary hypertension resulting from disorders of the respiratory system and/or from chronic hypoxaemia. We will only consider chronic cor pulmonale. Particular emphasis will be placed on chronic obstructive pulmonary disease (COPD) which is by far the main cause of cor pulmonale.