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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin converting enzyme inhibitors are established treatment for hypertension and heart failure. There are well documented differences between ACE inhibitors both in physicochemical properties and pharmacokinetics. Pharmacodynamic actions are similar for most members of the ACE inhibitor class but there are compounds with additional effects which may reflect protease inhibition or non-enzyme-directed pharmacological properties. Clinically relevant differences are few and far between, particularly in the treatment of hypertension when the optimal dose and dose intervals are used. In heart failure there may be a role for drugs with additional properties such as neutral endopeptidase inhibition. In addition, ACE inhibitors differ in the profile of blood pressure changes after the first dose. Early haemodynamic changes with a fall in blood pressure in heart failure patients may be disadvantageous in terms of subsequent outcome. Thus the haemodynamic effects of the first dose may be relevant to the choice of ACE inhibitors in heart failure.
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PMID:From kinetics to dynamics: are there differences between ACE inhibitors? 940 67

We examined for the first time the specific roles of angiotensin II and the natriuretic peptides during inhibition of angiotensin-converting enzyme (captopril, 25 mg bolus + 6 mg/3 h infusion) and endopeptidase 24.11 (SCH32615, 5 mg/kg bolus + 3 mg/kg/3 h infusion), both separately and in combination, in eight sheep with pacing-induced heart failure. Plasma atrial and brain natriuretic peptide levels were similarly increased by SCH32615 and to a lesser extent during combined inhibition but decreased with captopril. Captopril and combined inhibition induced identical increases in plasma renin activity and reductions in angiotensin II, whereas neither was changed by SCH32615 alone. Mean arterial pressure and peripheral resistance decreased during SCH32615 and further still during captopril and combined treatment. Left atrial pressure was reduced to a similar extent by SCH32615 and captopril alone and reduced further by combined inhibition. Cardiac output increased during all treatments. Urine volume and sodium excretion were significantly increased during SCH32615 and combined inhibition. Creatinine clearance increased during SCH32615, decreased during captopril, and was maintained during combined treatment. In conclusion, compared with captopril alone, cotreatment with an endopeptidase 24.11 inhibitor further improved filling pressures and induced a diuresis and natriuresis with preservation of renal glomerular filtration.
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PMID:Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. 945 86

Cardiac hypertrophy develops to compensate for hemodynamic overload of the myocardium. However, cardiac hypertrophy itself poses a serious risk to patients with heart failure. Whether natriuretic peptides enhanced by ecadotril, a neutral endopeptidase inhibitor, suppress the increase of left ventricular mass in the rat aortic insufficiency model was investigated. Ecadotril suppressed the increase of the left ventricular mass without affecting blood pressure (710.9 +/- 15.6 mg in the group treated with ecadotril and 865.0 +/- 27.3 mg in the control group, P < 0.01). Although the increase of atrial natriuretic peptide in the left ventricle was trivial and did not reach statistical significance (406.5 +/- 62.2 pg/mg in the ecadotril-treated group versus 269.8 +/- 35.7 pg/mg in the control group), urinary cGMP excretion was greater in the group given ecadotril than in the control group (10.6 +/- 2.5 pmol/mL and 1.7 +/- 0.6 pmol/mL, respectively, P < 0.01). Plasma angiotensin II concentration also decreased in the group treated with ecadotril compared with the control group (116.6 +/- 25.4 pg/mL versus 358.7 +/- 98.7 pg/mL, P < 0.05). In conclusion, ecadotril suppressed the increase of left ventricular mass in the overloaded heart. In ecadotril-treated rats, cGMP synthesis was augmented and angiotensin II concentration was reduced.
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PMID:Effect of ecadotril, a neutral endopeptidase inhibitor, on myocardial hypertrophy in the rat aortic insufficiency model. 948 75

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) offers the potential for improved therapy of hypertension and cardiac failure. S 21402-1 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido] propionic acid] is a sulfhydryl-containing potent inhibitor of both NEP (Ki = 1.7 nM) and ACE (Ki = 4.5 nM). S 21402-1 and the sulfhydryl-containing ACE inhibitor captopril were administered to rats by intraperitoneal injection (0, 0.3, 3, 30, 300 mg/kg). Urine was collected for 4 h; then plasma and kidneys were collected. The difference in NEP and ACE inhibition by S 21402-1 in vivo was greater than 1000-fold. All doses of S 21402-1 inhibited NEP, as indicated by plasma NEP activity, radioinhibitor binding to kidney sections, urinary sodium excretion and bradykinin-(1-7)/bradykinin-(1-9) ratio. However, only 300 mg/kg S 21402-1 inhibited ACE, as indicated by plasma angiotensin II/angiotensin I ratio, renin and angiotensinogen levels. Although S 21402-1 (30 and 300 mg/kg) inhibited renal NEP, as indicated by the bradykinin-(1-7)/bradykinin-(1-9) ratio in kidney, S 21402-1 had no effect on renal ACE, as indicated by the angiotensin II/angiotensin I ratio in kidney. Moreover, captopril was greater than 10-fold more potent than S 21402-1 as an ACE inhibitor in vivo. In separate experiments, the pressor response of anesthetized rats to angiotensin I showed more rapid decay in ACE inhibition by S 21402-1 than by captopril. These studies indicated that in vivo modification of S 21402-1 caused a much greater decrease in potency of ACE inhibition than NEP inhibition. Consequently, effective ACE inhibition by S 21402-1 required doses much higher than those required for NEP inhibition.
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PMID:Marked difference between angiotensin-converting enzyme and neutral endopeptidase inhibition in vivo by a dual inhibitor of both enzymes. 949 36

Arterial tone and water-electrolyte homeostasis are regulated by several peptides, including angiotensin II (AII), bradykinin (BK), atrial natriuretic peptide (ANP) and endothelins (ETs). Changing the concentrations of these peptides in the plasma, tissue, or urine by decreasing the levels of angiotensin II and endothelins and increasing BK and ANP concentrations, is one way of modulating the hemodynamic load. The metabolism of these peptides in essentially controlled by three enzymes, angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin converting enzyme (ECE), which all belong to the group of zinc metallopeptidases. Inhibition of these peptidases by a single compound (a dual inhibitor) that inhibits at once angiotensin II formation and BK and ANP inactivation, causes vasodilatation with reduction in blood pressure with reduction in blood pressure and increases natriuresis. The design of these inhibitors has often be relied on structure-activity studies, based on active-site models derived from structural data on thermolysin (TLN). The results of a large number of pharmacological experiments and those issued from some clinical studies using selective or mixed inhibitors show that in spontaneously hypertensive rats, dual ACE/NEP inhibitors such as S21,402 produce dose-related decreases (-15 to -40 mmHg) in mean arterial pressure and reductions in left ventricular hypertrophy and cardiac size. These compounds produce also an increase in urinary levels of BK, ANP and cGMP associated with enhanced urine output and sodium excretion. Moreover inhibition of NEP appears to improve the cardio- and reno-protective effects resulting from ACE inhibition and could also reduce hypertrophy of vascular walls. Inhibition of ECE seems to result in a weak reduction in blood pressure, an effect which could be emphasized by using dual ECE/ACE or ECE/NEP inhibitors. According to these results mixed dual inhibitors could be of great interest for the treatment of severe hypertension and chronic heart failure. Potent triple inhibitors blocking ACE, NEP and ECE could also be developed.
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PMID:Cell surface metallopeptidases involved in blood pressure regulation: structure, inhibition and clinical perspectives. 976 15

The combination of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.
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PMID:Effects of neutral endopeptidase inhibition and combined angiotensin converting enzyme and neutral endopeptidase inhibition on angiotensin and bradykinin peptides in rats. 980 82

Many therapeutic approaches are under evaluation in patients with cardiac failure. They include angiotensin receptor inhibitors, selective and non-selective endothelin receptor inhibitors, neutral endopeptidase inhibitors or mixed inhibitors of neutral endopeptidase and of the angiotensin converting enzyme and, finally, cytokinin modulators. Some of these drugs have already entered Phase II therapeutic trials and are at relatively advanced developmental stages. Others are at preliminary or experimental stages. If these new drugs prove to be effective and well tolerated, they will represent new tools for physicians to treat cardiac failure and prevent its progression. However, many questions concerning drug associations and poly-therapy will be raised, leading to a revision of the strategy of treatment of cardiac failure.
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PMID:[Drugs of the future]. 986 13

Increasing evidence suggests that angiotensin-converting enzyme (ACE) inhibitors can increase vascular nitric oxide (NO) production. Recent studies have found that combined inhibition of ACE and neutral endopeptidase (NEP) may have a greater beneficial effect in the treatment of heart failure than inhibition of ACE alone. Amlodipine, a calcium channel antagonist, has also been reported to have a favorable effect in the treatment of patients with cardiac dysfunction. The purpose of this study was to determine whether and the extent to which all of these agents used in the treatment of heart failure stimulate vascular NO production. Heart failure was induced by rapid ventricular pacing in conscious dogs. Coronary microvessels were isolated from normal and failing dog hearts. Nitrite, the stable metabolite of NO, was measured by the Griess reaction. ACE and NEP inhibitors and amlodipine significantly increased nitrite production from coronary microvessels in both normal and failing dog hearts. However, nitrite release was reduced after heart failure. For instance, the highest concentration of enalaprilat, thiorphan, and amlodipine increased nitrite release from 85 +/- 4 to 156 +/- 9, 82 +/- 7 to 139 +/- 8, and 74 +/- 4 to 134 +/-10 pmol/mg (all *p <.01 versus control), respectively, in normal dog hearts. Nitrite release in response to the highest concentration of these two inhibitors and amlodipine was reduced by 41% and 31% and 32% (all #p <.01 versus normal), respectively, in microvessels after heart failure. The increase in nitrite induced by either ACE or NEP inhibitors or amlodipine was entirely abolished by Nw-nitro-L-arginine methyl ester, HOE 140 (a B2-kinin receptor antagonist), and dichloroisocoumarin (a serine protease inhibitor) in both groups. Our results indicate that: 1) there is an impaired endothelial NO production after pacing-induced heart failure; 2) both ACE and NEP are largely responsible for the metabolism of kinins and modulate canine coronary NO production in normal and failing heart; and 3) amlodipine releases NO even after heart failure and this may be partly responsible for the favorable effect of amlodipine in the treatment of heart failure. Thus, the restoration of reduced coronary vascular NO production may contribute to the beneficial effects of these agents in the treatment of heart failure.
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PMID:Kinin-mediated coronary nitric oxide production contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors and amlodipine in the treatment in heart failure. 991 84

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.
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PMID:Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels. 1008 17

Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.
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PMID:Vasopeptidase inhibition: a new concept in blood pressure management. 1034 Aug 42


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