Angiotensin II receptors and functional correlates.
Angiotensin II (ANG II) is the primary mediator of the renin-angiotensin system, which has an important functional role in cardiovascular homeostasis. The angiotensin receptor and its functional correlates have been redefined by the cloning of angiotensin receptors and the discovery and widespread study of specific nonpeptide ANG II-receptor antagonists losartan (AT1 selective) and PD123177 (AT2 selective). With these antagonists, it has been possible to extend the concept of ANG II-receptor heterogeneity to virtually every tissue and species. The losartan-sensitive sites have been shown to mediate all of the major ANG II-induced biologic effects, including vasoconstriction, aldosterone and catecholamine release, and central, ANG II-induced drinking behavior. The function of the AT2 site is not fully understood, but it may be involved in neuronal ion channel modulation and in fibroblast collagen metabolism. The presence of AT2 sites in fetal tissues and in discrete locations in the brain has encouraged continued research. Losartan, which represents the first of a new class of therapeutic agents, is currently undergoing clinical trials. A growing number of other AT1-selective ANG II-receptor antagonists are under development, including L-158,809, SKF 108566, and GR117285. Rat AT1-receptor subtypes have been cloned and sequenced (AT1A and AT1B). Human ANG II receptors have also been cloned and shown to have high affinity for losartan. A number of atypical angiotensin-binding sites have been identified from mycoplasma, amphibians, and mouse neuroblastoma, which are not sensitive to either losartan or PD123177.(ABSTRACT TRUNCATED AT 250 WORDS)
Timmermans
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PB
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Benfield
P
P
Chiu
A T
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Herblin
W F
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Wong
P C
PC
Smith
R D
RD
D000179:Acrylates / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001794:Blood Pressure / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use; D019808:Losartan; D011725:Pyridines / Q000627:therapeutic use; D011945:Receptors, Angiotensin / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use; D013876:Thiophenes
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D013876:Thiophenes; C066253:PD 123177; C068373:eprosartan; D019808:Losartan