Nitrogen oxide blockade does not aggravate the endothelin-1-induced myocardial ischemia and release of purine metabolites from the dog heart

Increased intrapericardial levels of endothelin-1 (ET-1) induce myocardial ischemia and concomitant release of the purine metabolites adenosine (ADO), inosine (INO) and hypoxanthine (HXA) into the pericardial fluid. However, the potential modulatory role of nitrogen monoxide in compensating the ET-1-induced ischemic stress is not fully elucidated. The pericardial elevations of purine metabolite concentrations in the pericardial fluid after ET-1 administration (150 pmol/kg intrapericardially) were measured in the in situ dog heart with (n = 6) or without (n = 5) systemic nitrogen monoxide synthase blockade (30 mg/kg (G)-nitro-L-arginine methyl ester, followed by 6 mg/min intravenously). After control sampling, three consecutive pericardial infusate samples (ET1, ET2, ET3) were obtained for purine metabolite determinations (high-performance liquid chromatography-ultraviolet). It was found that intrapericardial ET-1 elevated the pericardial purine metabolite concentrations significantly in both groups. No significant differences were detected between the control and (G)-nitro-L-arginine methyl ester-treated groups in ischemic changes of pericardial ADOmax (+3.27 +/- 1.13 microM versus +1.84 +/- 0.56 microM), INOmax (+15.21 +/- 2.3 microM versus +12.09 +/- 4.04 microM) and HXAmax (+16.34 +/- 2.98 microM versus +17.09 +/- 5.22 microM) levels and in the maximal ST elevations (0.43 +/- 0.05 mV versus 0.61 +/- 0.08 mV). The hemodynamic variables did not change with ET-1 administration. In conclusion, systemic nitrogen monoxide synthase blockade does not aggravate the ET-1-induced acute myocardial ischemia and the release of purine metabolites, suggesting that endogenous nitrogen monoxide is not a supplementary factor to purine metabolites in this type of coronary adaptive responses.     

Incremental importance of peak-exercise plasma levels of endothelin-1 and natriuretic peptides in chronic heart failure

Chronic heart failure (CHF) studies investigating the clinical, hemodynamic, and therapeutic importance of endothelin-1 (ET-1), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) are largely based on resting plasma levels, which may vary with prior exertion and postprandial status. This study investigated the importance of peak-exercise plasma levels of ET-1, ANP, and BNP in the assessment of left ventricular (LV) systolic function. Thirty-six male-patients ages 58 +/- 10 (mean +/- SD ) with NYHA class I-IV CHF due to coronary artery disease or idiopathic dilated cardiomyopathy were enrolled. LV systolic function was assessed by echocardiography and radionuclide ventriculography. Resting and peak cardiopulmonary exercise venous blood sampling and treadmill exercise testing were performed in the fasting state. Resting plasma levels of ET-1, ANP, and BNP were elevated compared with reference laboratory normal values. Exercise induced significant (p < 0.0001) increase in plasma levels of ET-1, ANP, and BNP. On univariate analysis peak-exercise plasma levels of ET-1, ANP, and BNP were more closely related to echocardiographically determined LV end-diastolic diameter and end-systolic diameter than their resting values. Multiple step-wise regression models identified resting and peak-exercise plasma levels of ET-1 and ANP but only the resting BNP as independent predictors of LV dimensions and systolic function. Peak exercise plasma levels of ANP and ET-1 are potentially more reliable and important than their resting levels as markers of LV systolic dysfunction and LV dimensions in patients with heart failure.     

Intrapericardial adenine nucleosides induce elevation of endothelin-1 concentration in the pericardial space of the dog heart

The adenine nucleosides, adenosine (ADO) and inosine (INO), and the endothelin-1 (ET-1) play an important role in the regulation of coronary and myocardial functions. The pericardial fluid accumulates these regulatory agents and reflects well their levels in the myocardial interstitium. This offers a possibility to examine the local adenine nucleoside-endothelin interactions in heart tissue. We have previously demonstrated that increased levels of intrapericardial (i.p.) ET-1 enhanced significantly the adenine nucleoside concentrations of the pericardial fluid samples. In this study the effects of i.p.-administered ADO and INO were investigated on the pericardial concentrations of ET-1 in the in situ dog heart. The ET-1 concentrations were determined (enzymelinked immunosorbent assay) in the samples obtained from the pericardial fluid and from the arterial plasma before and after i.p. administration of increasing doses of ADO (10, 100 and 1000 muM, n = 8) and INO (1, 10 and 100 mM, n = 8). Standard hemodynamic variables were recorded continuously. We found that i.p. ADO and INO induced dose-dependent increases of pericardial ET-1 levels after a 15-minute incubation period in pericardial (ET-1max,ADO, +121 +/- 26%, P < 0.02; and ET-1max,INO, +84 +/- 27%, P < 0.05) but not in the plasma samples. The i.p. nucleosides elicited slight but characteristic alterations in the heart rate and ventricular contractility (dP/dt). The results suggest that the pericardial adenine nucleosides interact with the myocardial ET-1 and this effect may be provoked from, and can also be detected in, the pericardium.     

The effects of angiotensin II on circulating levels of natriuretic peptides.

We have evaluated the differential release of A, B and C-type natriuretic peptides in response to incremental doses of angiotensin II (2, 4 and 6 ng kg-1 min-1). Baseline plasma concentrations of ANP (5.99 +/- 0.74 pmol 1-1) were significantly (P < 0.05) higher than BNP (1.53 +/- 0.48 pmol 1-1) or CNP (0.41 +/- 0.11 pmol 1-1). Angiotensin II infusion caused a significant (P < 0.05) increase in plasma ANP to 53.76 +/- 17.3 pmol 1-1 at 6 ng kg-1 min-1. Plasma concentrations of BNP and CNP were not significantly affected by angiotensin II. Arterial blood pressures and systemic vascular resistance increased (P < 0.001) in response to angiotensin II infusion. Thus, ANP, unlike BNP or CNP, is released acutely in response to the pressor stimulus of angiotensin II. This may represent a dissociation in release of the natriuretic peptides, in terms of short and long term responses to activation of the renin-angiotensin system.     

Cardiovascular responses to catecholamines and interactions with endothelin-1 and adenine nucleosides in the pericardium of the dog heart

The pericardial fluid may accumulate endogenous regulatory agents, such as catecholamines, endothelin or adenine nucleosides. However, very little information is available on the cardiovascular effects of intrapericardial (i.p.) catecholamines and their interaction with the endogenous endothelins and adenine nucleosides. The cardiovascular effects of increasing doses of i.p.- administered dopamine boluses (0.06-8 micromol/kg, n = 8) were studied in the in situ canine heart: systemic blood pressure, heart rate and left ventricular dP/dt were recorded, and pericardial infusate samples were obtained to measure the changes in endothelin-1 (ET-1), adenosine and inosine levels (enzyme-linked immunosorbent assay and high-performance liquid chromatography methods, respectively). The responses to i.p. dopamine were compared with the effects of i.p. norepinephrine boluses (0.004-0.5 micromol/kg, n = 8). Dopamine elicited dose-dependent increases of heart rate (P < 0.01), and the highest dose of dopamine resulted in significant elevation in dP/dt and blood pressure (P < 0.01) with a nearly twofold increase of i.p. ET-1 (from 14.3 +/- 0.1 pg/mL to 26.1 +/- 0.1 pg/mL, P < 0.02) and a more than threefold augmentation of i.p. adenosine (from 2.9 +/- 0.5 microM to 11.1 +/- 3.0 microM, P < 0.05), but not of inosine levels. Similar responses were obtained with i.p. norepinephrine. The results confirm that i.p. catecholamines exert significant hemodynamic effects and modulate ET-1 and adenosine release from the heart. However, the pattern of catecholamine actions initiated from the pericardium may characteristically differ from that of intravascular ones.     

风湿性心脏病患者心包液和血液中心钠素与心功能的关系

目的 探讨心包液和血液中心钠素含量与风湿性心脏病患者心脏功能的关系.方法 风湿性心脏病需行瓣膜置换术患者33例,术中留取心包液和静脉血,利用放射免疫分析方法检测心包液和血浆中心钠素的含量,分析其与心功能的关系.结果 患者心包液中含有高浓度的心钠素,明显高于血浆中的水平[(0.61±0.49)μg/L比(0.45±0.18)μg/L,P=0.046];射血分数＜50%的患者心包液中心钠素的含量明显高于射血分数≥50%的患者[(0.98±0.81)μg/L比(0.48±0.18)μg/L].结论 人心包液中的心钠素可能和血液中的心钠素一样参与心功能的调节.

Abstract：

Objective To investigate the relationship between the cardiac function and the levels of atrial natriuretic peptide (ANP)in pericardial fluid and plasma in patients with rheumatic heart diseases. Methods The study involved 33 patients undergoing open heart surgery for either heart valvuloplasty or valve replacement. ANP concentrations in the plasma, pericardial fluid, and pericardial tissues were measured by using of radioimmunoassay (RIA). Results The level of ANP in human pericardial fluid was significantly higher than that in the plasma (0.614±0.486 ng/ml vs 0. 451 ±0. 184 ng/ml, P =0. 046). The ANP concentration in pericardial fluid of patients with left ventricular ejection fraction(LVEF) ＜ 50% was much higher than that of patients with LVEF ≥50%. Conclusion The ANP in the pericardial fluid may be involved in the deterioration of cardiac function in patients with rheumatic heart diseases.     

Neurohumoral changes in patients with left ventricular dysfunction following acute myocardial infarction and the effect of nitrate therapy: a randomized, double-blind, placebo-controlled long-term study

BACKGROUND: Several neurohumoral mechanisms involved in cardiovascular regulation are activated in the failing heart, but only limited information is available regarding the influence of long-term nitrate therapy. MATERIALS AND METHODS: This was a double-blind, randomized comparison of isosorbide-5-mononitrate (IS-5-MN), 60 mg given orally, once daily for 11 months to patients (n = 47) with left ventricular (LV) dysfunction following acute myocardial infarction (AMI). Forty-five patients received placebo. All patients received ramipril.Plasma natriuretic peptides (atrial [ANP] and brain [BNP] natriuretic peptide), epinephrine, norepinephrine (NEPI), antidiuretic hormone, aldosterone (Aldo), renin activity (PRA), substance P, neuropeptide Y-like immunoreactivity, calcitonin gene-related peptide, and vasoactive intestinal peptide were measured at baseline and at the end of the treatment period. Clinical, echocardiographic, and hemodynamic data were also obtained. RESULTS AND CONCLUSIONS: Chronic nitrate therapy does not significantly affect the neurohumoral status in patients with LV dysfunction after AMI, apart from a decrease in ANP. Some hormones are more closely associated with diastolic dysfunction/increased volume load (ANP and BNP) and others are more closely associated with systolic dysfunction (PRA, NEPI, Aldo). There is a temporal dissociation of these 2 groups of hormones 1 year post infarction: ANP and BNP decrease, whereas NEPI and Aldo show a slight increase. BNP levels do not reflect all important pathophysiologic mechanisms in heart failure. Consequently, the use of other neurohormonal factors than BNP for monitoring of heart failure therapy should be explored.     

Bioactivity of natriuretic peptide coinfusions; no evidence for unique effects of BNP in conscious sheep

Few studies have addressed the possibility that brain natriuretic peptide (BNP) possesses a profile of bioactivity that is distinct from that of atrial natriuretic peptide (ANP). Accordingly, we assessed the biologic actions of BNP in the setting of maximal or near-maximal ANP-induced biologic activity. Background ANP infusions (7.5 pmol/kg/min) administered on all study days, increased plasma ANP (approximately 120 pM) and cyclic guanosine monophosphate (GMP) levels (approximately 40 nM), and induced significant decreases in arterial pressure and cardiac output associated with increased heart rate, hematocrit, diuresis, and natriuresis. Increasing the dose twofold after 1 h (experiment 1, n = 5) showed no enhancement of these actions despite a further twofold increase in plasma ANP and cyclic GMP (both p values <0.001). Addition of low-dose BNP (2 pmol/kg/min) after 1 h background infusion (experiment 2, n = 8), increased plasma BNP levels (30 pM, p < 0.001) but caused no significant effects on the hemodynamic, renal, or hormonal indices measured. In conclusion, in the setting of maximal hemodynamic, renal, and endocrine responses to high-dose background infusions of ANP, coinfusion of BNP exhibits no enhancement of, or additional, biologic activity. This study provides no evidence for unique short-term biologic actions of ANP and BNP.     

EFFECT OF EXERCISE ON PLASMA ADRENOMEDULLIN AND NATRIURETIC PEPTIDE LEVELS IN MYOCARDIAL INFARCTION

1. We investigated the effect of exercise on plasma adreno-medullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects. 2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise. 3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P < 0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01). 4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.     

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.     

Increased plasma concentration of natriuretic peptides by selective beta1-blocker bisoprolol

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P < 0.001) by 93 +/- 88% (mean +/- SD) and 148 +/- 117%, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 +/- 45%, and increments in ANP and Nt-ANP were related (r =0.77, P < 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the beta-blocker-induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.     

DIFFERENTIAL REGULATION OF NATRIURETIC PEPTIDE GENES IN INFARCTED RAT HEARTS

1. We investigated the regulation of the atrial natriuretic peptide and brain natriuretic peptide genes in a rat model of myocardial infarction induced by isoproterenol (IP rat) and in a rat model of cardiac hypertrophy induced by aorto-caval shunt (AC shunt rat). 2. Brain natriuretic peptide (BNP) mRNA levels in atria were significantly higher in IP rats than in controls at 18 h after the administration of isoproterenol, but no significant increases were observed in atrial natriuretic peptide (ANP) mRNA expression levels at any time point examined. In the ventricles, the BNP mRNA levels peaked at 18 h after isoproterenol administration, whereas ANP mRNA levels gradually increased until 3 days after isoproterenol administration. 3. The BNP mRNA levels in both atria and ventricles were significantly increased at 1 day after the introduction of aorto-caval shunt, while the ANP mRNA levels were not. 4. Plasma BNP levels were closely correlated with left ventricular weight per bodyweight, in both IP rats and AC shunt rats. 5. These results suggest the differential regulation of ANP and BNP genes in both the atria and ventricles in these two pathological models.     

Renal effects of prolonged intrarenal infusions of angiotensin II and atrial natriuretic peptide in sheep.

Angiotensin II (AngII) and atrial natriuretic peptide (ANP) are two hormones that have antagonistic effects on volume and pressure regulation. Plasma levels of both hormones are elevated in sheep pregnancy. However, during pregnancy, volume expansion occurs despite elevated plasma ANP, implying an overriding role of AngII. In addition to counteracting the effects of ANP on the physiological level, AngII also may act on the receptor level. Therefore this study was designed to investigate the hemodynamic and renal effects of ANP and AngII separately and to define their selective effects on the renal natriuretic peptide receptor types in the various segments of the nephron. Eight unilaterally nephrectomized nonpregnant sheep received separately for 10 days, low doses of AngII (1 ng/kg/min) and ANP (0.5 ng/kg/min) directly infused into the renal arteries to avoid systemic effects. Intrarenal AngII infusion decreased sodium excretion (UNaV) from 111+/-11 to 36 +/-8 and 45+/-6 mmol/day (p<0.05) on days 3 and 8-10, respectively. Mean arterial pressure (MAP) increased from 94 +/-6 mm Hg to a maximum of 107+/-8 mm Hg on day 5 of infusion and stabilized at 101+/-7 mm Hg on days 8-10 (p<0.05). Intrarenal ANP infusion significantly increased UNaV on day 1 from 93+/-9 to 188+/-20 mmol/day (p<0.05), followed by sodium retention on days 4-6 (average, 60+/-13 mmol/day; p<0.05). UNaV again increased above control levels on days 8-10 to an average level of 111+/-15 mmol/day. MAP decreased from 99+/-4 to 90+/-5 mm Hg (p<0.05) on days 1-3, and remained lower than control throughout the infusion period. The kidneys were collected at control nephrectomy and at the end of infusion. The natriuretic peptide receptors were characterized by competitive-binding radioreceptor assays on glomerular, outer medullary, and inner medullary membranes. AngII infusion increased the dissociation constant (Kd) of inner medullary natriuretic peptide receptors from 186 +/-11 to 267+/-22 pM (p<0.05), and ANP infusion decreased maximal binding capacity (Bmax) of inner medullary receptors from 134+/-10 to 89+/-15 fmol/mg protein (p<0.05). Glomerular and outer medullary natriuretic peptide receptors were not affected by either AngII or ANP infusion. In conclusion, AngII stimulates antinatriuresis and counteracts the hemodynamic and renal effects of ANP in part by downregulating the renal inner medullary natriuretic peptide receptors.     

Atrial and brain natriuretic peptides share binding sites in the kidney and heart

We examined the distribution of binding sites for atrial natriuretic peptide (ANP) and the recently discovered brain natriuretic peptide (BNP) in rat kidney and heart by receptor autoradiography. In frozen kidney sections, both 125I-ANP and 125I-BNP exhibited localized binding to cortical glomeruli. The binding of each radiolabeled peptide was abolished by inclusion of either excess (1 microM) unlabeled ANP or excess unlabeled BNP, suggesting that ANP and BNP share cortical glomerular binding sites. In frozen cardiac sections, ANP and BNP binding sites were localized to the endothelium of the endomural channels and endocardium. As was the case for kidney, binding of each peptide at these sites was abolished by the presence of excess unlabeled ANP or BNP, suggesting that these natriuretic peptides share binding sites in the heart as well. To explore further the possibility that ANP and BNP utilize the same receptor(s), we performed competitive binding experiments using cultured pulmonary artery endothelial (CPAE) cells. ANP and BNP competitively displaced one another with equivalent IC50 values from CPAE cell binding sites. Furthermore, both ANP and BNP elevated the levels of cGMP, a putative second messenger for ANP, in these cells. These data are consistent with the observation that BNP, like ANP, causes a natriuresis and diuresis in rats, and suggest that BNP may possess other biological activities known for ANP.     

Effects of the angiotensin-converting enzyme inhibitor alacepril on exercise capacity and neurohormonal factors in patients with mild-to-moderate heart failure

1. Alacepril is a long-acting, sulphydryl-containing angiotensin-converting enzyme inhibitor. Data are limited regarding the effects of alacepril on exercise tolerance in patients with chronic heart failure (CHF). The aim of the present study was to determine the effects of chronic alacepril treatment on exercise capacity and neurohormones in patients with CHF. 2. The effects of 12 weeks treatment with alacepril on clinical, echocardiographic and cardiopulmonary exercise variables were studied in 18 CHF patients (mean age: 63 +/- 2 years; New York Heart Association (NYHA) class I n = 6, class II n = 10, class III n = 2) in a cross-over fashion. Resting levels of plasma noradrenaline, renin-angiotensin system activity and natriuretic peptides were evaluated. 3. Treatment with alacepril significantly improved NYHA functional class and decreased cardiothoracic ratio (60.1 +/- 2.0 vs 58.1 +/- 1.9% for baseline vs alacepril, respectively; P < 0.01). Cardiac dimensions by echocardiogram were decreased after alacepril therapy. Peak Vo2 (17.7 +/- 1.2 vs 19.5 +/- 1.3 mL/min per kg; P < 0.01) and anaerobic threshold (11.7 +/- 0.6 vs 13.2 +/- 0.9 mL/min per kg; P < 0.01) increased with alacepril treatment. Plasma noradrenaline and plasma angiotensin II levels were not altered, but plasma aldosterone (77.7 +/- 13.5 vs 51.7 +/- 9.7 pg/mL; P < 0.01), atrial natriuretic peptide (ANP; 86.5 +/- 20.3 vs 43.6 +/- 7.6 pg/mL; P < 0.05) and brain natriuretic peptide (BNP; 222.7 +/- 59.3 vs 117.7 +/- 34.3 pg/mL; P < 0.05) levels decreased after alacepril treatment. 4. These results suggest that treatment with alacepril improves functional status and exercise capacity in patients with mild-to-moderate CHF. Neurohormones were favourably influenced by alacepril therapy, with significant decreases in plasma aldosterone, ANP and BNP levels.     

Carvedilol enhances atrial and brain natriuretic peptide mRNA expression and release in rat heart

To clarify the role of the natriuretic peptide (NP) system in the myocardial protective effects of carvedilol, a beta-blocking agent, we investigated the effects of carvedilol on the NP system in the rat heart. After oral administration of carvedilol (low-dose group: 2 mg/kg/day, group C2; high-dose group: 20 mg/kg/day, group C20) for 1 week, plasma rat atrial NP (r-ANP), atrial mRNA levels of ANP, left ventricular mRNA of brain NP (BNP), NP receptor-A and NP receptor-C (NPR-C) (as a clearance receptor) were measured. Values were compared with those in vehicle-treatment rats (group V). The concentration of r-ANP was significantly higher in group C2 (135 +/- 9 pg/ml) and group C20 (161 +/- 11 pg/ml) than group V (75 +/- 6 pg/ml; both p < 0.01). ANP and BNP mRNA levels were significantly increased and NPR-C was significantly down regulated in group C2 (151 +/- 7, 120 +/- 8 and 78 +/- 7%, respectively, vs. group V) and group C20 (164 +/- 8. 133 +/- 7 and 72 +/- 8%, respectively, vs. group V) compared with group V (all p < 0.01). These results suggest that not only a high dose, but a low dose of carvedilol has the effect of increasing plasma ANP and BNP levels. This effect was closely related to the upregulation of ANP and BNP mRNA expression, and the down regulation of NPR-C mRNA expression in the heart. These mechanisms seem to account for a sizable portion of the protective effect of carvedilol for heart diseases.     

Acute actions of natriuretic peptides in coronary vasculature and ischaemic myocardium

The natriuretic peptides are a family of widely distributed polypeptide mediators that exert a range of actions in several body systems. In cardiovascular homeostasis, the endocrine roles of the cardiac-derived atrial and B-type natriuretic peptide (ANP and BNP) in regulating central fluid volume and blood pressure have been recognised for two decades. However, there is a growing realisation that natriuretic peptide actions go far beyond their endocrine effects and that local (autocrine/paracrine) regulatory actions within the heart and coronary vasculature may be of comparable importance, especially in disease states where tissue and circulating levels of the peptides rise markedly. In acute myocardial ischaemia, release of BNP occurs rapidly from ventricular myocardium, prompting speculation that the early activation of the natriuretic peptide receptor/cGMP signalling system may be an important autocrine/paracrine response in cardiac ischaemia. The autocrine/paracrine actions include inotropic effects, the acute regulation of coronary vascular tone and the attenuation of the susceptibility of myocardium to ischaemic injury. The effects of longer-term upregulation of natriuretic peptide expression in the heart could include the suppression of growth and proliferative responses in a variety of myocardial and vascular cells. In a variety of preparations, acute exposure of epicardial coronary arteries to pharmacological concentrations of natriuretic peptides evokes vasorelaxation, although in coronary microvessels, evidence for a vasorelaxant action of the peptides is less consistent. The mechanisms of the coronary vasorelaxant action are unclear but limited evidence suggests an endothelium-dependent component. In ischaemic myocardium, acute treatment with BNP prior to and during coronary artery occlusion exerts a markedly protective, concentration-dependent infarct-limiting action. This cytoprotective effect of the natriuretic peptide signalling pathway might conceivably represent an alternative endogenous salvage pathway in myocardium which is potentially exploitable therapeutically. Taken together, the acute actions of natriuretic peptides on the coronary vasculature and in myocardial ischaemia suggest a profile of activity that may be therapeutically beneficial in the management of patients with acute coronary syndromes.     

Effect of a hypocaloric diet on adrenomedullin and natriuretic peptides in obese patients with essential hypertension

We examined the effect of a hypocaloric diet on adrenomedullin (AM), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) in 12 obese patients with essential hypertension (age, 48-81 years; body mass index, 26-34 kg/m2). For the initial week, a standard diet of 2000 kcal/day was given, followed by 3 weeks of a hypocaloric diet of 850 kcal/day, with a constant intake of sodium. The patients lost 3.7 +/- 0.2 kg body weight during the hypocaloric diet period (p < 0.0001). The decrease in blood pressure during the study period was 10.3 +/- 3.6 mmHg systole (p = 0.017) and 4.2 +/- 3.2 mmHg diastole (NS). Plasma AM concentration was decreased significantly from 4.88 +/- 0.46 to 3.97 +/- 0.38 pmol/l by the hypocaloric diet (p = 0.004). Plasma ANP and BNP concentrations were also decreased significantly by the hypocaloric diet (p = 0.042 for each). These results demonstrate, for the first time, that plasma AM concentration as well as plasma ANP and BNP concentrations are decreased by a hypocaloric diet in obese patients with essential hypertension. These vasodilator peptides may act against further elevation in blood pressure in obese patients with essential hypertension.     

Natriuretic peptide-induced cyclic GMP accumulation in adult guinea-pig cerebellar slices.

1. Second messenger responses to natriuretic peptides were studied in guinea-pig cerebellar slices by use of radioactive precursors. 2. The rank order of potency of the different natriuretic peptides in generating [3H]-guanosine 3':5'-cyclic monophosphate (cyclic GMP) was atrial natriuretic peptide (ANP) > brain natriuretic peptide (BNP) >> C-type natriuretic peptide (CNP) with EC50 values of 19.5 +/- 8.8 nM for ANP and 169 +/- 41 nM for BNP. CNP induced [3H]-cyclic GMP accumulation only at concentrations greater than 1 microM. 3. An additive response to ANP (1 microM) was observed in the presence of the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA, 10 microM) or the soluble guanylyl cyclase activator, sodium nitroprusside (SNP, 100 microM) for [3H]-cyclic GMP accumulation. 4. ANP, BNP and CNP (all at 1 microM) failed to alter significantly either basal-, forskolin- (10 microM), isoprenaline- (100 microM), or NECA- (10 microM) induced [3H]-cyclic AMP generation. Natriuretic peptides also did not change the [3H]-cyclic AMP steady-state reached after 10 min of treatment with 10 microM forskolin. 5. Natriuretic peptides failed to elicit significant accumulation of [3H]-inositol phosphates at concentrations up to 10 microM. 6. These data are consistent with the presence of ANPA, rather than ANPB or clearance receptors (C-receptors), linked to second messenger cascades in guinea-pig cerebellar slices.