Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminopeptidase inhibitors have been demonstrated to enhance the behavioral effects of both exogenously applied and endogenously released neuropeptides. In this study peptidase inhibitors were used as probes for involvement of central neuropeptides in osmotically-induced drinking behavior. Intracerebroventricular (i.c.v.) injections of amastatin, an aminopeptidase A inhibitor, potentiated water intake induced by subcutaneous injections of hypertonic saline. Drinking responses to i.c.v. infusions of hypertonic saline were also enhanced when amastatin was added to the infusions. The effect was not attenuated by the angiotensin receptor antagonist, [Sar1, Thr8]angiotensin II, which suggests that angiotensins do not play a role in the over-drinking. Drinking responses to centrally infused hypertonic saline were not enhanced by i.c.v. thiorphan, an endopeptidase inhibitor; this provides evidence that the effects of amastatin are specific for a particular class of peptidases. These results suggest that there is a role for an endogenous, non-angiotensinergic brain peptide in the mediation of osmotic thirst.
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PMID:Amastatin potentiates drinking elicited by osmotic stimuli: evidence for peptidergic mediation of intracellular dehydration-induced thirst. 142 35

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. The blood pressure-lowering and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors are thought to be based primarily on a reduction in vascular angiotensin II (Ang-II) formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. 2. Incubation of endothelial cells with ACE inhibitors indeed causes an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2) which can be completely blocked by the B2-kinin receptor antagonist Hoe 140, suggesting that the vascular endothelium is capable of generating vasoactive kinins from an endogenous source. 3. Moreover, ACE inhibitors not only prevent the breakdown of bradykinin but, by virtue of an as yet unidentified mechanism, also enhance the potency of bradykinin at the receptor level and reverse the desensitization of the B2-kinin receptor following continuous exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. 4. Furthermore, ACE inhibition leads to the accumulation of Ang-I which can be metabolised to Ang-(1-7) by another endothelial enzyme, neutral endopeptidase 24.11. By activating an as yet unidentified angiotensin receptor, Ang-(1-7), but not other known angiotensin peptides, stimulates endothelial NO release in porcine coronary arteries as well as in the isolated perfused rat heart. This effect is, albeit to a different degree, dependent on the release of vasoactive kinins from the endothelium. The shift in Ang-I metabolism towards an enhanced formation of Ang-(1-7) in the presence of an ACE inhibitor may thus contribute to the hypotensive action of this class of compounds as well.
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PMID:Mechanisms involved in the angiotensin II-independent hypotensive action of ACE inhibitors. 774 81

Despite the wide range of anti-hypertensive drugs currently available many more are being developed, including entirely novel classes of compounds. This is not entirely surprising as a minority of patients do not respond to existing agents or are unable to tolerate them at therapeutic doses. It is also true that hypertension represents a very large international market. This brief review deals with the following classes of agents which are at various stages of development: (1) angiotensin receptor antagonists of the AT1 subtype, the first of which has recently been marketed in the UK; (2) renin inhibitors, whose development has been hindered by the poor bioavailability of all but the most recent compounds; (3) imidazoline (I1) receptor agonists, centrally acting drugs with relatively little sedating activity; (4) potassium channel openers, which act as potent vasodilators; (5) neutral endopeptidase inhibitors which potentiate the actions of atrial natriuretic peptides; and (6) endothelin antagonists, which are still in pre-clinical development. The potential clinical significance of these compounds is discussed.
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PMID:New ideas for treating hypertension. 852 85

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

Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.
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PMID:Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. 987 42

The development of pharmacological agents that block the renin-angiotensin system (RAS) specifically have helped to define all the components of the system and their contribution to blood-pressure control and to the pathogenesis of hypertension, congestive heart failure and chronic renal failure. The angiotensin converting-enzyme inhibitors (ACEi) are among all available drugs that interfere with the RAS, the most efficient, so far, in the treatment of several cardiovascular diseases, with comfortable posologic schemes and an acceptable safety profile. The most important difference between them are more related to pharmacokinetic profile rather than to pharmacodynamic characteristics. With the use of ACEi the interference with other neurohumoral systems is unavoidable and the controversy has been pharmacologically and clinically installed. With the advent of oral selective AT1 angiotensin II receptor blockers (ARB) the pharmacological interference became eventually much more selective. Their antihypertensive efficacy is identical and their tolerability is better than that showed by ACEi. The ARBs differ mainly in their pharmacokinetics and in their binding capacity to the AT1 angiotensin receptor. The results of several ongoing clinical trials will show if the ARBs as ACEi will be capable to protect target-organs and to promote a significant reduction in cardiovascular morbility and mortality. In parallel there is an intense experimental and clinical research with other groups of drugs which also markedly interfere with RAS: renin inhibitors, chymase inhibitors and simultaneous inhibitors of vasopeptidases (ACE, endothelin converting-enzyme, neutral endopeptidase). From the pharmacological point of view, it is now possible to block effectively RAS with some relevant clinical results that will be certainly widen in the near future.
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PMID:[Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists. Pharmacologic features]. 1130 8

Clinical trials have proved that blockade of the renin-angiotensin-aldosterone system (RAAS) offers primary and secondary protection of the cardiovascular system, brain, and kidneys. Drugs that interrupt the RAAS do so by several diverse mechanisms but it remains to be fully proved whether these mechanistic differences are associated with meaningful differences in clinical outcomes. This review summarizes current information about the basic mechanisms of action of three classes of anti-RAAS drugs: angiotensin-converting enzyme (ACE) inhibitors, combined ACE-neutral endopeptidase inhibitors, and angiotensin receptor antagonists as well as results of major clinical outcome trials with these agents. Basic and clinical science information is then blended with insights from the clinical pharmacology of anti-RAAS drugs to address four current controversies in clinical medicine: whether ACE inhibitors and angiotensin receptor antagonists are interchangeable, optimal dosing of available agents, potential justification of ACE inhibitor/angiotensin receptor antagonist combinations, and first-line use of anti-RAAS drugs in antihypertensive therapy.
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PMID:Clinical impact of renin-angiotensin system blockade: angiotensin-converting enzyme inhibitors vs. angiotensin receptor antagonists. 1246 16

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.
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PMID:Targeting the renin-angiotensin system: what's new? 1563 41

Heart failure (HF) is a clinical syndrome characterized by chronic, persistent activation of the neuroendocrine system, which has been assumed to be linked to disease progression and adverse outcomes. Clinical trials have shown that adrenergic modulators, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and beta-blockers, improve long-term outcomes in patients with HF. These findings have led to the hypothesis that inhibition of a single neurohormonal or cytokine pathway may continue to provide incremental benefits. However, the results of recent clinical trials, using centrally acting agents--endopeptidase inhibitors or endothelin and cytokine antagonists--suggest that selective inhibition of neurohormonal systems may not be advantageous and actually may have serious adverse effects. The reasons for this lack of benefit may be ascribed to the fact that long-term mortality benefits in patients with chronic HF are primarily the result of treatment of the diseases that have caused HF in the first place rather than treatment of neurohormonal abnormalities.
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PMID:Neurohormonal inhibition in heart failure: insights from recent clinical trials. 1639 87


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