Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.
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PMID:Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan. 252 43

Alert spontaneously hypertensive (SH) rats, prepared with indwelling carotid artery catheters, demonstrated heightened and prolonged blood pressure (BP) responses to intracerebroventricular (i.c.v.) injections of 10 and 100 pmol angiotensin II and III (AII and AIII) as compared with Wistar-Kyoto (WKY) and Sprague-Dawley normotensive animals. Pretreatment with the aminopeptidase B inhibitor bestatin (10 nmol, i.c.v.) potentiated and prolonged the heightened pressor response to AIII (100 pmol, i.c.v.) in SH rats. These results suggest that dysfunction of angiotensin peptidase activity may be contributing to the progressive and sustained elevations in blood pressure noted to occur in the SH rat model of human essential hypertension.
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PMID:Dysfunction of central angiotensinergic aminopeptidase activity in spontaneously hypertensive rats. 300 99

This study was designed to evaluate the hypothesis that impaired brain angiotensin signal termination contributes to the sustained blood pressure elevations noted in the genetically hypertensive rat model of human essential hypertension. A technique that combined the intracerebroventricular injection of [125I]angiotensins, followed by focused microwave fixation to stop all peptidase activity and subsequent HPLC analyses, was used for determining half-lives of [125I]angiotensin II and [125I]angiotensin III in the ventricular space. The results indicate that the spontaneously hypertensive rat evidenced significantly longer half-lives for intracerebroventricularly injected [125I]angiotensin II over those measured for the Wistar-Kyoto and Sprague-Dawley normotensive rat strains: 45.0, 27.2, and 25.0 s, respectively. This was also true for intracerebroventricularly administered [125I]angiotensin III: 19.5, 11.4, and 9.0 s, respectively. These results support the notion that a dysfunction in central aminopeptidase activity in the spontaneously hypertensive rat may result in prolonged half-lives of endogenously synthesized angiotensins II and III, which are known to serve as ligands at central angiotensin receptors responsible for the control of cardiovascular function. The extended half-lives of these ligands may contribute to the sustained elevations in blood pressure observed in this animal model.
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PMID:Delayed cerebroventricular metabolism of [125I]angiotensins in the spontaneously hypertensive rat. 359 91

Due to its physiological and pharmacological action ANF could be an ideal diuretic and vasorelaxation product in the treatment of oedema and essential hypertension. Experimental and clinical investigations in oedematous conditions revealed a very slight diuretic and natriuretic effect of ANF, as compared with healthy subjects. This is due to the reduced renal perfusion pressure, the increased RAAS activity, enzymatic degradation of ANF by endopeptidase and also its inactivation via C-receptors. Moreover the use of ANF is very limited due to its short half-life and peptide structure. In recent years therefore new possibilities are sought how to influence the metabolism of endogenous ANF and thus increase its activity. Neutral endopeptidase inhibitors (NEP) inhibit ANF degradation, increase thus its plasma level and in cardiac weakntlakess have a marked diuretic and natriuretic effect. The administration of NEP inhibitors in patients with essential hypertension did not reveal so far an adequate effect on blood pressure. Inhibitors of C-receptors potentiate also the effect of endogenous ANF. In experiments they enhance Na excretion and lead to a drop of blood pressure. Recently another natriuretic peptide was detected--urodilatine. In experimental and clinical studies in cardiac failure urodilatine administration leads to an increase of diuresis and natriuresis greater than after ANF. Haemodynamic effects after urodilatine are also greater than after ANF whereby urodilatine does not cause reflex tachycardia and is resistant to peptidase degradation. Its therapeutic administration is a new perspective in the treatment of oedematous conditions and essential hypertension.
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PMID:[Use of natriuretic peptides in clinical practice]. 818 76

Endogenous peptidases participate in a major way in the formation of peptide pressor substances such as angiotensin II (A II) and endothelin (ET) as well as in the degradation of depressor substances, e.g. atrial natriuretic peptide (ANP) or bradykinin. They include on the one hand the angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE), on the other hand kinase II for bradykinin and neutral endopeptidase 24.11 (NEP) for ANP. Inhibition of these enzymatic reactions leads to a decline of vasopressors A II and ET and conversely delays the break-down of vasodilatating bradykinin and ANP. The main haemodynamic consequence of this double inhibition is a reduced peripheral vascular resistance and decline of the blood pressure. The concurrent block of both systems (dual inhibition) is more effective than the isolated block of one substance. The first dual endopeptidase inhibitors were ACE inhibitors blocking the conversion of angiotensin I to A II and inhibiting at the same time the degradation of bradykinin by kininase II which is identical with ACE. At present further substances were synthetized with a dual inhibitory effect e.g. on ECE and on NEP (phosphoramidone, thiorphan, ecadatril etc.). Under experimental conditions they have a long-term antihypertensive effect on the vascular wall and heart muscle. The development of another dual ACE and NEP inhibitor has reached already the stage of clinical tests and the first clinical studies. The preparation omapatrilate in amounts of 2.5-80 mg significantly reduced the BP in a dose-dependent way in mild and medium advanced essential hypertension. Normalization of the blood pressure, i.e. a drop below 140/90 mm Hg, was achieved with omapatrilate monotherapy in as many as 83% of patients with hypertension stage I and in 53% patients with essential hypertension stage II. The drop of blood pressure after 20-80 mg/day depended on the degree of hypertension and was comparable or better than monotherapy with lisonopril 20 mg/day or amlodipine 10 mg/day. Treatment with omapatrilate was well tolerated. Dual peptidase inhibitors interfering with the formation of pressor substances and with the degradation of depressor substances seem to be a perspective class of antihypertensives also useful in the treatment of other cardiovascular diseases (heart failure, primary pulmonary hypertension). Before its final inclusion in the therapeutic pattern, further comparative and clinical mortality studies must be implemented.
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PMID:[Dual endopeptidase inhibitors--a new direction in the development of hypertensive agents]. 1104 16