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Angiotensin II receptor antagonists: a new approach to blockade of the renin-angiotensin system.

Abstract：

:A-II exerts its activity on various target tissues by binding to its receptors. The discovery of local RASs and A-II receptors within various tissues has generated interest in the clinical usefulness of RAS inhibition by directly blocking the action of A-II at the receptor level. Different A-II receptor subtypes have been identified and subsequently termed AT1 and AT2. AT1-receptor subtypes are the predominant receptor subtypes existing in most organs and, by coupling to a transmembrane G protein, seem to be the main subtypes participating in the vasoactive responses of A-II. Saralasin, a peptide with specific A-II receptor-antagonistic activity, had limited practical long-term usefulness as a result of its short half-life, significant agonistic properties, and lack of oral bioavailability. The discovery of simple benzyl-substituted imidazoles, which possess weak but highly selective A-II receptor antagonistic properties, led to the development of losartan (DuP 753). Losartan is a potent, orally active, specific, competitive nonpeptide A-II receptor antagonist that appears to be an effective antihypertensive agent both in animal studies and in preliminary clinical trials. The therapeutic usefulness of losartan, however, is not limited to its antihypertensive effects. The potential benefits of A-II receptor antagonists include roles in postmyocardial infarction therapy, slowing A-II-induced cardiac hypertrophy, 154, 155 slowing the progression of heart failure, preventing postangioplasty restenosis, and in slowing the progression of renal disease. Furthermore, losartan, a selective A-II type 1 (AT1) receptor antagonist, has also been a valuable pharmacologic probe for studying the mechanism of A-II stimulation of its receptors. A-II receptor antagonism appears to be as effective as ACE inhibition in the treatment of hypertension and other pathologic processes that involve the RAS and may offer an alternative to those patients who cannot tolerate ACE inhibitors because of their side effects.

journal_name

Am Heart J

journal_title

American heart journal

authors

Kang PM,Landau AJ,Eberhardt RT,Frishman WH

doi

10.1016/0002-8703(94)90061-2

subject

Has Abstract

pub_date

1994-05-01 00:00:00

pages

1388-401

issue

eissn

0002-8703

issn

1097-6744

pii

0002-8703(94)90061-2

journal_volume

127

pub_type

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Angiotensin II receptor antagonists: a new approach to blockade of the renin-angiotensin system.