Brain natriuretic peptide and neutral endopeptidase inhibition in left ventricular impairment

Brain natriuretic peptide (BNP) is increased in left ventricular impairment and neutral endopeptidase (NEP) is involved in its metabolism. In random order, eight patients with left ventricular impairment received placebo, a 4-h infusion of human BNP (3.0 pmol/kg min), a single oral dose of NEP inhibitor (SCH 42495, 300 mg), and combined BNP and SCH 42495. Plasma BNP, cGMP, and cortisol were significantly increased by all three treatments (P < 0.05-P < 0.001). Combined treatment had a synergistic effect on plasma cGMP. The metabolic clearance rate of exogenous BNP was reduced (25%) by NEP inhibition. Endogenous plasma ANP was augmented more than BNP by NEP inhibition. Plasma aldosterone, unchanged during infusions, rose markedly after BNP and after the combined treatment (P < 0.05 for both). Urine sodium excretion, increased by NEP inhibition (P < 0.05) and by BNP (P = 0.05), was unchanged during combined treatment. Urine cGMP excretion was increased, whereas blood pressure was reduced by all active treatments (P < 0.05-0.01 for all). Heart rate increased only with combined treatment (P = 0.007). Plasma renin activity, norepinephrine, and cardiac output were unaffected. BNP infusion and NEP inhibition both induced significant hemodynamic and renal responses. The augmented hypotensive effect of combined treatments, and consequent fall in renal perfusion pressure, may underly the observed blunting of the natriuretic response that occurred despite greater than additive increments in plasma BNP, ANP, and cGMP.     

Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension

OBJECTIVE: Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS: We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS: CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION: These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.     

Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition

OBJECTIVES: We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND: The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS: HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS: FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS: We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.     

Enhanced natriuretic response to neutral endopeptidase inhibition in heart-transplant recipients

Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6+/-2.3 to 33.2+/-5.9 pmol/L, P<0.01; controls, 7.7+/-1. 2 to 10.6+/-2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650+/-370% versus 450+/-150%, P=0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9+/-2.0% versus 7.4+/-2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation.     

Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function

Objective—±Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.     

Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function

Objective—±Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects.Design—This was a single blind, randomised comparison of ±candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of ±candoxatrilat and two placebo doses on four consecutive days.Setting—A teaching hospital department of cardiology.Patients—Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37·5% and mean peak oxygen consumption was 20·4 ml/min/kg.Main outcome measures—Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after ±candoxatrilat and placebo.Results—±Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0·005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6·7 to 4·7 mm Hg (NS) and pulmonary artery wedge pressure fell from 9·2 to 6·7 mm Hg (p < 0·05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39·5 to 34·2 cm/s (p < 0·05), along with a non-significant rise in peak atrial filling velocity from 39·7–41·6 cm/s after ±candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1·04 to 0·87 (p < 0·05).Conclusions—±Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.     

Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function.

OBJECTIVE--+/- Candoxatrilat was used to raise atrial natriuretic factor (ANF) concentrations in patients with heart failure, and the effects on left ventricular systolic and diastolic function were studied to determine the contribution of peripheral and central mechanisms to the haemodynamic effects. DESIGN--This was a single blind, randomised comparison of +/- candoxatrilat and placebo in patients with mild heart failure. All patients received two intravenous doses of +/- candoxatrilat and two placebo doses on four consecutive days. SETTING--A teaching hospital department of cardiology. PATIENTS--Six men (mean age 52 years) with mild heart failure (New York Heart Association class II) due to ischaemic heart disease (four patients) or dilated cardiomyopathy (two patients) were included. Mean ejection fraction was 37.5% and mean peak oxygen consumption was 20.4 ml/min/kg. MAIN OUTCOME MEASURES--Plasma ANF concentrations, haemodynamic indices and left ventricular diastolic function measured by early to atrial filling rate (E:A ratio) with Doppler echocardiography were determined before and after +/- candoxatrilat and placebo. RESULTS--+/- Candoxatrilat caused a threefold rise of plasma ANF compared with placebo (p < 0.005), but there was no significant change in heart rate, blood pressure, or cardiac output. Mean right atrial pressure fell from 6.7 to 4.7 mmHg (NS) and pulmonary artery wedge pressure fell from 9.2 to 6.7 mmHg (p < 0.05). Doppler echocardiographic measurements of transmitral blood flow showed a significant fall in peak early left ventricular filling velocity from 39.5 to 34.2 cm/s (p < 0.05), along with a non-significant rise in peak atrial filling velocity from 39.7-41.6 cm/s after +/- candoxatrilat. The E:A ratio, a Doppler index of left ventricular diastolic function, fell from a mean of 1.04 to 0.87 (p < 0.05). CONCLUSIONS--+/- Candoxatrilat increased plasma ANF concentrations and reduced right atrial and pulmonary artery wedge pressures. No evidence of an improvement in left ventricular systolic or diastolic function was found, so the fall in preload was due to peripheral effects, either an increase in venous capacitance or a fall in circulating blood volume.     

老年慢性肾功能不全伴高血压病患者血浆中利钾尿肽与心钠素的变化

目的　探讨老年慢性肾功能不全 (CRF)伴高血压病患者血浆中利钾尿肽 (KP)与心钠素 (ANP)的变化。方法　选择老年CRFⅡ～Ⅲ期伴有高血压病的患者 2 6例 ;选择同期老年原发性高血压病 (EH) 1～ 3级高危患者而肾功能正常者 2 5例为对照组。应用超声心动图仪测量室间隔、左室后壁厚度、左室舒张末内径并计算出左室心肌重量 (LVM ) ;监测 2 4h动态血压 ,测出平均收缩压 (SBP)及舒张压 (DBP) ;同时测定血浆中的KP与ANP、血肌酐、尿素氮 ,进行统计学分析。结果　CRF组SBP ,DBP及LVM均高于EH组 ,而且KP ,ANP及KP ANP亦高于EH组 ,两组间有明显差异。结论　KP ,ANP可能在老年CRF患者伴发高血压的发生及发展中起一定作用     

Inhibition of neutral endopeptidase amplifies the effects of endogenous atrial natriuretic peptide on blood pressure and fluid partition.

Neutral endopeptidase (EC 3.4.24.11) is a wide-spread enzyme that degrades atrial natriuretic peptide (ANP). We studied the effects of a potent neutral endopeptidase inhibitor, SQ 28,603, given intravenously (30 mg/kg over 45 min) to anesthetized, bilaterally nephrectomized Sprague-Dawley rats. Infusion of vehicle alone was accompanied by a modest increase, 3.2 +/- 2.2% (mean +/- SE), in mean arterial blood pressure (MAP) and a slight rise in hematocrit (Hct) of 0.9 +/- 0.7%. After administration of SQ 28,603, MAP fell 3.2 +/- 0.5%, and Hct rose 4.9 +/- 0.5%, both significantly different from the changes with vehicle alone; the lesser increase in plasma protein concentration (2.5 +/- 0.4%) suggested an increase in vascular permeability to both plasma protein and fluid similar to that caused by ANP. When SQ 28,603 was given to rats pretreated with rabbit antirat ANP antiserum, blood pressure rose by 3.8 +/- 0.5%, and Hct increased by 1.0 +/- 0.4%, values very similar to those observed with vehicle alone. Inhibition of neutral endopeptidase therefore amplifies the actions of endogenous ANP on blood pressure and fluid partition.     

Delayed metabolism of human brain natriuretic peptide reflects resistance to neutral endopeptidase

Metabolism of natriuretic peptides is regulated by two degradative pathways: uptake by the clearance receptor (natriuretic peptide receptor C--NPR-C) and hydrolysis by neutral endopeptidase (NEP). Affinity studies favour a dominant role of NPR-C in hormone degradation in several species but do not account for the efficacy of NEP inhibitors in vivo, nor the uniquely prolonged half life (t((1/2))) of human brain natriuretic peptide (hBNP). Postulating that (1) delayed metabolism of hBNP reflects resistance to NEP and (2) interactions between NPR-C and NEP increase enzyme activity, we have used purified ovine and human NEP, plus ovine lung plasma membranes to study the relative importance of receptor and enzyme pathways. We have also related the findings to hormone metabolism in vivo. Binding affinities of atrial natriuretic peptide (ANP), hBNP and ovine BNP (oBNP) to oNPR-C were similar (K(d)=8-16 pM). In contrast, unlike ANP and oBNP, hBNP was not significantly degraded by purified oNEP or plasma membranes. Despite similar (and high) affinity of oNPR-C for oBNP and hBNP, the t((1/2)) of hBNP (12.7 min) was more than fourfold that of oBNP (2.6 min). Although we found no evidence for receptor-enzyme interaction, our results show that the delayed metabolism of hBNP reflects resistance to NEP. These findings have important implications for future treatment strategies in human disease.     

Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide dendroaspis natriuretic peptide

OBJECTIVES: The objectives of the current study were to define for the first time the roles of the natriuretic peptide (NP) receptors and neutral endopeptidase (NEP) in mediating and modulating the renal actions of Dendroaspis natriuretic peptide (DNP), a new therapeutic synthetic NP. BACKGROUND: Recent reports have advanced the therapeutic potential of a newly described synthetic NP called DNP. Dendroaspis natriuretic peptide is a 38-amino acid peptide recently isolated from the venom of Dendroaspis augusticeps (the green mamba snake). METHODS: Synthetic DNP was administered intra-renally at 5 ng/kg/min to 11 normal anesthetized dogs, 5 of which received the NP receptor antagonist HS-142-1 (3 mg/kg intravenous bolus) while the remaining 6 dogs received an infusion of the NEP inhibitor, candoxatrilat (8 and 80 microg/kg/min) (Pfizer, Sandwich United Kingdom). RESULTS: Intra-renal DNP resulted in marked natriuresis associated with increased urinary cyclic guanosine monophosphate excretion (UcGMPV), glomerular filtration rate (GFR), and renal blood flow (RBF) and decreased distal fractional sodium reabsorption (FNaR) compared with baseline. HS-142-1 attenuated the natriuretic response to DNP, resulting in decreased UcGMPV, GFR, and RBF and increased distal FNaR. In contrast, low and high doses of NEP inhibitor did not potentiate the renal actions of DNP. CONCLUSIONS: We report that the NP receptor blockade attenuated the renal actions of synthetic DNP and that the NEP inhibitor did not alter the renal response to DNP. This latter finding is a unique property of synthetic DNP, as distinguished from other known NPs, supporting its potential as a therapeutic agent.     

老年血液透析患者血浆中利钾尿肽与心钠素的变化

目的　探讨行血液透析的老年患者血浆中利钾尿肽 (KP)与心钠素 (ANP)的变化。方法　选择 2 0 0 1年我科收治的伴有高血压的终末期肾病 (ESRD)行血液透析的老年患者 8例 ;选择同期老年原发性高血压病 (EH) 1～ 3级高危患者而肾功能正常者 2 5例为对照组。应用超声心动图仪测量室间隔、左室后壁厚度、左室舒张末内径并计算出左室心肌重量 (L VM) ;监测 2 4 h动态血压 ,测出平均收缩压 (SBP)及舒张压 (DBP) ;同时测定血浆中的 KP与 ANP、血肌酐、尿素氮。结果　 ESRD组左室心肌重量 (LVM)高于 EH组 (P<0 .0 5) ,且 KP及 ANP亦高于 EH组 ,尤其 KP更有明显差异 (P<0 .0 0 1 )。血透结束时收缩压升高 (P<0 .0 0 1 ) ,KP、ANP也高于血透前。结论　老年 ESRD血透患者血浆中 KP、ANP升高可能与伴发高血压有关。     

Role of altered systemic hemodynamics in the blunted renal response to atrial natriuretic peptide in rats with cirrhosis and ascites

The natriuretic effect of pharmacological doses of atrial natriuretic peptide (ANP) is markedly reduced in cirrhosis with ascites. The current study, which includes two protocols, was carried out to investigate whether this phenomenon is related to the altered systemic hemodynamics present in cirrhosis. In protocol A, the administration of ANP (2.5 micrograms.kg-1 as a bolus followed by a constant infusion of 0.1 microgram.kg-1.min-1) to 10 rats with carbon tetrachloride-induced cirrhosis and ascites produced a significantly lower increase in diuresis (13.4 +/- 1.3 microliters/min) and natriuresis (2.3 +/- 0.3 mu Equiv/min) than in 10 control rats (56.3 +/- 1.4 microliters/min and 8.7 +/- 0.5 mu Equiv/min, respectively), indicating a renal resistance to the effect of ANP in this experimental model of cirrhosis. The reduction of arterial pressure induced by ANP was similar in both groups. However, since baseline mean arterial pressure was significantly lower in cirrhotic rats, the degree of hypotension during ANP infusion was also greater in this group of animals (82 +/- 3 vs. 109 +/- 2 mmHg). The aim of protocol B was to assess whether normalization of arterial pressure in cirrhotic rats increases the renal response to ANP. This protocol includes two groups of 10 rats with cirrhosis and ascites infused with a glucose solution containing norepinephrine (CT-NE rats) or angiotensin II (CT-AII rats) at doses to normalize arterial pressure and an additional control group of 10 cirrhotic rats with ascites receiving only glucose solution (CT rats). Angiotensin II, but not norepinephrine or glucose solution administration, was associated with a significant increase in urine volume and sodium excretion. During ANP infusion, CT rats showed a blunted diuretic and natriuretic response. In contrast, the ANP-induced increase in urine volume and sodium excretion observed in CT-NE (53.6 +/- 10.4 microliters/min and 9.3 +/- 2.2 mu Equiv/min) and CT-AII rats (98.3 +/- 11.6 microliters/min and 15.5 +/- 2.9 mu Equiv/m), was similar or even greater than that showed by the healthy rats of protocol A. The degree of hypotension during ANP administration was also similar (CT-NE, 104 +/- 2; CT-AII, 108 +/- 5 mmHg). These results suggest that the blunted response to pharmacological doses of ANP in cirrhosis with ascites is related to altered systemic hemodynamics of cirrhosis, which further deteriorates during the infusion of the peptide.     

Decreased atrial natriuretic peptide binding in renal medulla in rats with chronic heart failure

The relations between atrial natriuretic peptide (ANP) binding sites in the renal medulla, plasma ANP concentration, and ventricular dysfunction have been studied in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. Plasma ANP concentration was measured by radioimmunoassay, and quantitation of receptors was performed by computerized in vitro autoradiography with 125I-labeled alpha-rat ANP (1-28) as the radioligand. When compared with controls, rats with myocardial infarction had markedly elevated plasma immunoreactive ANP concentrations (462 +/- 82 versus 124 +/- pg/ml, p less than 0.01) and reduced densities of ANP binding in the inner renal medulla (2.93 +/- 0.19 versus 3.53 +/- 0.22 fmol/mg protein, p less than 0.01). Extensive myocardial infarction was associated with a significant decrease in receptor numbers in the inner medulla (33.6 +/- 5.7 versus 95.6 +/- 9.6 fmol/mg protein, p less than 0.01) without significantly altering the affinity constant (1.76 +/- 0.51 versus 1.03 +/- 0.15 x 10(9) M-1, p greater than 0.05). Right ventricular weight increased in proportion to infarct size (r = 0.71, p less than 0.01), and both were correlated with plasma immunoreactive ANP levels (r = 0.74, p less than 0.01 and r = 0.75, p less than 0.01, respectively). Binding densities in the inner medulla of rats with infarcts were negatively correlated with right ventricular weight, plasma immunoreactive ANP concentrations, and also with infarct size (r = -0.92, p less than 0.001; r = -0.78, p less than 0.001; r = -0.77, p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men

This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy.     

Long-term treatment with neutral endopeptidase inhibitor improves cardiac function and reduces natriuretic peptides in rats with chronic heart failure

OBJECTIVE: Increased secretion of atrial and brain natriuretic peptide (ANP and BNP) from hearts is known to exhibit favorable effects in patients and animals with heart failure, and inhibition of neutral endopeptidase (NEP), an enzyme that degrades ANP and BNP, may further increase these peptide levels. However, it is still unknown whether such elevation of the ANP and BNP may offer a therapeutic benefit to the progression of chronic heart failure (CHF). We examined the effects of ONO-9902, a novel NEP inhibitor, on changes in hemodynamic parameters, NEP activity and neurohumoral factors in rats with CHF induced by left coronary artery ligation (CAL). METHODS: Male Wistar rats (220-240 g) were subjected to induction of acute myocardial infarction by CAL. Rats were orally treated with ONO-9902 (300 mg/kg/day) from the 1st to 6th week after the operation. Hemodynamic and/or biochemical assessments were performed at the 1st and 6th weeks after the operation. RESULTS: A single administration of ONO-9902 inhibited the plasma and kidney NEP activities and thereby further augmented the elevation of plasma ANP concentration in rats with CAL at the 1st week after the operation. In rats with CAL at the 6th week after the operation, the left ventricular end-diastolic pressure (LVEDP) increased and cardiac output index (COI) decreased as compared with those of sham-operated rats. These changes were accompanied by marked increases in the plasma ANP, BNP and endothelin-1 (ET-1). Chronic treatment with ONO-9902 attenuated the increase in LVEDP and the decrease in COI. These changes were associated with a decrease in plasma ANP, BNP and ET-1 concentrations. CONCLUSIONS: The results suggest that chronic treatment with NEP inhibitor improves depressed cardiac function in rats with CHF. ONO-9902 may offer a new and possible therapeutic approach in patients with CHF.     

The effect of oxygen with exercise on atrial natriuretic peptide in chronic obstructive lung disease.

A recent study on stable, hypoxemic, COLD patients in which ANP was stimulated by LBPP demonstrated that in these individuals elevation of ANP does not exert a "normal" suppressing effect on the PRA-PA axis. Accordingly, we exercised ten comparable COLD patients, another maneuver known to stimulate ANP and to elicit cardiorespiratory responses substantially different from those observed with LBPP. Patients were studied breathing room air and on 40 percent O2 to determine whether the level of oxygenation would modify ANP secretion. Basal levels of ANP on room air were markedly elevated above controls (269 +/- 65 SE vs 70 +/- 20 pg/ml, p less than 0.05); PRA (13.0 +/- 5.4 ng/ml/90 min) and PA (8.6 +/- 3.5 ng/100 ml) were elevated (greater than 2 SD over control levels of 8.1 +/- 1.3 and 2.6 +/- 0.7) in 6/10 and 2/10 patients, respectively. During exercise while breathing O2, only ANP increased; PRA and PA remained unchanged when breathing air and O2. Comprehensive statistical analyses failed to demonstrate a negative relationship between ANP and PRA or ANP and PA. We conclude that in patients with advanced COLD, ANP response to moderate exercise is significantly affected by correction of hypoxemia. This effect may be mediated through changes in airway resistance and consequently cardiac filling pressure.     

Effect of prolonged inhibition of neutral endopeptidase on cardiac hypertrophy in rats with myocardial infarction

Summary Myocardial infarction was induced in rats by ligation of the left coronary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18–20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the end of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hemodynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15–20%, whereas the treatment had no effect on the left ventricle and septum weights. Treatment led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p<0.05) in plasma ACE activity. Plasma ANF level increased 3.8-fold after ligation, and treatment resulted in a slight (+29%) and nonsignificant additional increase in the ANF level. The amount of hydroxyproline in the right ventricle was enhanced by +207% in control ligated rats and by +140% (NS) in treated rats. These data indicate that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and atrial hypertrophy. These effects may result from an improvement in hemodynamic conditions, leading to a reduction in cardiac preload.     

Regulation of plasma atrial natriuretic peptide and the cardiopulmonary baroreflex in the rat

To study the physiological regulation of atrial natriuretic peptide (ANP), we examined the effects of volume expansion and depletion and the influence of cardiopulmonary baroreflex on plasma ANP levels in pentobarbital-anesthetized male Wistar rats. The volume expansion by acute intravenous saline infusion (2% of body weight) increased central venous pressure (CVP) and decreased heart rate (HR) in rats with intact baroreflex. The plasma ANP level in the volume expanded group was significantly higher than that in the control rats (453 +/- 100 vs 170 +/- 40 pg/ml, p less than 0.01). Conversely the plasma ANP level decreased from 214 +/- 15 to 125 +/- 13 pg/ml (p less than 0.01) accompanied by a fall in CVP and an increase in HR after nonhypotensive hemorrhage (0.8% of body weight). Hypotensive hemorrhage (2% of body weight) caused a progressive decrease in CVP while plasma ANP did not decrease further (141 +/- 25 pg/ml). Bilateral vagotomy did not modify either the basal plasma ANP level or the plasma ANP responses to volume expansion and depletion, though it inhibited HR response. These results indicate that in the rat, plasma ANP responds not only to volume expansion but also to moderate volume depletion suggesting that ANP may have a physiological role in body fluid homeostasis. The ANP response to changes in blood volume appears to be independent of the cardiopulmonary baroreflex with vagal afferent.