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Airway Hypocapnia Increases Microvascular Leakage in the Guinea Pig Trachea
Abstract
We have previously shown that airway hypocapnia induced bronchoconstriction in the guinea pig lung by releasing tachykinins. To examine whether airway hypocapnia could also cause an increase in airway microvascular leakage, a tracheal segment was isolated in vivo in anesthetized guinea pigs and unidirectionally ventilated (200 ml/min) for 1 h with fully conditioned air (0% CO2) or isocapnic gas (5% CO2). The lungs were ventilated through a distally placed tracheal cannula. Microvascular leakage was quantitated by the injection of Evans blue (EB) and its extraction from the tracheal segment. EB extravasation was increased in tracheae exposed to 0% CO2 (52.3 +/- 2.0 micrograms/g wet tissue) compared with tracheae exposed to 5% CO2 (26.4 +/- 2.9 micrograms/g; p less than 0.05) and to tracheae from spontaneously breathing guinea pigs (25.2 +/- 2.3 micrograms/g; p less than 0.05). Groups of animals in which trachea were unidirectionally ventilated with 0% CO2 were then pretreated with a range of drugs in an attempt to determine the mediators responsible for the microvascular leakage with 0% CO2. Capsaicin and morphine pretreatment did not significantly alter 0% CO2-induced EB extravasation, and phosphoramidon prevented rather than increased extravasation, suggesting that tachykinins did not play a role. The hypocapnia-induced increase in microvascular leakage was, however, prevented by indomethacin pretreatment and significantly attenuated by dazmegrel, a thromboxane synthetase inhibitor. We conclude that airway hypocapnia causes microvascular leakage in the guinea pig trachea and that this effect is mediated by prostaglandins and/or thromboxane.
... Several lines of evidence complement these clinical concerns relating to hypocapnia. First , a significant body of laboratory data confirm that experimentally induced hypocapnia results in significant adverse pulmonary effects, including bronchospasm (5), increased airway permeability (6), dysfunctional surfactant (7), and reduced lung compliance (8). Second , hypocapnia is associated with significant adverse systemic consequences. ...
... Significant concerns exist regarding potential adverse effects of lowered CO 2 tension on several aspects of both pulmonary (5)(6)(7)(8)12) and systemic organ (9, 10) dysfunction. Hypocapnia has been associated with worsened lung injury in the context of bronchopulmonary dysplasia (4) and ARDS (3). ...
... Hypocapnia may exert adverse pulmonary effects via several distinct mechanisms. Airway hypocapnia increases tracheal microvascular permeability (6). Furthermore, hypocapnia de-creases lung compliance in healthy volunteers and in patients with chronic obstructive lung disease (8), probably as a result of increased production of dysfunctional surfactant (7). ...
Mechanical ventilation can worsen morbidity and mortality by causing ventilator-associated lung injury, especially where adverse ventilatory strategies are employed. Adverse strategies commonly involve hyperventilation, which frequently results in hypocapnia. Although hypocapnia is associated with significant lung alterations (e.g., bronchospasm, airway edema), the effects on alveolar-capillary permeability are unknown. We investigated whether hypocapnia could cause lung injury independent of altering ventilatory strategy. We hypothesized that hypocapnia would cause lung injury during prolonged ventilation, and would worsen injury following ischemia-reperfusion. We utilized the isolated buffer-perfused rabbit lung model. Pilot studies assessed a range of levels of hypocapnic alkalosis. Experimental preparations were randomized to control groups (FI(CO(2)) = 0.06) or groups with hypocapnia (FI(CO(2)) = 0.01). Following prolonged ventilation, pulmonary artery pressure, airway pressure, and lung weight were unchanged in the control group but were elevated in the group with hypocapnia; elevation in microvascular permeability was greater in the hypocapnia versus control groups. Injury following ischemia-reperfusion was significantly worse in the hypocapnia versus control groups. In a preliminary series, degree of lung injury was proportional to the degree of hypocapnic alkalosis. We conclude that in the current model (1) hypocapnic alkalosis is directly injurious to the lung and (2) hypocapnic alkalosis potentiates ischemia-reperfusion-induced acute lung injury.
... Introduction: Chronic Obstructive pulmonary disease (COPD) is characterized by airflow obstruction with breathing-related symptoms such as chronic cough, exertion dyspnoea, expectoration, and wheeze [1]. The Buteyko concept is a system of breathing exercises originally devised in the 1950s by Professor Konstantin Buteyko, a Russian physician and academic personality [2]. ...
... Following its popularity in Russia, the concept has gradually spread to western countries over the last 20 years, notably Australia and New Zealand and other parts of Europe. The technique offers a complementary method of reliving respiratory symptoms based 104 Physiotherapy and Occupational Therapy Journal on the voluntary control of breathing, as well as considering the effects of environmental and dietary triggers [2]. ...
Introduction: Chronic Obstructive pulmonary disease (COPD) is characterized by airflow obstruction with breathing-related symptoms such as chronic cough, exertion dyspnoea, expectoration, and wheeze [1]. The Buteyko concept is a system of breathing exercises originally devised in the 1950s by Professor Konstantin Buteyko, a Russian physician and academic personality [2].
... Hypocapnia and respiratory alkalosis also lead to pulmonary vasodilation (19) and bronchoconstriction (21), which result in ventilation to perfusion (V/Q) mismatch and secondary hypoxemia in TBI patients with pre-existing lung injury. In animal studies, hypocapnia also decreased surfactant production (22) and increases the permeability of the alveolo-capillary barrier (23), although this has not well-demonstrated in humans. Hyperventilation may also increase intra-abdominal pressure, which can secondarily increase ICP (24); hypocapnia decreases blood flow to the kidneys, skin and muscles tissues and increases platelet adhesion and aggregation (12). ...
Hyperventilation is a commonly used therapy to treat intracranial hypertension (ICTH) in traumatic brain injury patients (TBI). Hyperventilation promotes hypocapnia, which causes vasoconstriction in the cerebral arterioles and thus reduces cerebral blood flow and, to a lesser extent, cerebral blood volume effectively, decreasing temporarily intracranial pressure. However, hyperventilation can have serious systemic and cerebral deleterious effects, such as ventilator-induced lung injury or cerebral ischemia. The routine use of this therapy is therefore not recommended. Conversely, in specific conditions, such as refractory ICHT and imminent brain herniation, it can be an effective life-saving rescue therapy. The aim of this review is to describe the impact of hyperventilation on extra-cerebral organs and cerebral hemodynamics or metabolism, as well as to discuss the side effects and how to implement it to manage TBI patients.
... There are also other controversial findings reported morphine effects on the airway microvascular leakage. Morphine does not alter microvascular leakage increased by airway hypocapnia in guinea pig trachea (19) and by Nformyl-methionyl-leucyl-phenylalanine (FMLP) inhalation in rabbit trachea (20). On the other hand, morphine has an inhibitory effect, through inhibition of neurotransmission, on airway plasma leakage induced by cigarette smoke (21). ...
Aim: To investigate the effect of morphine on ovalbumin-evoked airway microvascular leakage in sensitized rats. Materials and methods: Rats were sensitized on days 0, 14, and 21 with ovalbumin. Intravenous ovalbumin (2 mg/kg) or capsaicin (50 μg/kg) increased the extravasation of Evans blue dye in trachea, bronchi, and intra-pulmonary tissues of sensitized rats. Results: Morphine (1-10 mg/kg) inhibited ovalbumin-evoked increase in microvascular plasma leakage in a dosedependent manner; however, it had no significant effect at the doses of 0.1 or 30 mg/kg. In addition, morphine, at the doses of 1-30 mg/kg, abolished microvascular leakage increased by capsaicin. The inhibition caused by morphine was blocked by the peripheral opioid receptor antagonist, naloxone methiodide, in ovalbumin or capsaicin series. Morphine or naloxone methiodide has alone no effect on plasma leakage. Conclusion: These results conclude that morphine inhibits microvascular leakage, maybe mediated by neurogenic inflammation in sensitized rats, via peripheral opioid receptors.
... There are also other controversial findings reported morphine effects on the airway microvascular leakage. Morphine does not alter microvascular leakage increased by airway hypocapnia in guinea pig trachea (19) and by Nformyl-methionyl-leucyl-phenylalanine (FMLP) inhalation in rabbit trachea (20). On the other hand, morphine has an inhibitory effect, through inhibition of neurotransmission, on airway plasma leakage induced by cigarette smoke (21). ...
Aim: To investigate the effect of morphine on ovalbumin-evoked airway microvascular leakage in sensitized rats. Materials and methods: Rats were sensitized on days 0, 14, and 21 with ovalbumin. Intravenous ovalbumin (2 mg/kg) or capsaicin (50 μg/kg) increased the extravasation of Evans blue dye in trachea, bronchi, and intra-pulmonary tissues of sensitized rats. Results: Morphine (1-10 mg/kg) inhibited ovalbumin-evoked increase in microvascular plasma leakage in a dose-dependent manner; however, it had no significant effect at the doses of 0.1 or 30 mg/kg. In addition, morphine, at the doses of 1-30 mg/kg, abolished microvascular leakage increased by capsaicin. The inhibition caused by morphine was blocked by the peripheral opioid receptor antagonist, naloxone methiodide, in ovalbumin or capsaicin series. Morphine or naloxone methiodide has alone no effect on plasma leakage. Conclusion: These results conclude that morphine inhibits microvascular leakage, maybe mediated by neurogenic inflammation in sensitized rats, via peripheral opioid receptors. Morfin, ovalbumin ile duyarlı kılınmış sıçanların solunum yolundaki dolaşım sıvısı çıkışını doza bağlı olarak değiştiriyor Amaç: Bu araştırma, ovalbumin ile duyarlılaştırılmış sıçanlarda solunum yolundaki dolaşım sıvısı çıkışı üzerine morfinin etkisini görebilmek için düzenlendi. Yöntem ve gereç: Sıçanlarda, 0, 14 ve 21. günlerde ovalbumin uygulanarak alerjik duyarlılık oluşturuldu. Ovalbumin (2 mg/kg) ve kapsaisin (50 μg/kg) sıçanlara damar içi verilerek, solunum yolundaki dolaşımda damar dışına Evans mavisi kaçışı ölçüldü. Bulgular: Morfin (1-10 mg/kg aralığında) doza bağlı olarak ovalbuminin solunum yolunda yol açtığı plazma sızıntısını durdurdu (0,1 ve 30 mg/kg dozlarda ise önemli etkisi yoktu). Ayrıca morfin (1-30 mg/kg doz aralığında) kapsaisinin yaptığı plazma çıkışını engelledi. Morfinin çevre dokulardaki reseptör antagonisti olan nalokson metiyodid bu etkilerin tamamını tersine çevirdi. Morfin ve nalokson metiyodid tek başına uygulandıklarında plazma sızıntısına yol açmadılar. Sonuç: Bu bulgular, morfinin solunum yolundaki alerjik duyarlı dokulardan plazma sızıntısını durdurduğunu ortaya koyuyor. Plazma sızıntısı nörojenik inflamasyonla ilişkili olabilir ve bu olayda çevresel opioid reseptörler rol alabilir.
... Sev-eral lines of evidence are important in this regard. First, although hypocapnia is associated with increased airway microvascular permeability (6), the effects of hypercapnia on permeability at the airway or alveolar level have not been described. Second, hypercapnia or acidosis may have protective effects in tissue ischemia in the central nervous system (7) and the myocardium (8), and metabolic acidosis is known to be protective against ischemia-reperfusion lung injury in the isolated buffer-perfused rat lung (9). ...
Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.
... Because lungs take up oxygen for their own metabolism from the alveolar air [17] and have stored enough substrate for several hours without perfusion [18] the absence of perfusion should not have affected the results. The lungs were ventilated with 5% CO 2 in air to avoid hypocapnia, which may have resulted in adverse pulmonary effects, i.e. increased airway permeability or dysfunctional surfactant192021. For extrapolation of the results to the in vivo setting various methodical aspects have to be considered. ...
During partial liquid ventilation perfluorocarbons are eliminated mainly by evaporation via the airways. The effects of intrapulmonary perfluorocarbon volume, respiratory rate, tidal volume, as well as the level of end-expiratory pressure on perfluorocarbon elimination from isolated lungs, were studied.
Nonperfused rabbit lungs underwent partial liquid ventilation (2–15 mL·kg ⁻¹ perfluorocarbon) with variable levels of end-expiratory pressure (0–10 cmH 2 O), respiratory rates (15–60 breaths·min ⁻¹ ) and tidal volumes (3.3–10.0 mL·kg ⁻¹ ). Evaporative loss of perfluorocarbon was determined gravimetrically as rate of change in lung weight.
At constant respiratory settings, intrapulmonary liquid volume determined evaporative loss in a nonlinear fashion. Mean evaporation at a liquid volume of 5 mL·kg ⁻¹ was 13% lower compared to evaporation at a liquid volume of 15 mL·kg ⁻¹ . Any increase in end-expiratory pressure reduced perfluorocarbon evaporation, e.g. by ∼50% when end-expiratory pressure was increased from 0 to 10 cmH 2 O. At constant end-expiratory pressure and perfluorocarbon filling evaporation increased in a linear fashion with increasing respiratory rate and tidal volume.
In summary, the experiments suggested that evaporative loss of perfluorocarbons during partial liquid ventilation of isolated lungs is increased with increasing intrapulmonary liquid volume, respiratory rate and tidal volume and is reduced in a level-dependent fashion by the application of positive end-expiratory pressure.
Hypoplastic left heart syndrome (HLHS) is a group of congenital cardiac malformations consisting of various degrees of underdevelopment of the left heart and the aorta, resulting in significant obstruction to blood flow and the inability of the left heart to support the systemic circulation. With the introduction of fetal echocardiography, it has become evident that congenital heart diseases including HLHS evolve throughout gestation. The HLHS encompasses a spectrum of cardiac malformations that are characterized by significant underdevelopment of the components of the left heart and the aorta, including the left ventricular cavity and mass. Increasingly the diagnosis of HLHS is made by fetal echocardiogram prior to delivery. After birth, the medial smooth muscle fibers in the arterial duct contract, which results in wall thickening, lumen obliteration, and shortening of the duct. Patient attrition mostly occurs before stage 2 palliation; cumulative mortality until stage 2 palliation ranges from 5% to 30%.
Acute respiratory distress syndrome (ARDS) mainly involves acute respiratory failure. In addition to this affected patients feel progressive arterial hypoxemia, dyspnea, and a marked increase in the work of breathing. The only clinical solution for the above pathological state is ventilation. Mechanical ventilation is necessary to support life in ARDs but it itself worsen lung injury and the term is known clinically as ‘ventilation induced lung injury’ (VILI). At the cellular level, respiratory epithelial cells are subjected to cyclic stretch, i.e. repeated cycles of positive and negative strain, during normal tidal ventilation. In aerated areas of diseased lungs, or even normal lungs subjected to injurious positive pressure mechanical ventilation, the cells are at risk of being over distended, and worsening injury by disrupting the alveolar epithelial barrier. Further, hypercapnic acidosis (HCA) in itself confers protection from stretch injury, potentially via a mechanisms involving inhibition of nuclear factor κB (NF-κB), a transcription factor central to inflammation, injury and repair. Mesenchymal stem cells are the latest in the field and are being investigated as a possible therapy for ARDS.
Die maschinelle Beatmung auf der Intensivstation erfolgt praktisch immer durch einen positiven Atemwegsdruck, der intermittierend oder kontinuierlich erzeugt wird. Die hierdurch hervorgerufenen unphysiologischen Druckschwankungen und -gradienten im Thoraxraum sind für den Großteil der Nebenwirkungen und Komplikationen dieser Therapie verantwortlich. Die übrigen Komplikationen sind durch Verwendung künstlicher Atemwege bedingt. Im folgenden werden die Sekundäreffekte der Beatmung auf andere Organfunktionen sowie auf das respiratorische System dargestellt.
As Laffey accurately pointed out ten years ago [1], we are all used to thinking that the range of normal values commonly accepted for healthy individuals are also useful for critical patients, but this approach is certainly not based on reality. For example, administering oxygen to premature neonates to achieve “normal” PaO2 levels may lead to retinopathy and bronchopulmonary dysplasia; giving transfusions to critical patients trying to reach normal haematocrit levels may increase mortality rates; and aiming for normal pressure levels in patients with multiple trauma may reduce their chances of survival. We should therefore not forget that elevated PaCO2 levels in critical patients (or even maintaining lower levels than normal), can have harmful effects.
Die Therapie des schweren akuten Lungenversagens des Erwachsenen (acute respiratory distress syndrome=ARDS) umfaßt bis heute vorwiegend unterstützende, auf eine Normalisierung des Gasaustauschs ausgerichtete Maßnahmen. Druckbegrenzte Beatmung mit positiv endexspiratorischem Druck in Verbindung mit permissiver Hyperkapnie, seitendifferenter Beatmung, Seiten- und Bauchlagerung und Dehydratation zielen auf eine Reduktion der zur Aufrechterhaltung annähernd normaler Blutgase notwendigen hohen Atemwegsspitzendrücke und inspiratorischen Sauerstoffkonzentrationen und somit auf eine Abschwächung iatrogener Faktoren, die wesentlich zur Progression der Lungenschädigung beitragen können. Extrakorporale Verfahren zur Unterstützung des Gasaustauschs sollten dann in Betracht gezogen werden, wenn mit diesen etablierten Behandlungsregimen keine Besserung des pulmonalen Gasaustauschs erzielt werden kann und wenn die Prognose der Grunderkrankung als günstig anzusehen ist. Mit diesem Therapiekonzept konnte im eigenen Patientengut eine Überlebensrate von 75% (67 von 89 Patienten) erreicht werden.
Come acutamente faceva notare Laffey dieci anni fa [1], siamo tutti abituati a considerare utili per i pazienti critici i
range di normalità comunemente accettati per i sani, ma questo tipo di strategia non è certamente fondato sulla realtà dei
fatti. Per esempio, somministrando ai neonati prematuri O2 per raggiungere valori “normali” di PaO2 abbiamo contribuito alla produzione delle retinopatie e delle displasie broncopolmonari; trasfondendo i pazienti critici
sino a raggiungere valori normali di Htc abbiamo aumentato la mortalità; avendo come obiettivo i valori pressori normali nei
politraumatizzati abbiamo ridotto la loro possibilità di sopravvivenza. Non possiamo quindi aprioristicamente escludere che,
tenendo la PaCO2 a valori elevati nei pazienti critici (o addirittura tenendola a valori più bassi del normale), si faccia un danno.
Hypocapnia is used in the management of acute brain injury and may be life-saving in specific circumstances, but it can produce neuronal ischemia and injury, potentially worsening outcome. This review re-examines the rationale for the use of hypocapnia in acute brain injury and evaluates the evidence for therapeutic and deleterious effects in this context.
A MEDLINE/PubMed search from 1966 to August 1, 2009, was conducted using the search terms "hyperventilation," "hypocapnia," "alkalosis," "carbon dioxide," "brain," "lung," and "myocardium," alone and in combination. Bibliographies of retrieved articles were also reviewed.
Hypocapnia--often for prolonged periods of time--remains prevalent in the management of severely brain-injured children and adults. Despite this, there is no proof beyond clinical experience with incipient herniation that hypocapnia improves neurologic outcome in any context. On the contrary, hypocapnia can cause or worsen cerebral ischemia. The effect of sustained hypocapnia on cerebral blood flow decreases progressively because of buffering; subsequent normocapnia can cause rebound cerebral hyperemia and increase intracranial pressure. Hypocapnia may also injure other organs. Accidental hypocapnia should always be avoided and prophylactic hypocapnia has no current role.
Hypocapnia can cause harm and should be strictly limited to the emergent management of life-threatening intracranial hypertension pending definitive measures or to facilitate intraoperative neurosurgery. When it is used, Paco2 should be normalized as soon as is feasible. Outside these settings hypocapnia is likely to produce more harm than benefit.
Hypocapnia/alkalosis is a consequence of several lung and metabolic pathologies. The aim of this study was to determine whether the increase of fluid filtration rate (FFR) that occurs during Hypocapnia/alkalosis circumstances is determined by hypocapnia, alkalosis or both. 7 groups were formed (N=36) using isolated rabbit lungs. Group 1: Control (PCO2 6%, pH: 7.35-7.45); Group 2 (n=6): Hypocapnia/Alkalosis (CO2 1%, pH: 7.9); Group 3 (n=6): Hypocapnia/Normo-pH (CO2 1% pH 7.35-7.45), Group 4 (n=6) Normocapnia/Alcalosis (CO2 6%, pH: 7.9). Fenoterol, papaverine and hydrocortisone were added to Groups 5, 6 and 7 (n=4) respectively, all under Normocapnia/Alkalosis. FFR and Pulmonary Arterial Pressure (Pap) were considerably higher in group 2 than in control (FFR: 1.92g/min +/- 0.6 vs 0.0 g/min +/- 0.006). A strong influence exerted by pH was observed when Group 3 and group 4 were compared (FFR: 0.02 g/min +/- 0.009 vs 2.3 g/min +/- 0.9) and (Pap: 13.5 cmH2O +/- 1.4 vs 90 cmH2O +/- 15). A reduced effect was observed in groups 5 and 6 (papaverine and hydrocorisone) and a totally abolished effect was observed in group 7 (fenoterol) (FFR: 0.001 +/- 0.0003 mL/min and Pap: 14 +/- 0.8 cmH2O). Pulmonary edema induced by Hypocapnia/alkalosis is a consequence of alkalosis and not of hypocapnia. This effect could be due to inflammatory damage in the lung parenchyma and alkalosis-mediated vasoconstriction.
We studied whether nitric oxide (NO), added at 80 ppm to inspired gas, can exert a bronchodilatory effect in humans. Four groups were studied: (1) healthy adult volunteers (n = 6), (2) adult subjects with hyperreactive airways (n = 6) during provocation with inhaled methacholine (MCh), (3) patients with bronchial asthma (n = 13), and (4) patients with chronic obstructive pulmonary disease (COPD, n = 6). All subjects were studied in a body plethysmograph, measuring volume-corrected specific airway conductance (SGaw). No patient or volunteer reacted with bronchoconstriction during NO inhalation. Nitric oxide did not affect SGaw in healthy volunteers or in patients with COPD. Inhaled NO modulated the MCh-induced bronchoconstriction toward dilatation. In patients with bronchial asthma, SGaw increased (p < 0.05) from 0.4 +/- 0.1 to 0.6 +/- 0.2 (kPa.s)-1. In a succeeding test with inhalation of a beta 2-agonist immediately after NO inhalation, a more marked increase in SGaw was seen, to 1.2 +/- 0.3 (kPa.s)-1 (p < 0.001). We conclude that NO inhaled at 80 ppm has no effect on airway tone in healthy volunteers, but modulates the response to MCh provocation toward bronchodilation. It exerts a weak bronchodilatory effect in bronchial asthma, but not in COPD.
The tracheobronchial microcirculation consists of a subepithelial capillary network and in some species deeper capacitance vessels and an adventitial network. Postcapillary venules are the main site of plasma extravasation in inflammatory conditions. There are surprising species differences. The subepithelial capillary network is dense in species such as sheep and dog but relatively scanty in rabbit and humans. Sheep have conspicuous capacitance vessels or blood sinuses, especially in the trachea and at points of bronchial branching with walls that lack smooth muscle. The rabbit also has a well‐developed capacitance system but the blood sinuses have thick muscular walls. Although the capacitance system in humans has not been studied much it is probably present with muscular walls. It is absent in rats but present in guinea pigs. Thus, in some species the tracheobronchial vasculature may give the mucosa an erectile capacity, as in the nose of each species. Arteriovenous anastomoses (AVA) cannot be demonstrated physiologically in sheep but they seem to be present as thoroughfare vessels in rats and guinea pigs. Whether they exist in humans is not known. The absence of AVA might indicate a weak or absent thermoregulatory and air conditioning role for the lower airway vasculature.
Extensive studies of neurogenic inflammation in rodents show that sensory neuropeptides can open gaps between the endothelial cells of postcapillary venules and the same change can be caused by a large number of inflammatory mediators. These opened gaps cause extravasation of plasma into the interstitium. Small increases in interstitial pressure lead to spaces opening between the epithelial cells and exudation of plasma into the airway lumen.
The role of the airway microvasculature in asthma is controversial. Cold and hyperosmolar solutions cause vasodilatation as do the mediators released in the mucosal inflammation of asthma. However, quantitation of the thickening of the airway wall due to vascular engorgement, mucosal edema, or increased luminal liquid does not prove that these changes are a cause of airway obstruction. The contraction of airway smooth muscle superimposed on the mucosal inflammatory pathology might lead to a synergistic mechanism to increase airway resistance.
1. Both hypoxia and hypocapnia can cause broncho-constriction in humans, and this could have a bearing on performance at high altitude or contribute to altitude sickness. We studied the relationship between spirometry, arterial oxygen saturation and end-tidal carbon dioxide (ETCO2) concentration in a group of healthy lowland adults during a stay at high altitude, and then evaluated the response to supplementary oxygen and administration of a β2 agonist
2. We collected spirometric data from 51 members of the 1994 British Mount Everest Medical Expedition at sea level (barometric pressure 101.2–101.6 kPa) and at Mount Everest Base Camp in Nepal (altitude 5300 m, barometric pressure 53–54.7 kPa) using a pocket turbine spirometer. A total of 205 spirometric measurements were made on the 51 subjects during the first 6 days after arrival at Base Camp. Further measurements were made before and after inhalation of oxygen (n = 47) or a β2 agonist (n = 39). ETCO2 tensions were measured on the same day as spirometric measurements in 30 of these subjects.
3. In the first 6 days after arrival at 5300 m, lower oxygen saturations were associated with lower forced expiratory volume in 1 s (FEV1; P < 0.02) and forced vital capacity (FVC; P < 0.01), but not with peak expiratory flow (PEF). Administration of supplementary oxygen for 5 min increased oxygen saturation from a mean of 81%–94%, but there was no significant change in FEV1 or FVC, whilst PEF fell by 2.3% [P < 0.001; 95% confidence intervals (CI) −4 to −0.7%]. After salbutamol administration, there was no significant change in PEF, FEV1 or FVC in 35 non-asthmatic subjects. Mean ETCO2 at Everest Base Camp was 26 mmHg, and a low ETCO2 was weakly associated with a larger drop in FVC at altitude compared with sea level (r = 0.38, P < 0.05). There was no correlation between either ETCO2 or oxygen saturation and changes in FEV1 or PEF compared with sea-level values.
4. In this study, in normal subjects who were acclimatized to hypobaric hypoxia at an altitude of 5300 m, we found no evidence of hypoxic broncho-constriction. Individuals did not have lower PEF when they were more hypoxic, and neither PEF nor FEV1 were increased by either supplementary oxygen or salbutamol. FVC fell at altitude, and there was a greater fall in FVC for subjects with lower oxygen saturations and probably lower ETCO2.
Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury. Conversely, hypocapnia is associated with many acute illnesses (eg, asthma, systemic inflammatory response syndrome, pulmonary oedema), and is thought to reflect underlying hyperventilation. Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious. We hypothesise that therapeutic hypercapnia might be tested in severely ill patients to see whether supplemental carbon dioxide could reduce the adverse effects of hypocapnia and promote the beneficial effects of hypercapnia. Such an approach could also expand our understanding of the pathogenesis of disorders in which hypocapnia is a constitutive element.
Airway microvascular leakage is considered to be an important component of airway inflammation in asthma. In the present study we examined the effect of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha) on airway microvascular leakage in vivo.
Tracheal Evans blue extravasation was examined in an isolated tracheal segment, in anaesthetized mechanically ventilated guinea pigs. Baseline tracheal microvascular leakage was measured in five animals. As a control group for aerosol challenge, the isolated tracheal segment (n = 5) underwent saline aerosol challenge. To test whether a combination of IL-1beta (10 ng/mL) and TNFalpha (100 ng/mL) induced Evans blue extravasation, the trachea was exposed to an aerosol of these cytokines (n = 5). As a positive control the tracheal segment was challenged with histamine aerosol (5 x 10(-2) mol) (n = 3). All aerosol challenges were for 1 min.
TNFalpha and IL-1beta aerosol challenge significantly increased Evans blue extravasation (28.9 +/- 1.6 microg/g wet tissue, mean +/- SE) compared to saline challenge (13.8 +/- 3.0 microg/g; P < 0.05). Tracheal dye extravasation without aerosol challenge, was not significantly different from saline-challenged animals (17.5 +/- 2.9 and 13.8 +/- 3.0 microg/g, respectively). Histamine significantly increased Evans blue extravasation (50.1 +/- 4.8 microg/g; P < 0.05) compared to saline challenge.
Pro-inflammatory cytokines, TNFalpha and IL-1beta are able to induce significant microvascular leakage in the guinea pig trachea.
Initial Implementation of Mechanical Ventilation was focused on providing adequate oxygenation and relief of work of breathing. Over the last few decades it has become apparent that stretch-induced lung injury, associated with normocapnia or hypocapnia, is a real phenomenon. Attempts to reduce stretch-induced injury led to development of permissive hypercapnia in the neonatal population, and later to its acceptance as a standard of care in adult patients with ARDS. Here, the elevated CO2 was a result of reduced minute ventilation, and was considered to be a by-product of the technique that could be tolerated in most instances. It is now apparent that hypercapnia by itself can be protective. In addition, hypocapnia can be harmful. These observations led to the hypothesis of therapeutic hypercapnia, i.e., deliberate production of high CO2 as a goal in the care of critically ill patients.
Deliberate elevation of PaCO2 (therapeutic hypercapnia) protects against lung injury induced by lung reperfusion and severe lung stretch. Conversely, hypocapnic alkalosis causes lung injury and worsens lung reperfusion injury. Alterations in lung surfactant may contribute to ventilator-associated lung injury. The potential for CO2 to contribute to the pathogenesis of ventilator-associated lung injury at clinically relevant tidal volumes is unknown. We hypothesized that: 1) hypocapnia would worsen ventilator-associated lung injury, 2) therapeutic hypercapnia would attenuate ventilator-associated lung injury; and 3) the mechanisms of impaired compliance would be via alteration of surfactant biochemistry.
Randomized, prospective animal study.
Research laboratory of university-affiliated hospital.
Anesthetized, male New Zealand Rabbits.
All animals received the same ventilation strategy (tidal volume, 12 mL/kg; positive end-expiratory pressure, 0 cm H2O; rate, 42 breaths/min) and were randomized to receive FiCO2 of 0.00, 0.05, or 0.12 to produce hypocapnia, normocapnia, and hypercapnia, respectively.
Alveolar-arterial oxygen gradient was significantly lower with therapeutic hypercapnia, and peak airway pressure was significantly higher with hypocapnic alkalosis. However, neither static lung compliance nor surfactant chemistry (total surfactant, aggregates, or composition) differed among the groups.
At clinically relevant tidal volume, CO2 modulates key physiologic indices of lung injury, including alveolar-arterial oxygen gradient and airway pressure, indicating a potential role in the pathogenesis of ventilator-associated lung injury. These effects are surfactant independent.
We compared tracheobronchial injury following short-term intratracheal pulmonary ventilation (ITPV) and conventional mechanical ventilation (CMV) in a healthy rabbit model. ITPV, a form of tracheal gas insufflation, has been shown to decrease deadspace ventilation and increase CO2 removal and therefore may reduce ventilator-induced lung injury.
Medical center laboratory.
Twenty-five rabbits.
Rabbits were randomly assigned to either ITPV or CMV (n = 15 and 10, respectively). Both groups were mechanically ventilated for 8 hrs at the same ventilator settings (FIO2, 0.4; rate, 30 breaths/min; flow, 4 L x min(-1); positive end-expiratory pressure, 4 cm H2O; tidal volume, 40 mL). Peak, mean, and end-expiratory carinal pressures, ITPV flow rate, and hemodynamic variables were continuously monitored. Tissue samples for histologic analysis were obtained postmortem from the trachea contiguous to the tip of the endotracheal tube, the distal trachea, the carina, and the main bronchus. The histologic sections were scored, in a single-blind fashion, for ciliary damage, ulceration, hemorrhage, overall inflammation, intraepithelial inflammatory infiltrate, and edema.
ITPV was associated with significantly lower Paco and deadspace ventilation ratio than CMV. The combined tracheobronchial injury scores for all samples were significantly higher in the ITPV group compared with the CMV group (p <.005; Mann-Whitney U test). The ITPV injury scores, compared with CMV injury scores, were significantly higher at the carina and main bronchus (p <.01; Kruskal-Wallis test followed by Dunn's multiple comparison test). The area adjacent to the endotracheal tube showed the same degree of damage in both groups. Analysis of the injury scores in individual damage categories demonstrated the greatest difference in the ulceration category (p <.001).
In our study, ITPV, compared with CMV at the same minute ventilation, was associated with a significantly greater difference in tracheobronchial damage at the carina and main bronchus. We postulate that this difference may have been caused by the turbulence of the gas flow generated by the small-caliber ITPV catheter used in our neonatal-size animal model.
The aim of this review was to consider the effects of induced hypocapnia both on systemic physiology and on the physiology of the intracranial system. Hyperventilation lowers intracranial pressure (ICP) by the induction of cerebral vasoconstriction with a subsequent decrease in cerebral blood volume. The downside of hyperventilation, however, is that cerebral vasoconstriction may decrease cerebral blood flow to ischemic levels. Considering the risk-benefit relation, it would appear to be clear that hyperventilation should only be considered in patients with raised ICP, in a tailored way and under specific monitoring. Controversy exists, for instance, on specific indications, timing, depth of hypocapnia, and duration. This review has specific reference to traumatic brain injury, and is based on an extensive evaluation of the literature and on expert opinion.
1. Increased local thromboxane (Tx) formation has been considered to be a contributing factor in digitalis-induced arrhythmias.
2. A potent Tx synthetase inhibitor (TxSI), UK 38,485 (0.1, 1.0 or 10.0 mg/kg per h, administered intravenously) and a Tx receptor antagonist (TxRA), ICI 185, 282 (1, 2 or 10 mg/kg bolus and 1, 2 or 10 mg/kg per h, administered intravenously) were tested for their ability to reduce digoxin-induced arrhythmias in anaesthetized guineapigs.
3. Electrocardiograms, mean blood pressure, heart rate and arrhythmias were recorded, starting 30 min before digoxin administration and continued for 60 min afterwards.
4. ICI 185,282, at the doses used, significantly delayed the time of onset of arrhythmias, and reduced the incidence of ventricular fibrillation, mortality and arrhythmia score. In contrast, UK 38,485 was found to be effective on all measured variables only at the dose rate of 1.0 mg/kg per h, except for time required for the development of arrhythmias. These protective effects of both TxSI and TxRA were not found to be dose-dependent.
5. Arterial blood pressure and heart rate changes caused by either UK 38,485 or ICI 185,282 infusions did not have any marked effects on digoxin-induced arrhythmias.
6. These data suggest that endogenously released TxA2 and prostaglandin endoperoxides may play an important role in digoxin-induced arrhythmias in guinea-pigs.
Intact human neutrophils hydrolyzed N-formyl-Met-Leu-[3H]Phe (fMLP) and released Leu-[3H]Phe, cleaving 45-50% of the peptide within 20 min at 37 degrees C. The dipeptide after its release was then hydrolyzed to free amino acids by a dipeptidase (EC 3.4.13.11). This activity, present in plasma membrane-enriched fractions of neutrophil lysates, was also inhibited over 90% by phosphoramidon, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11). Dithiothreitol and EDTA inhibited the activity to a comparable degree, suggesting the requirement for a heavy metal cofactor. Bestatin and amastatin, inhibitors of aminopeptidases (but not human kidney NEP), did not inhibit the rate of fMLP degradation but prevented the production of free phenylalanine and enhanced the accumulation of Leu-Phe. Of other inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin slightly enhanced the rate of fMLP hydrolysis by neutrophils, and others tested were ineffective. Rabbit antiserum to homogeneous human kidney NEP reacted specifically with a 100-kDa protein present in sodium dodecyl sulfate-solubilized neutrophils. The Mr of this protein was slightly larger than that of the kidney enzyme in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The antiserum incubated with intact cells specifically inhibited the degradation of fMLP over 70%. First, we confirm that NEP present on the plasma membrane cleaves fMLP at the Met-Leu bond; then the dipeptide Leu-Phe is cleaved by a dipeptidase. Finally, inhibition of NEP completely blocks fMLP-mediated chemotaxis. Thus, the enzyme may play an important role in modulating chemotactic responses.
Previous studies have documented the phasic pulmonary vascular response to infused Eschericha coli endotoxin in unanesthetized sheep. Cyclooxygenase inhibition attenuates the initial vasoconstrictive phase (phase I) but not the late phase of increased microvascular permeability (phase II). We undertook to selectively inhibit thromboxane A2 synthesis and assess the pulmonary microvascular response to endotoxin. Twelve paired studies were carried out in six sheep prepared with chronic lung lymph fistulas and pressure monitoring catheters. Each sheep received E. coli endotoxin (0.5 μg/kg) at time 0, both alone (control group) and 1 hr after pretreatment with a thromboxane synthetase inhibitor (UK-38485, 2 mg/kg). The animals were monitored for 1–2 hr prior to and 5 hr following endotoxin infusion to ensure a steady-state baseline and a complete late response. The pairs of studies were done in random order. In the presence of UK-38485, endotoxin caused significantly less pulmonary hypertension and shorter duration of leukopenia and lower lung lymph flow and lymph protein clearance rates than did endotoxin alone. The differences in lymph protein clearance were more pronounced in phase II. These data suggest that both the vasoconstrictive and permeability phases of the pulmonary vascular response to endotoxin may be modified on endogenous thromboxane A2.
In the guinea pig isolated perfused lung, we have examined the relationship between the effects of capsaicin and neuropeptide release and the possible existence of an axon reflex arrangement. Bolus injections into the pulmonary artery of capsaicin (1-100 pmol), substance P (10-1,000 pmol), and neurokinin (NK) A (10-100 pmol) produced a concentration-dependent bronchoconstriction, whereas calcitonin gene-related peptide (CGRP, 20-40 nmol) was without effect. Repeated administration of capsaicin at 40- to 60-min intervals was not associated with tachyphylaxis. These data support the presence of a NK2- (or NKA) type of tachykinin receptor in the guinea pig airways. Tetrodotoxin (0.3-3 microM) inhibited the effect of capsaicin, indicating that an axon reflex was operant. Capsaicin increased overflow of CGRP-like immunoreactivity (-LI) and NKA-LI, the latter only during concurrent infusion of the enkephalinase inhibitor phosphoramidon (3 microM). Phosphoramidon also increased overflow of CGRP-LI, suggesting that both NKA and CGRP were catabolized by a similar enzyme. The purine nucleoside adenosine did not cause any detectable overflow of CGRP-LI, indicating that neuropeptides may not be involved in adenosine-evoked bronchoconstriction and that bronchoconstriction per se does not induce neuropeptide overflow. Capsaicin and NKA had only minor effects on buffer flow, whereas substance P produced pulmonary vasoconstriction. These data clearly demonstrate that capsaicin acts via an axon reflex in the guinea pig airways. Supramaximal concentrations of capsaicin are needed to detect neuropeptide overflow, but the possibility exists that released neuropeptides mediate its effects.
We tested the hypothesis that tachykinins mediate hyperpnea-induced bronchoconstriction (HIB) in 28 guinea pigs. Stimulus-response curves to increasing minute ventilation with dry gas were generated in animals depleted of tachykinins by capsaicin pretreatment and in animals pretreated with phosphoramidon, a neutral metalloendopeptidase inhibitor. Sixteen anesthetized guinea pigs received capsaicin (50 mg/kg sc) after aminophylline (10 mg/kg ip) and terbutaline (0.1 mg/kg sc). An additional 12 animals received saline (1 ml sc) instead of capsaicin. One week later, all animals were anesthetized, given propranolol (1 mg/kg iv), and mechanically ventilated (6 ml/kg, 60 breaths/min, 50% O2 in air fully water saturated). Phosphoramidon (0.5 mg iv) was administered to five of the noncapsaicin-treated guinea pigs. Eucapnic dry gas (95% O2-5% CO2) hyperpnea "challenges" were performed by increasing the tidal volume (2-6 ml) and frequency (150 breaths/min) for 5 min. Capsaicin-pretreated animals showed marked attenuation in HIB, with a rightward shift of the stimulus-response curve compared with controls; the estimated tidal volume required to elicit a twofold increase in respiratory system resistance (ES200) was 5.0 ml for capsaicin-pretreated animals vs. 3.7 ml for controls (P less than 0.03). Phosphoramidon-treated animals were more reactive to dry gas hyperpnea compared with control (ES200 = 2.6 ml; P less than 0.0001). Methacholine dose-response curves (10(-11) to 10(-7) mol iv) obtained at the conclusion of the experiments were similar among capsaicin, phosphoramidon, and control groups. These findings implicate tachykinin release as an important mechanism of HIB in guinea pigs.
The aim of this study was to determine whether hypocapnia causes bronchoconstriction by releasing tachykinins (TKs) from C-afferent nerves in airways. Hypocapnia-induced bronchoconstriction (HIBC) was induced in anesthetized vagotomized guina pigs by ventilating lungs with a heated humidified hypocapnic gas mixture for 15 min after sudden circulatory arrest. The intensity of bronchoconstriction was assessed by calculating changes in dynamic compliance and by measuring the relaxation lung volume at the completion of experiments. Visualization of the airways by tantalum bronchography showed constriction of segmental bronchi with relative sparing of more proximal airways. Hypocapnia-induced bronchoconstriction was prevented by prior administration of salbutamol aerosol. Three experimental interventions were used to investigate the role of TKs in HIBC: 1) repeated capsaicin injections to deplete airway sensory nerves of TKs, 2) treatment with phosphoramidon, an inhibitor of enkephalinase, the main enzyme responsible for TK inactivation, and 3) topical airway anesthesia. Capsaicin pretreatment markedly attenuated the hypocapnia-induced changes in dynamic compliance (P less than 0.0005) and relaxation lung volume (P less than 0.0002), whereas phosphoramidon augmented these changes (P less than 0.02, P less than 0.03, respectively). Topical anesthesia of airways with lignocaine postponed the onset of bronchoconstriction, whereas the longer-acting, more lipid-soluble local anesthetic, bupivacaine, almost completely prevented HIBC. We conclude that, in the guinea pig lung, HIBC is mediated by TKs that are released after the activation of bronchial axonal reflexes.
We have studied the effects of liquids of various osmolalities and temperatures on the tracheal vasculature, smooth muscle tone, and transepithelial albumin flux. In 10 anesthetized dogs a 10- to 13-cm length of cervical trachea was cannulated to allow instillation of fluids into its lumen. The cranial tracheal arteries were perfused at constant flow, with monitoring of the perfusion pressures (Ptr) and the external tracheal diameter (Dtr). Control fluid was Krebs-Henseleit solution (KH) with NaCl added to result in a 325-mosM solution (isotonic). Hypertonic solutions were KH with NaCl (warm hypertonic) or glucose (hypertonic glucose) added to result in a 800-mosM solution. All solutions were at 38 degrees C, with isotonic and the hypertonic NaCl solutions also given at 18 degrees C (cold isotonic and cold hypertonic). Fluorescent labeled albumin was given intravenously, and the change in fluorescence in the fluid was measured during each 15-min period. Changing from warm isotonic to cold isotonic decreased Dtr and Ptr. Changing from warm isotonic to warm hypertonic or hypertonic glucose decreased Ptr with no change in Dtr. The cold hypertonic responses were not different from cold isotonic responses. Warm hypertonic solution increased albumin flux into the tracheal lumen over a 15-min period to three times that of the control period, persisting for 15 min after replacement with warm isotonic solution. Cooling induces a vasodilation and smooth muscle contraction of the trachea, whereas hypertonic solutions result in vasodilation and, if osmolality is increased with NaCl, an increase in albumin flux into the tracheal lumen.
The present study was performed to determine whether neurogenic inflammation in the rat trachea can be exaggerated by inhibiting neutral endopeptidase, an enzyme that degrades tachykinins that are believed to mediate neurogenic inflammation. Neurogenic inflammation was produced by antidromic electrical stimulation of one vagus nerve (2.5 Hz, 1 ms, 5 V for 5 min) in the presence of atropine or by an intravenous injection of capsaicin (100 micrograms/kg). Neutrophils that adhered to the endothelium of venules were visualized and counted in tracheal whole mounts that were stained by a histochemical reaction for myeloperoxidase. Neural inflammation increased the number of adherent neutrophils. Pretreatment with the neutral endopeptidase inhibitor phosphoramidon (1.0 or 2.5 mg/kg iv) increased neutrophil adhesion induced by neural inflammation. As assessed by the amount of extravasation of Monastral blue pigment, neural inflammation also increased vascular permeability, and this change was potentiated by phosphoramidon. These results are consistent with the concept that neuropeptides released from sensory nerves in the tracheal mucosa cause neutrophils to adhere to venules and increase vascular permeability and that these effects are modulated by neutral endopeptidase.
We describe a new in vivo chemotaxis assay in the dog trachea using a double-balloon endotracheal catheter. When inflated, the two balloons isolate a segment of trachea, which is perfused through Silastic tubes using a peristaltic pump. After instilling a chemotactic agent, the perfusate is sampled periodically to permit characterization of the chemotactic response. We anesthetized four mongrel dogs and ventilated them mechanically through the double-balloon catheter. Two mediators, leukotriene B4 (LTB4) and 8S,15S-dihydroxyeicosatetraenoic acid (8,15-diHETE) were tested in each dog by perfusing the trachea with each mediator in Hanks' balanced salt solution (HBSS) containing ethanol and antibiotics. Aliquots were removed for differential cell counts at fixed time intervals over a 4-h period. Control experiments performed in each dog with the identical concentrations of ethanol and antibiotics in HBSS showed no cellular response before 180 min. At 240 min, the cell counts were 86 +/- 28 (SE) granulocytes/microliter (n = 4). In contrast, both LTB4 and 8,15-diHETE gave a significant cellular response at 120 min (309 +/- 125 and 141 +/- 41 granulocytes/microliter, respectively; P less than 0.05) but did not differ significantly from each other. These results suggest that both LTB4 and 8,15-diHETE can incite inflammatory responses in the dog trachea in vivo. Furthermore, the double-balloon catheter technique promises to be a useful in vivo chemotaxis assay.
Six patients who injected talc containing drugs intended for oral use were assessed over a period of ten or more years from the time of initiation of this habit. Despite discontinuation of the drug abuse, all developed severe respiratory disability and three died from their disease. An evolving spectrum of roentgenographic and functional patterns is considered to be virtually diagnostic of this disorder. Roentgenographically, an initial diffuse, pin-point micronodularity subsequently becomes associated with conglomerates, usually in the upper lobes, closely resembling the progressive massive fibrosis (PMF) of the pneumoconioses. The lower lobes, on the other hand, become relatively translucent, in some instances with bulla formation and the development of pneumothorax. Pulmonary function, initially with both restrictive and obstructive features, eventually becomes markedly obstructive with hyperinflation and air trapping. At this late stage, pathologic examination reveals emphysema in addition to the granulomatous inflammation and fibrosis surrounding the talc particles in the pulmonary interstitium.
Specific binding sites for calcitonin gene-related peptide (CGRP) were demonstrated in the rat heart and spleen. Autoradiography revealed rat [125I]iodo CGRP binding associated with the intima and media of the aorta, the coronary arteries and the heart valves, and the red pulp of the spleen. Half-maximal inhibition of rat [125I]iodo-CGRP binding to membranes of the rat atria and the spleen was obtained with, respectively, 5 and 0.35 nM unlabeled rat CGRP; these values correspond to EC50 values of 3 and 0.14 nM for activation of adenylate cyclase by CGRP. In the isolated, spontaneously beating right atrium, the EC50 values of stimulation of the force and rate of contraction by rat CGRP were 120 and 70 nM, respectively. Rat CGRP caused relaxation of splenic strips, precontracted with noradrenaline; the EC50 was 50 nM. The beta-adrenergic blocking agent metoprolol, while obliterating the increase in the force and rate of contraction evoked by noradrenaline in the right atrium, did not significantly change the action of CGRP. Similarly, preserved action of CGRP in the presence of indomethacin as well as mepyramine and cimetidine argues against a role of prostaglandins or histamine in the functional responses of CGRP. Much like CGRP, capsaicin, which releases mediators from sensory neurons, caused stimulation of the force and rate of contraction of the isolated right rat atrium. After tachyphylaxis to CGRP, the response to noradrenaline was intact, while the positive chronotropic and inotropic effects of capsaicin were suppressed. The results indicate that the cardiac effects of capsaicin may be due to the release of endogenous CGRP through a local mode of action.
Severe postmortem bronchoconstriction has been shown previously in guinea pig lungs and linked to pulmonary blood loss during exsanguination (Lai et al., J. Appl. Physiol. 56: 308-314, 1984). To reexamine this phenomenon we measured postmortem airway function in anesthetized open-chest guinea pigs after sudden circulatory arrest. Animals were divided into 4 groups of 10 and ventilated for 15 min postmortem with different gases: 1) room air, 2) conditioned air, 3) dry 5% CO2-21% O2-74% N2, and 4) conditioned 5% CO2-21% O2-74% N2. In room air-ventilated lungs there was a 50% decrease in dynamic compliance (Cdyn) by 15 min and marked gas trapping compared with control lungs. Conditioning the room air did not attenuate these changes, but when 5% CO2 was added to the conditioned postmortem inspirate, gas trapping was eliminated and the fall in Cdyn was almost abolished. Ventilation with a dry 5% CO2 gas mixture at room temperature resulted in a 31% fall in Cdyn at 15 min but no gas trapping. We conclude that marked abnormalities of airway function occur postmortem in room air-ventilated guinea pig lungs in the absence of pulmonary blood loss. The changes are mainly due to airway hypocarbia, a known cause of bronchoconstriction, but a reduction in Cdyn can also occur if there is marked airway cooling and drying. Acute postmortem airway dysfunction can be prevented in the guinea pig by maintaining normal airway gas composition.
Simple quantitative radiochemical and spectrophotometric methods have been employed for the simultaneous determination of prostaglandins (PGs) E2, F2α, D2 (11-dehydro-PGF2α), and malondialdehyde (MDA) produced by action of the arachidonate oxygenase (prostaglandin synthetase) system of bovine seminal vesicle. Several differences were observed in the optimal incubation conditions for formation of each product. Although several nonsteroidal anti-inflammatory agents inhibited the formation of all four products to the same degree, benzydamine and phenylbutazone differentially inhibited the formation of one or more of the products. These results indicate that more than one site, or more than one enzyme, is involved in the last step of the synthetase reaction, the breakdown of the cyclic endoperoxide intermediate. For many types of studies, the spectrophotometric determination of MDA formation provides an assay of prostaglandin synthetase activity much more convenient than those previously employed.
The quantitative distribution of five biologically active peptides was determined by RIA and immunocytochemistry in various regions of cat, rat, and guinea pig respiratory tracts. Vasoactive intestinal polypeptide (VIP) and substance P were found in higher concentrations than cholecystokinin (CCK), SRIF, and bombesin. In general, higher concentrations were found in the main airways than in lung tissue. Immunocytochemistry localized VIP and substance P to autonomic nerves, whereas bombesin was found in very scattered mucosal endocrine cells of the cat bronchial epithelium. CCK and SRIF could not be convincingly localized by immunocytochemistry because of their low tissue concentrations.
Species differences were noted, with high VIP but low substance P concentrations in the main airways of the cat; this relationship was reversed in the rat and guinea pig. Gel permeation chromatography of extracts revealed one peak, coeluting with the pure standard peptide, for CCK-8, SRIF, substance P, and VIP. Bombesin immunoreactivity was separable into two peaks, the major of which corresponded in position to that of gastrin-releasing peptide, and a later minor peak to the position of the bombesin standard. Thus, several potent peptides are present in the respiratory tract, which suggests the possibility that they play a significant role in controlling respiratory function.
UK-38,485, a novel imidazole derivative, was used in two clinical trials with health male subjects to study the influence of thromboxane synthetase inhibition on prostanoid formation. In an open pharmacokinetic study, UK-38,485 administered orally in doses of 10, 20, 40, 60, and 100 mg significantly reduced serum thromboxane (TXB2) concentrations. With lower doses (10 and 20 mg) peak inhibition of serum thromboxane occurred 2 hr after dosing, with a mean percentage inhibition of 78% and 91%, respectively. For the higher doses (40, 60, and 100 mg) peak inhibition exceeded 99% 1 hr after dosing. After 8 hr the inhibition was dose related, ranging between 59% and 75%, and after 24 hr between 0 and 35%. In a second multiple-dose, double-blind, placebo-controlled, cross-over study, 50 mg UK-38,485 given twice daily for 1 week selectively inhibited thromboxane synthetase. The excretion of 2,3-dinor-TXB2, the major urinary metabolite of endogenously formed thromboxane, was significantly reduced, whereas the urinary excretion of 2,3-dinor-6-keto-PGF(1α), the main metabolite of endogenous prostacyclin, and the plasma concentrations of 6-keto-PGF(1α) showed no significant increases compared with levels in the placebo period. In platelet suspensions stimulated ex vivo with arachidonic acid and in serum of incubated whole blood, TXB2 concentrations were reduced and a significant redirection of endoperoxide metabolism to antiaggregatory and vasodilatory prostaglandins I2, E2, and D2 was demonstrated after the influence of UK-38,485. Platelet lipoxygenase metabolites were not measurably altered. The drug was well tolerated. In both studies, no clinically relevant changes in laboratory safety and hemodynamic parameters, bleeding, or clotting time were observed. From the time course of the plasma drug concentrations, the inhibition of thromboxane synthesis, and the redirection of endoperoxide metabolism it can be concluded that UK-38,485 is rapidly absorbed and has a long-lasting effect on prostanoid formation.