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

The biological actions of Atrial Natriuretic Peptide (ANP) make it potentially useful in the treatment of hypertension and heart failure. We review here the physiology of ANP, the effects of infusion in heart failure and hypertension and preliminary data suggesting that inhibition of endopeptidase 24.11, the enzyme degrading ANP, is an effective mechanism of raising circulating levels of endogenous ANP. Due to the rate of progress in this field we have restricted ourselves to recent work much of which is still available only in abstract form. For more complete accounts the reader is referred to recent reviews [9, 11, 14].
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PMID:Harnessing the therapeutic potential of atrial natriuretic peptide. 253 Mar 92

UK 69 578 is a competitive inhibitor of endopeptidase 24.11 (the enzyme that degrades atrial natriuretic factor) in vitro. In vivo, UK 69 578 has renal and cardiovascular effects similar to low-dose atrial natriuretic factor infusion, and may be a useful agent in hypertension and heart failure.
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PMID:Effects of UK 69 578: a novel atriopeptidase inhibitor. 257 Feb 86

Ketanserin, a recently developed 5-HT2 receptor antagonist, competitively and selectively blocks the vasoconstrictor activity of 5-hydroxytryptamine (serotonin). We explored a possible contribution of serotonin to augmented vascular tone in patients with severe heart failure, using intravenous and oral formulations of ketanserin. When administered intravenously (10 mg bolus, 4 mg/hr infusion for +/- 40 min) to 10 patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (n = 8) or ischemic heart disease (n = 2), the drug produced a significant increase in cardiac output (rest 24%, p less than 0.001; exercise 19%, p less than 0.01) which was accompanied by a fall in systemic arterial pressure (rest 7%, p less than 0.001; exercise 10%, p less than 0.05) and pulmonary wedge (rest 17%, p less than 0.05; exercise 23%, p less than 0.001) pressure. Calculated systemic vascular resistance (SVR, rest 27%, p less than 0.001; exercise 23%, p less than 0.05) decreased significantly. No significant hemodynamic changes were observed when 40 mg of ketanserin was administered orally to the same group of patients. Plasma catecholamines (norepinephrine, NEP:epinephrine, EP:dopamine) were measured before and after ketanserin at rest and during exercise. Baseline NEP levels were markedly elevated at rest and during exercise in all patients (rest: 878 +/- 381 ng/mL, exercise: 1453 +/- 697 ng/mL). Baseline EP levels were within normal limits. Ketanserin did not produce any change in catecholamine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and neurohumoral effects of ketanserin, a 5-HT2 receptor antagonist in patients with congestive heart failure. 356 10

Combined neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition produces greater acute hemodynamic effects than either treatment alone. We investigated whether BMS-182657 (BMS), which bears inhibitory activities against both NEP and ACE, elicited similar enhanced effects. BMS inhibited NEP and ACE, in vitro (IC50 = 6 and 12 nM, respectively) and the pressor response to Ang I in rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats sensitive to NEP inhibition but not to ACE inhibition, BMS at 100 mumol/kg i.v. lowered mean arterial pressure (MAP) from 180 +/- 6 to 151 +/- 5 mm Hg. In sodium-depleted, spontaneously hypertensive rats (SHR) sensitive to ACE inhibition but not to NEP inhibition, BMS at 100 mumol/kg p.o. lowered MAP from 151 +/- 4 to 123 +/- 5 mm Hg. Cardiomyopathic hamsters with heart failure were administered vehicle or one of the following (30 mumol/kg i.v.): the ACE inhibitor enalaprilat; the NEP inhibitor SQ-28603; or BMS. Enalaprilat and SQ-28603 had minimal hemodynamic effects. BMS decreased left ventricular end-diastolic pressure by 12 +/- 2 and 10 +/- 1 mm Hg and left ventricular systolic pressure by 27 +/- 2 and 23 +/- 3 mm Hg at 30 and 60 min, respectively (P < .05 vs. each other group). These changes were associated with a 40% increase in cardiac output, a 47% decrease in peripheral vascular resistance and a lowering of MAP by 21 +/- 3 mm Hg at 60 min (P < .05 vs. each other group). There were no significant differences in the changes in heart rate or left ventricular stroke work index among the four groups. Hence, BMS-182657 is a dual inhibitor of NEP and ACE, is antihypertensive irrespective of the activity of the renin-angiotensin system and has acute hemodynamic effects in hamsters with heart failure greater than those produced by selective inhibition of NEP or ACE. The NEP and ACE inhibitory activities of BMS-182657 act synergistically and mimic the interaction resulting from combining selective inhibitors of these enzymes.
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PMID:Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure. 747 62

The purpose of this study was to determine the effects of bradykinin (BK), substance P (SP) and histamine on plasma exudation in the skin of conscious dogs with and without pacing-induced heart failure. We also determined the role tissue angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP) play in modulating these responses. We found that intradermal injection of BK, SP and histamine induced a significant, concentration-dependent Evans blue exudation in normal dogs (p < 0.05). Bradykinin-induced responses were significantly potentiated by captopril (p < 0.05). In contrast, phosphoramidon potentiated BK-induced responses only at low concentrations of BK. Both captopril and phosphoramidon had no significant effects on SP- and histamine-induced Evans blue exudation. BK- and SP-induced responses were significantly attenuated, whereas histamine-induced Evans blue exudation was significantly potentiated in dogs with heart failure. We conclude that heart failure is associated with attenuation of BK- and SP-, but not histamine-induced plasma exudation in the peripheral microcirculation and that these responses are not modulated by tissue ACE and NEP.
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PMID:Plasma exudation in conscious dogs with experimental heart failure. 753 20

Neurohormonal activation is one of the major determining factors in the process of transition from asymptomatic ventricular dysfunction to end-stage heart failure, in the prognosis of heart failure, and in the efficacy and, hence, choice and timing of pharmacological therapy. Although various counteracting hormonal systems are involved, emphasis in terms of functionality is on vasopressor and growth-promoting systems. In contrast, ANF and N-terminal proANF probably have a significant prognostic value, even at an early stage. The focus of heart failure therapy is moving from measures aimed at improving cardiac function to ones that concentrate on modulating neuroendocrine changes during failure and their effects on intrinsic peripheral and cardiac alterations. Although ACE inhibition undoubtedly constitutes a major step forward in this approach, alternative ways to modulate neurohormonal activation pharmacologically are needed. Several such novel approaches are being developed, including angiotensin receptor antagonists, dopaminergic stimulation, neutral endopeptidase inhibition, aldosterone antagonism and beta blockade. In addition to their positive inotropic properties digitalis glycosides may act as neurohormonal modulators. Finally, the realization that several well-established forms of heart failure therapy may aggravate neuroendocrine stimulation demands careful consideration as to whether such agents are really necessary, and underlines the desirability of co-administering neurohormonal modulating therapy.
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PMID:Therapeutic strategies and neurohormonal control in heart failure. 771 2

1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihypertensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an angiotensin converting enzyme (ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose-related manner in conscious dogs with tachycardia-induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metalloprotease inhibitor BMS-182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of natriuretic peptides by neutral endopeptidase inhibitors. 776 36

Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.
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PMID:Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes. 785 75

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure. 785 75

We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of alpha-rat atrial natriuretic peptide (alpha-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating alpha-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/min/kg) was equal to that of exogenously administered alpha-rANP (100 pmol/min/kg) in MI rats, whereas plasma alpha-rANP concentration under NEP inhibition was much lower than that after administration of alpha-rANP. The endogenous alpha-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to alpha-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous alpha-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating alpha-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.
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PMID:Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure. 789 35


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