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

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.
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PMID:Vasopeptidase inhibitors. 1194 97

Left ventricular remodeling in hypertension is associated with cardiac interstitial and perivascular collagen deposition. The dual angiotensin I converting enzyme/neutral endopeptidase inhibitor omapatrilat (also called vasopeptidase inhibitor) improves left ventricular remodeling in experimental heart failure. We hypothesized that omapatrilat would induce regression of cardiac and vascular fibrosis in hypertension. We, therefore, investigated the effect of omapatrilat on collagen deposition in heart and aorta of stroke-prone spontaneously hypertensive rats (SHRSP). Twenty-week-old normotensive Wistar-Kyoto (WKY) rats, untreated SHRSP, and SHRSP treated with omapatrilat (40 mg/kg per day, orally) for 10 weeks were investigated. Collagen in the heart and the descending thoracic aorta was stained with Sirius red. After 10 weeks, systolic blood pressure (BP) was significantly (P < .01) reduced in omapatrilat-treated versus untreated SHRSP. Interstitial collagen density was significantly decreased in the subendocardial myocardium (to 2.71 +/- 0.24% v 4.12 +/- 0.30%, respectively, P < .05) and in the midmyocardium of omapatrilat-treated versus untreated SHRSP (to 3.01 +/- 0.25 v 4.19 +/- 0.17% respectively, P < .05). Perivascular collagen was significantly (P < .05) decreased in the subepicardial, mid-myocardial and, subendocardial regions of the myocardium of omapatrilat-treated versus untreated SHRSP. Aortic collagen content decreased in omapatrilat-treated versus untreated SHRSP (to 36.1 +/- 2.8 v 58.8 +/- 6.1 x 10(3) microm2/mm section, respectively, P < .05). In conclusion, in addition to being a potent antihypertensive agent, omapatrilat significantly improves cardiac and vascular fibrosis in SHRSP.
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PMID:Effect of ACE/NEP inhibition on cardiac and vascular collagen in stroke-prone spontaneously hypertensive rats. 1171 Jul 87

The pharmacological profile of a vasopeptidase inhibitor is dependent on the ratio of neutral endopeptidase (NEP)vs angiotensin converting enzyme (ACE) inhibition of the particular drug. We used in vitro autoradiography to determine the local renal and cardiac NEP and ACE inhibition after oral treatment with the dual NEP/ACE inhibitor omapatrilat in rat. Maximal inhibition of both renal NEP and ACE was achieved at the omapatrilat dose of 40 mg kg(-1)day(-1). Effective local ACE inhibition was detected also in the myocardium. The haemodynamic effects were similar to captopril, but omapatrilat treatment produced more favorable effect on natriuretic peptide levels. In conclusion, good tissue penetration of omapatrilat and balanced NEP/ACE inhibition may prove to be useful in the treatment of hypertension and heart failure.
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PMID:Dual inhibition of angiotensin converting enzyme and neutral endopeptidase by omapatrilat in rat in vivo. 1171 72

Vasopeptidase (VP) inhibitors are novel molecules that co-inhibit neutral endopeptidase 24.11 (NEP), which degrades natriuretic peptides and angiotensin-converting enzyme (ACE). We review the biology of the natriuretic peptide system and a recent study of the role for the natriuretic peptide system in the mechanism of action of omapatrilat (the most clinically advanced VP inhibitor). This study compared the cardiorenal and humoral actions of omapatrilat with those of ACE inhibition. The actions of omapatrilat were further defined in the presence and absence of a natriuretic peptide receptor antagonist. This investigation provided insight into a unique new pharmacologic agent that has beneficial renal actions in experimental mild heart failure that exceed those seen with ACE inhibition alone and that are linked to the natriuretic peptide system.
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PMID:Role of the natriuretic peptides in the cardiorenal and humoral actions of omapatrilat: insights from experimental heart failure. 1171 1

In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.
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PMID:Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease. 1171 4

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor-alpha (TNF-alpha) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of beta-blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)-inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin-angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large-scale trials with ACE-inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non-peptide antagonists is ongoing. Endothelin-1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N-terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF-alpha has drawn attention. Experimental studies suggest that TNF-alpha is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF-alpha seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a 'neuroendocrine profile' which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to beta-blockers, ACE-inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.
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PMID:Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. 1172 73

Omapatrilat is the most clinically advanced of a new class of drugs, vasopeptidase inhibitors, which are being studied for the treatment of patients with cardiovascular disease. Omapatrilat inhibits the enzymatic activities of angiotensin-converting enzyme and neutral endopeptidase. The end result is blockade of angiotensin-II formation and inhibition of the catabolism of vasodilatory hormones, such as the natriuretic peptides, bradykinin, and adrenomedullin. Some of the ultimate pharmacologic effects include vasodilation, natriuresis, and diuresis, which may be beneficial in the management of various cardiovascular diseases, such as hypertension and heart failure. The pharmacokinetics of omapatrilat are compatible with once-daily dosing and a duration of antihypertensive efficacy of more than 24 hours. Omapatrilat decreases blood pressure in both high-renin and low-renin states, which suggests antihypertensive efficacy that is independent of the status of the renin-angiotensin system. Furthermore, the antihypertensive effect of omapatrilat is indiscriminate of age or race. Omapatrilat has consistently shown efficacy in decreasing both systolic and diastolic blood pressure to a similar or greater extent than either lisinopril or amlodipine; however, systolic pressure is more responsive to omapatrilat treatment than diastolic pressure. Although the role of omapatrilat in heart failure is still evolving, preliminary results are promising: hemodynamic improvements and clinical benefits of omapatrilat are similar or greater to those achieved with an angiotensin-converting enzyme inhibitor. Future studies (specifically the OVERTURE Study) will be of pivotal importance in establishing the role of omapatrilat in the treatment of patients with heart failure. The side-effect and drug-interaction profiles of omapatrilat are largely incomplete, but suggest excellent tolerability and a side-effect profile that is similar to placebo. Omapatrilat could be a revolutionary addition to the management of cardiovascular disease, and its clinical development will be followed closely by many who are curious if larger clinical trials will echo the impressive preliminary data that have been seen thus far.
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PMID:Omapatrilat: a unique new agent for the treatment of cardiovascular disease. 1172 68

Blockade of the renin-angiotensin-aldosterone cascade is now recognised as a very effective approach to treat hypertensive, heart failure and high cardiovascular risk patients and to retard the development of renal failure. The purpose of this review is to discuss the state of development of currently available drugs blocking the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II receptor antagonists, with a special emphasis on the results of the most recent trials conducted with AT(2) receptor antagonists in heart failure and Type 2 diabetes. In addition, the future perspectives of drugs with dual mechanisms of action, such as NEP/ACE inhibitors, also named vasopeptidase inhibitors, are presented.
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PMID:Novel angiotensin II inhibitors in cardiovascular medicine. 1177 99

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin-converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin-angiotensin-aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agent's effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long-term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.
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PMID:A review of vasopeptidase inhibitors: a new modality in the treatment of hypertension and chronic heart failure. 1179 28

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.
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PMID:Combined endopeptidase inhibition and adrenomedullin in sheep with experimental heart failure. 1179 85


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