Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure.
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PMID:Neutral endopeptidase inhibition potentiates the effects of natriuretic peptides in renin transgenic rats. 898 53

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.
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PMID:Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. 1108 29

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
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PMID:Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure. 1156 14

Angiotensin-converting enzyme and neutral endopeptidase (EC 3.4.24.11; neprilysin) are metallopeptidases present on the endothelium that metabolize bradykinin. Inhibitors of angiotensin-converting enzyme potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. Combined angiotensin-converting enzyme and neutral endopeptidase inhibition may have additional beneficial cardiovascular effects mediated through bradykinin potentiation. We investigated the effects of local neutral endopeptidase inhibition on the vascular actions of bradykinin in heart failure patients maintained on chronic angiotensin-converting enzyme inhibition. Ten patients received intrabrachial infusion of thiorphan (30 nmol/min), a neutral endopeptidase inhibitor, in a randomized double-blind placebo-controlled crossover trial. Thiorphan was coinfused with Lys-des-Arg9-bradykinin (1 to 10 nmol/min), bradykinin (30 to 300 pmol/min), atrial natriuretic peptide (10 to 100 pmol/min), and sodium nitroprusside (2 to 8 mug/min). Bradykinin, atrial natriuretic peptide, and sodium nitroprusside caused dose-dependent vasodilatation (peak blood flow 14.4+/-2.2, 3.6+/-0.6, and 8.6+/-1.3 mL per 100 mL/min, respectively; P<0.0001). Bradykinin caused dose-dependent increases in tissue plasminogen activator antigen and activity (peak concentration 31.8+/-3.4 ng/mL and 21.9+/-7.6 IU/mL, respectively; P<0.001) and estimated antigen and activity release (peak release 152+/-46 ng per 100 mL/min and 154+/-22 IU/100 mL/min, respectively; P<0.005). Compared with placebo, thiorphan augmented bradykinin-mediated vasodilatation (1.4-fold; P<0.0001) and net tissue plasminogen activator release (1.5-fold; P<0.005). Neutral endopeptidase contributes to bradykinin metabolism in heart failure patients maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the clinical effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition, including the greater vasodepressor effect observed with combined therapy when compared with angiotensin-converting enzyme inhibition alone.
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PMID:Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. 1549 33