ANGIOTENSIN-II RECEPTORS AND FUNCTIONAL CORRELATES

被引:155
作者
TIMMERMANS, PBMWM
BENFIELD, P
CHIU, AT
HERBLIN, WF
WONG, PC
SMITH, RD
机构
[1] The Du Pont Merck Pharmaceutical Company, Wilmington, DE
[2] The Du Pont Merck Pharmaceutical Company, Experimental Station, Wilmington, DE, 19880-0400
关键词
ANGIOTENSIN-II; LOSARTAN (DUP-753); ANGIOTENSIN-II RECEPTOR; RENIN-ANGIOTENSIN SYSTEM;
D O I
10.1093/ajh/5.12.221S
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 dinical 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. Our view of the ANG II receptor continues to grow in its complexity, as losartan and other nonpeptide antagonists are used as tools to define the functional role(s) of ANG II.
引用
收藏
页码:S221 / S235
页数:15
相关论文
共 44 条
  • [1] Peach M.J., Dostal D.E., The angiotensin II receptor and the action of angiotensin II, J Cardiovasc Pharmacol, 16, pp. S25-S30, (1990)
  • [2] Ferrario C.M., Importance of the renin-angiotensin- aldosterone system (RAS) in the physiology and pathology ofhypertension, Drugs, 39, (1990)
  • [3] Laragh J.H., Vasoconstriction volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles, Am J Med, 55, (1973)
  • [4] Guyton A.C., Blood pressure control—special role of the kidney and body fluids, Science, 252, (1991)
  • [5] Skeggs L.T., Historical overview of the renin-angiotensin system, Hypertension and the Angiotensin System: Therapeutic Approaches, pp. 31-45, (1984)
  • [6] Regoli D., Park W.K., Rioux F., Pharmacology of angiotensin, Pharmacol Rev, 26, pp. 69-123, (1974)
  • [7] Regoli D., Receptors for angiotensin: A critical analysis, Can J Physiol Pharmacol, 57, pp. 129-139, (1979)
  • [8] Papdimitriou A., Worcel M., Dose-response curves for angiotensin II and synthetic analogues in three types of smooth muscle: Existence of different forms of receptor sites for angiotensin II, Br J Pharmacol, 50, (1974)
  • [9] Goodfriend T.L., Peach M.J., Angiotensin III: (des-aspartic acid-angiotensin II, Circ Res, 37, (1975)
  • [10] Devynck M.A., Pemollet M.G., Matthews P.G., Et al., Specific receptors for des-Asp1-angiotensin II ("angiotensin III") in rat adrenals, Proc Natl Acad Sci USA, 74, pp. 4029-4032, (1977)