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ABSTRACT: 1. Cardiac natriuretic peptides act on cardiopulmonary chemoreceptor afferents to enhance the von Bezold-Jarisch reflex (BJR). Activity of the natriuretic peptide particulate guanylyl cyclase receptor is essential for full expression of the BJR. Whether natriuretic peptides act directly on cardiac afferents or they require another intermediate factor(s) for their effects on the BJR is unknown. Endogenous candidates tested as possible intermediates in the present study were prostanoids and nitric oxide (NO), plausible endogenous chemical mediators of cardiac chemoreflex activity. 2. Dose-dependent BJR bradycardia was evoked by the 5-HT(3) receptor agonist, phenylbiguanide (range 5-89 μg/kg), in conscious instrumented adult sheep (n = 6). The influence of B-type natriuretic peptide (BNP; the most potent of the natriuretic peptides) on the BJR was assessed before and after blockade of prostanoids (using indomethacin, 1 mg/kg per h i.v.) or nitric oxide (using N-nitro-l-arginine (NOLA), 3 mg/kg bolus, then 3 mg/kg per h infusion i.v.). 3. On their own, indomethacin and NOLA did not significantly alter the BJR, showing that prostanoids and NO are not essential endogenous mediators of the BJR. As shown in previous studies, BNP (10 pmol/kg per min i.v.) infusion enhanced the BJR by 85 ± 36%, P < 0.05. When the production of either prostanoids or nitric oxide was inhibited, BNP still enhanced the BJR. 4. The present study provides evidence that BNP does not require the activity or influence of prostaglandins or NO for its sensitising effects on the BJR. We propose that natriuretic peptides act directly on cardiac afferents, in synergy with 5-HT(3) agonists, to facilitate the BJR.
Clinical and Experimental Pharmacology and Physiology 04/2011; 38(7):410-5. · 1.85 Impact Factor
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ABSTRACT: Arterial baroreflex function diminishes with age, but whether cardiopulmonary vagal reflexes are similarly altered with physiological aging has not been fully elucidated. In this study, predominantly cardiac high pressure mechanoreceptor-activated (ramp baroreflex) and cardiopulmonary chemoreceptor-activated (von Bezold-Jarisch reflex) vagal reflexes in conscious, instrumented rats were impaired by 30% to 40% (P<0.05) in 24-month-old (n=12) compared with 6-month-old rats (n=12). To determine whether this is a restorable deficit, the influence of atrial natriuretic peptide (ANP), either by infusion or blockade of its breakdown, was studied. ANP infusion was previously shown to enhance Bezold-Jarisch reflex and ramp baroreflex bradycardia in young adult rats. The present study confirmed that vagal reflex augmentation by ANP (50 pmol/kg per minute) also occurs in old rats (increased by 60+/-18% (Bezold-Jarisch reflex) and 91+/-15% (ramp baroreflex; P<0.05). Direct vagal stimulation in anesthetized animals showed that the target for ANP was not the cardiac vagus itself in old rats (n=7), although in young rats only, we confirmed the published finding that ANP enhances vagal bradycardia (by 58+/-14%, n=7). Neutral endopeptidase 24.11 degrades ANP and several other peptides. The neutral endopeptidase inhibitor candoxatrilat (5 mg/kg per day IV for 7 to 9 days) restored vagal reflex bradycardia in old rats (n=6) to levels similar to those in young neutral endopeptidase inhibitor-treated rats (n=6). Impaired cardiopulmonary vagal reflex control of heart rate is thus a feature of normal aging, and this deficit may be ameliorated by either ANP infusion or chronic neutral endopeptidase inhibition.
Hypertension 09/2008; 52(4):696-701. · 6.21 Impact Factor
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ABSTRACT: The von Bezold-Jarisch reflex (BJR) is a vagally mediated chemoreflex from the heart and lungs, causing hypopnea, bradycardia, and inhibition of sympathetic vasomotor tone. However, cardiac sympathetic nerve activity (CSNA) has not been systematically compared with vasomotor activity during the BJR. In 11 urethane-anesthetized (1-1.5 g/kg iv), artificially ventilated rats, we measured CSNA simultaneously with lumbar sympathetic activity (LSNA) while the BJR was evoked by right atrial bolus injections of phenylbiguanide (0.5, 1.0, 1.5, and 2 microg). Nerve and heartbeat responses were analyzed by calculating normalized cumulative sums. LSNA and heartbeats were always reduced by the BJR. An excitatory "rebound" component often followed the inhibition of LSNA but never outweighed it. For CSNA, however, excitation usually (in 7 of 11 rats) outweighed any initial inhibition, such that the net response to phenylbiguanide was excitatory. The differences in net response between LSNA, CSNA, and heartbeats were all significant (P < 0.01). A second experimental series on seven rats showed that methyl atropine (1 mg/kg iv) abolished the bradycardia of the BJR, whereas subsequent bilateral vagotomy substantially reduced LSNA and CSNA responses, both excitatory and inhibitory. These findings show that, during the BJR, 1) CSNA is often excited, 2) there may be coactivation of sympathetic and parasympathetic drives to the heart, 3) divergent responses may be evoked simultaneously in cardiac vagal, cardiac sympathetic, and vasomotor nervous pathways, and 4) those divergent responses are mediated primarily by the vagi.
AJP Regulatory Integrative and Comparative Physiology 08/2007; 293(2):R714-20. · 3.34 Impact Factor
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ABSTRACT: Neutral endopeptidase (NEP, EC 3.4.24.11) metabolises endogenous vasoactive peptides that may protect against atherogenesis. Since NEP is found in the adventitia of arteries, we investigated the anti-atherogenic effects of chronic adventitial NEP inhibition.
Intimal hyperplasia of rabbit carotid arteries was induced by placement of soft, non-occlusive, peri-arterial silastic collars. NEP localisation was studied with autoradiography 7 and 14 days after collar placement. Vascular NEP was inhibited in vivo by local superfusion of one collared carotid artery with Candoxatrilat (50 pmol/h), for 7 days (n = 7). The contralateral collar was filled with saline vehicle. After 7 days, ring segments of collared and normal (proximal to the collar) arteries were obtained and in vitro functional measurements, immunohistochemical determination of the pro-atherogenic factor plasminogen activator inhibitor-1 (PAI-1), localization of macrophages and morphometric analyses were carried out.
Vascular NEP radiolabelled substrate binding, mainly in the media, was increased by approximately 50% after 7 days (n = 5; p < 0.05) and by approximately 300% after 14 days of collar placement (n = 5; p < 0.05). Compared with normal artery segments from the same animal, vehicle-filled collared sections displayed significantly impaired vasorelaxation to acetylcholine (endothelium-independent vasodilatation was preserved), increased PAI-1 immunostaining, macrophage accumulation and intimal thickening. In Candoxatrilat-treated collared arteries, vasorelaxation to acetylcholine was improved, along with reductions in PAI-1 levels, macrophage numbers and intimal area (all p < 0.05).
Enhancing the activity of local, endogenous peptides by adventitial inhibition of vascular NEP may protect against early atherogenesis. This is of particular relevance to using adventitial therapies to prevent intimal hyperplasia leading to restenosis.
Cardiovascular Research 07/2006; 71(1):179-88. · 6.06 Impact Factor
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ABSTRACT: Elevated vascular plasminogen activator inhibitor-1 (PAI-1) levels are associated with atherosclerosis. In vitro, C-type natriuretic peptide (CNP) has anti-proliferative effects and inhibits the production of PAI-1 in cultured vascular cells. Whether CNP can affect PAI-1 in vivo, particularly in the setting of atherosclerosis, has not been reported.
Using the rabbit carotid arterial collar model of intimal hyperplasia (collar in place for 7 days), PAI-1 protein was compared in normal, vehicle (saline)-collared, and CNP-treated-collared arteries from the same animal. PAI-1 levels were measured by immunohistochemistry and densitometry and by Western blot. CNP was either infused into the peri-arterial space within one collar (10 fmol/h) or infused directly into the arterial lumen under one collar (100 pmol/h). In some rabbits (n=8), superoxide production in collared and normal artery segments was measured in vitro by chemiluminescence.
PAI-1 was present throughout the vascular wall. Endothelial PAI-1 was elevated in saline-collared arteries (approximately 16%, P<0.05; n=7 rabbits) compared with normal carotid segments. The collar induced both a neointima that contained PAI-1 and the accumulation of macrophages in the adventitia. Peri-arterial CNP reduced PAI-1 (P<0.05) in the endothelium (33%), adventitia (47%) and neointima (39%), compared with levels in the contralateral, saline-collared carotid artery, while macrophage infiltration was reduced. Elevated superoxide production in collared arteries was not altered by chronic in vivo treatment with CNP (n=8). Peri-arterial CNP treatment did not reduce intimal thickening. Intra-luminal CNP (n=6) reduced endothelial, neointimal and total vessel (Western blot) PAI-1, macrophage accumulation, and intimal thickening (all P<0.05).
CNP treatment of collared carotid arteries in vivo for 1 week suppressed endothelial and neointimal PAI-1, independently of intimal thickening. The CNP effects were not via superoxide. This is the first evidence that CNP inhibits activated PAI-1, in vivo.
Cardiovascular Research 06/2005; 66(3):574-82. · 6.06 Impact Factor
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Robyn L Woods
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ABSTRACT: 1. If one was to design a hormone to protect the heart, it would have a number of features shown by the cardiac natriuretic peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). These hormones are made in cardiomyocytes and are released into the circulation in response to atrial and ventricular stretch, respectively. Atrial natriuretic peptide and BNP can reduce the preload and after-load in normal and failing hearts. They reduce blood volume over the short term by sequestering plasma and over the longer term by promoting renal salt and water excretion and by antagonizing the renin-angiotensin-aldosterone system at many levels. Each of these actions affords indirect benefit to a volume- or pressure-threatened heart. 2. Recent studies have identified additional modes of action of the natriuretic peptides that may also confer cardioprotective benefits, especially in heart disease. The emerging findings are: (i) that ANP and BNP antagonize the cardiac hypertrophic action of angiotensin II and continue working under conditions where endothelial nitric oxide (NO) function is compromised, such as in the presence of high glucose in diabetes; (ii) they potentiate the bradycardia caused by inhibitory ('autoprotective') cardio-cardiac reflexes; and, furthermore, (iii) BNP can suppress cardiac sympathetic nerve activity in humans, including those with heart failure. Thus, it appears that natriuretic peptides can shift sympathovagal balance in a beneficial direction (away from the sympathetic). The vagal reflex and antihypertrophic actions of the peptides are mediated by particulate guanylyl cyclase (pGC) natriuretic peptide receptors. 3. The multiple synergistic actions of the natriuretic peptides make them and their pGC receptors attractive targets for therapy in heart disease. Encouragingly, exogenous natriuretic peptides remain effective even when endogenous peptide levels are raised, as is the case in heart failure. They also remain effective in disease states where other protective mechanisms, such as the NO system, have become ineffective, offering yet further encouragement for the therapeutic use of the natriuretic peptides.
Clinical and Experimental Pharmacology and Physiology 12/2004; 31(11):791-4. · 1.85 Impact Factor
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ABSTRACT: While atrial and B-type natriuretic peptides (ANP and BNP) have been shown to enhance reflex responses attributed to cardiac vagal afferents, their effects on arterial baroreceptor reflex function remain controversial. The actions of C-type natriuretic peptide (CNP) in this regard are unknown. To clarify their actions on arterial baroreflexes, we tested whether i.v. infusions of ANP, BNP or CNP at 10 pmol kg(-1) min(-1) modified the steady-state mean arterial blood pressure-heart rate (MAP-HR) relationship in conscious sheep. At this dose, all three natriuretic peptides are known to enhance the cardiac chemoreflex response to phenylbiguanide (Bezold-Jarisch reflex). Sigmoid MAP-HR relationships were constructed from the steady-state responses to alternating injections of vasopressor (phenylephrine, 1-15 microg kg(-1)) and vasodepressor agents (nitroprusside, 1-15 microg kg(-1)) in the absence and presence of infused ANP, BNP or CNP (tested in random order at least 1 week apart). No parameter of the steady-state baroreflex relationship was significantly altered by infusion of any of the three natriuretic peptides. We conclude that in conscious sheep, normal arterial baroreceptor-HR reflex function prevails in the presence of moderate doses of ANP, BNP or CNP.
Experimental Physiology 12/2004; 89(6):709-15. · 3.21 Impact Factor
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ABSTRACT: Atrial natriuretic peptide (ANP) enhances cardiac vagal baroreflexes in normotensive animals. In spontaneously hypertensive rats (SHRs) this effect of ANP was absent. The reflex actions of ANP were preserved if hypertrophy was completely prevented in SHRs. However even a small amount of cardiac hypertrophy, with no hypertension, in SHRs was accompanied by a loss of the reflex bradycardic actions of ANP. In the present study, we investigated whether pathophysiological cardiac hypertrophy, induced by one-kidney, one-clip renovascular hypertension (1K-1C; n = 6), or physiological cardiac hypertrophy induced by chronic spontaneous, wheel-running exercise training (n = 7), similarly prevented vagal reflex actions of ANP. Cardiac baroreceptor-activated bradycardia was measured during rapid ramp increases ( approximately 5 s) in blood pressure after bolus doses of methoxamine or vehicle in conscious, chronically instrumented rats during infusions of ANP (50 pmol kg(-1) min(-1)). Compared with uninephrectomised control rats (n = 10), rats with 1K-1C had cardiac hypertrophy (approximately 55% increase in left ventricle:body weight (LV:BW) ratio; P < 0.05) and blunted vagal baroreflex gain (-0.93 +/- 0.18 versus-0.50 +/- 0.13 beats min(-1) mmHg(-1); P < 0.05). ANP did not augment baroreflex function in 1K-1C. Compared with their sedentary controls (n = 7), exercise-trained rats with cardiac hypertrophy ( approximately 20% increase LV:BW ratio; P < 0.05) also had blunted ramp baroreflex bradycardia (-1.28 +/- 0.23 versus-0.57 +/- 0.09 beats min(-1) mmHg(-1); P < 0.05). In contrast, ANP more than doubled baroreflex bradycardia in exercise-trained rats (P < 0.05). The aetiology of cardiac hypertrophy therefore influenced whether ANP retained its vagal baroreflex enhancing properties.
Experimental Physiology 07/2004; 89(4):445-54. · 3.21 Impact Factor
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ABSTRACT: Stimulation of cardiomyocyte guanosine 3',5'-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by high-glucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [(3)H]phenylalanine incorporation and atrial natriuretic peptide and beta-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.
Diabetes 10/2003; 52(9):2389-95. · 8.29 Impact Factor
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ABSTRACT: Atrial natriuretic peptide (ANP) prevents hypertrophy of neonatal cardiomyocytes. However, whether this effect is retained in the adult phenotype or if other members of the natriuretic peptide family exhibit similar antihypertrophic properties, has not been elucidated.
Our objective was to examine whether the natriuretic peptides protect against adult cardiomyocyte hypertrophy in vitro.
Adult rat cardiomyocytes were incubated with angiotensin II (Ang II)+/-ANP, B-type (BNP) or C-type (CNP) natriuretic peptides for determination of [3H]phenylalanine incorporation, c-fos mRNA expression and cyclic GMP. The effects of 8-bromo-cyclic GMP (cyclic GMP analogue), HS-142-1 (particulate guanylyl cyclase inhibitor) and KT5823 (cyclic GMP-dependent protein kinase inhibitor) were also investigated.
Ang II-stimulated increases in markers of hypertrophy, [3H]phenylalanine incorporation (to 136+/-3% of control, n=9) and c-fos mRNA expression (4.3+/-1.4-fold, n=5), were completely prevented by each of ANP, BNP or CNP. This protective action was accompanied by increased cardiomyocyte cyclic GMP. Inhibitory actions on [3H]phenylalanine incorporation were mimicked by 8-bromo-cyclic GMP, and were abolished by HS-142-1. KT5823 blocked the response to BNP and CNP, but not to ANP.
ANP prevents hypertrophy of adult rat cardiomyocytes. This protective action is shared by BNP and CNP and involves activation of particulate guanylyl cyclase receptors. Antihypertrophic effects of BNP and CNP are mediated through cyclic GMP-dependent protein kinase, but ANP can activate additional pathways independent of cyclic GMP to prevent adult cardiomyocte hypertrophy. These novel findings are of interest particularly since BNP appears to exert antifibrotic rather than antihypertrophic actions in vivo, while CNP is thought to act at least in part via the endothelium.
Cardiovascular Research 03/2003; 57(2):515-22. · 6.06 Impact Factor
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ABSTRACT: Atrial natriuretic peptide (ANP) potentiates vagal cardiopulmonary reflexes due to chemosensory (Bezold-Jarisch [B-J] reflex) or mechanosensory (ramp baroreflex) activation. The ANP receptor mediating these actions is unknown. We examined the role of particulate guanylyl-cyclase (pGC) receptors in ANP-induced enhancement of cardiopulmonary vagal reflexes. Cardiopulmonary baroreceptor reflex function was assessed by bradycardic responses to ramp blood pressure rises after rapid intravenous methoxamine (100 micro g/kg bolus dose). The B-J reflex was evoked by 3 intravenous doses of serotonin (1 to 10 micro g/kg). In conscious, chronically instrumented rats (n=9), these tests were performed on each animal during randomized infusions of rat ANP (150 ng/kg per minute IV), saline (270 micro L/h IV), the pGC receptor antagonist HS-142-1 (3 mg/kg IV), or combined HS-142-1+ANP treatment. HS-142-1 alone attenuated normal B-J reflex (by 33+/-8%, P<0.05) but not ramp baroreflex responses. As we showed previously, ANP enhanced baroreflex and B-J reflex bradycardia (by approximately 140% and approximately 30%, respectively, P<0.05), compared with saline infusion. These ANP effects were completely blocked by HS-142-1, demonstrating that the cardiopulmonary vagal reflex actions of ANP occurred through pGC natriuretic peptide receptors. Additionally, we have provided evidence for the first time that pGC natriuretic peptide receptors are essential for the full expression of the B-J reflex but not for that of cardiopulmonary vagal baroreflexes. This tonic interaction between pGC natriuretic peptide receptors and cardiopulmonary chemosensitive receptors may be important during pathophysiological activation of B-J reflex, such as with myocardial infarction.
Hypertension 02/2003; 41(2):279-85. · 6.21 Impact Factor
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ABSTRACT: The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3'5'-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 micromol/L) against Ang II (1 micromol/L)-induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 micromol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)-induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 micromol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 micromol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.
Hypertension 11/2002; 40(4):498-503. · 6.21 Impact Factor
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ABSTRACT: Previous findings indicate that atrial natriuretic peptide (ANP) enhances the reflex bradycardia arising from stimulation of cardiac mechanoreceptors and chemoreceptors, but not that from arterial baroreceptors. The present study tests this proposal by examining the effect of ANP on these reflexes in six chronically sinoaortic-denervated (SAD), and eight sham-operated (sham), conscious rats. Arterial baroreceptor-heart rate (HR) reflex function was examined by constructing full-range steady-state blood pressure (BP)-HR curves using alternating doses of pressor (methoxamine, 2-100 microg/kg) and depressor (nitroprusside, 1-50 microg/kg) agents. Nonarterial baroreceptor reflex function was assessed by the 'ramp' bradycardic response to the rapid BP rise after i.v. methoxamine (100 microg/kg bolus dose). The cardiopulmonary chemoreflex was evoked by i.v. injections of serotonin (1-20 microg/kg). These three tests were performed on each rat during infusions, in random order, of rat ANP (150 ng/kg/min i.v.) and saline vehicle. The ability of ANP to significantly enhance ramp reflex bradycardia was not diminished in SAD compared with sham rats (+54 +/- 12% vs. +42 +/- 15%, respectively). ANP also significantly enhanced cardiopulmonary chemoreflex bradycardia in both groups (+60 +/- 15% in SAD, +40 +/- 8% in sham). Neither the normal steady-state BP-HR response in sham rats nor the small residual response in SAD rats was enhanced by ANP (-1 +/- 7% in sham, -11 +/- 8% in SAD). We conclude that ANP enhances reflex bradycardias of nonarterial, probably cardiac mechanoreceptor, origin.
Autonomic Neuroscience 06/2002; 97(2):89-98. · 1.86 Impact Factor
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ABSTRACT: Since the pathophysiology of natriuretic peptides in chronic heart failure (HF) is not uniform, we hypothesized that atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) may also have differential effects in acute HF. Our aim was to compare the haemodynamic actions of ANP with BNP, using a classical vasodilator as the control, in greyhound dogs with acute pacing-induced HF.
The right ventricles of eight anaesthetized dogs were paced (193 +/- 4 bpm) until pulmonary capillary pressure (PCP) increased to approximately 15 mmHg. In each animal, according to a randomized within-animal design, haemodynamic responses to equimolar (10 pmol/kg per min) infusions of ANP and BNP were compared with those to sodium nitroprusside (SNP).
Acute pacing alone increased PCP from 6.6 +/- 0.7 to 15.7 +/- 0.3 mmHg, right atrial pressure (RAP) from 1.9 +/- 0.5 to 4.0 +/- 0.6 mmHg, and systemic vascular resistance (SVR) from 1706 +/- 110 to 2179 +/- 106 dyne s/cm5, and reduced cardiac output (CO) from 4.1 +/- 0.4 to 2.5 +/- 0.2 l/min and arterial pressure from 86.1 +/- 2.4 to 74.5 +/- 2.1 mmHg (all P < 0.01). BNP and SNP improved haemodynamics similarly (CO +13 +/- 3% and +9 +/- 5%; PCP -12 +/- 2% and -12 +/- 2%; RAP -28 +/- 9% and -34 +/- 6%, SVR -15 +/- 3% and -11 +/- 3%, all P < 0.01, except CO with SNP, not significant), but effects of BNP on preload outlasted those of SNP. By contrast, ANP did not improve the haemodynamics. Haematocrit was significantly higher during BNP infusion than with ANP (P < 0.05) or with SNP (P < 0.001).
The haemodynamic responses to exogenous BNP and ANP in acute heart failure were strikingly different. Whereas ANP actions were blunted, BNP response was preserved. Hypothetically, the presence of a putative BNP receptor may explain this finding.
Journal of Hypertension 06/2002; 20(6):1195-201. · 4.02 Impact Factor
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ABSTRACT: Atrial and C-type natriuretic peptides (ANP and CNP), acting through different receptors, have antiproliferative effects in vitro. Beneficial effects of CNP in vivo on early atherosclerosis have been described, but it is not known if ANP is antiproliferative in vivo. In the present study, the effects of chronic in vivo ANP were tested and compared with CNP on endothelial dysfunction and intimal thickening caused by peri-arterial collars.
Non-occlusive collars were placed bilaterally around the common carotid arteries of rabbits. One collar was filled with saline vehicle. The contralateral collar was filled with ANP or CNP (1 or 10 microM, n = 5-7) with slow replacement of peptide via mini-pump (1 or 10 fmol/h).
After 7 days, endothelium-dependent vasorelaxation in saline-collared arteries was 33 +/- 3% of maximum [averaged over 0.03-1 muM acetylcholine (ACh)] compared to 64 +/- 2% in normal (uncollared) arteries (p < 0.05, n = 23). In vivo ANP restored the ACh relaxation to normal (e.g., 57 +/- 6%, 1 microM ANP), similar to effects seen with CNP in vivo. Endothelium-independent vasorelaxation of collared-vessels was not altered by either peptide. Intimal hyperplasia induced by the collars was not prevented by peri-arterial natriuretic peptides. In additional rabbits (n = 6), CNP (100 pmol/h) given directly into the lumen of collared carotid arteries for 7 days reduced neointima formation by 16 +/- 5% (p < 0.05), whereas ANP given intraluminally (100 pmol/h; n = 6) did not.
The more potent actions of CNP on vascular smooth muscle cell migration and proliferation (established in vitro) may explain differences between the peptides on intimal hyperplasia in vivo. The major hallmark of atherosclerosis and restenosis, endothelial dysfunction, was prevented by chronic, peri-arterial administration of ANP or CNP.
Journal of Vascular Research 42(2):101-10. · 2.65 Impact Factor
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ABSTRACT: 1. The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2. Baseline plasma BNP levels were 15.0 +/- 2.3 fmol/mL and rose approximately 10-fold to 159 +/- 23 fmol/mL after 20-25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 +/- 0.14 min and a terminal half-life of 301 +/- 85 min. The metabolic clearance rate of BNP was 2.29 +/- 0.34 L/min. 3. The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10-15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4. These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered.
Clinical and Experimental Pharmacology and Physiology 30(5-6):369-75. · 1.85 Impact Factor
