title: Effect of an AT1 receptor antagonist (CV-11974) on angiotensin II-induced cardiomyocyte hypertrophy in vitro.
abstract: Angiotensin (ANG) II, a potent vasoconstrictor is known to be a hypertrophic factor for cardiomyocytes. Recently, endothelin (ET)-1 has also been shown to be an autocrine/paracrine growth factor for cardiomyocytes. To determine the cellular mechanism by which ANG II induces cardiac hypertrophy, we studied the effects of ANG II on the gene expression of ET-1 and ET receptor subtypes (ETA, ETB), as well as its effects on the expression of immediate early oncogenes (c-fos, c-myc) in cultured rat cardiomyocytes in vitro. ANG II (10(-7) M) increased steady-state mRNA levels of ET-1 in the same manner as c-fos and c-myc during a short incubation period (0.5-1 h), while ANG II induced ETB receptor mRNA, but not ETA receptor mRNA, during a long incubation period (6-12 h). CV-11974, an antagonist of ANG II receptor type-1 (AT1), inhibited the ANG II-induced expression of c-fos, c-myc and ET-1 mRNAs, as well as that of ETB receptor mRNA, whereas PD-123319, an antagonist of the ANG II type-2 (AT2) receptor, failed to block such induction. CV-11974 similarly blocked ANG II-induced immediate-early oncogenes (c-fos, c-myc) in cultured rat vascular smooth muscle cells. Our findings indicate that ANG II immediately upregulates the cardiac ET-1 gene in the same manner as it does the immediate early protooncogenes, while the late induction of the ETB receptor, mainly via the cardiac AT1 receptor, suggests the involvement of endogenous ET-1 in ANG II-induced cardiac hypertrophy.
authors.affiliation: Department of Medicine, Tokyo Mekical and Dental University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: K
authors.initials: K
authors.lastname: Kanno
authors.forename: S
authors.initials: S
authors.lastname: Eguchi
authors.forename: H
authors.initials: H
authors.lastname: Kano
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000139:chemically induced* / Q000188:drug therapy*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018076:DNA, Complementary; D019332:Endothelin-1; D016232:Endothelins; D007093:Imidazoles; D011498:Protein Precursors; D011725:Pyridines; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C081643:candesartan