title: Effects of an angiotensin II receptor antagonist, CV-11974, on angiotensin II-induced increases in cytosolic free calcium concentration, hyperplasia, and hypertrophy of cultured vascular smooth muscle cells.
abstract: The effects of CV-11974, a potent nonpeptide antagonist of the angiotensin II (AII) type-1 receptor (AT1), on cytosolic free calcium concentration ([Ca2+]i), hyperplasia, and hypertrophy of cultured vascular smooth muscle cells (VSMC) from rat aorta were studied. [Ca2+]i was measured by fura 2, and hyperplasia and hypertrophy were determined by incorporation of [3H]thymidine and [3H]leucine, respectively. CV-11974 had no effect on [Ca2+]i itself, but suppressed 10(-7) M AII-induced increase in [Ca2+]i dose dependently at concentrations from 10(-10) M and completely at 10(-7) M. CV-11974 suppressed both Ca2+ release from intracellular Ca2+ stores and Ca2+ influx from the extracellular space. However, CV-11974 had no effect on the increases in [Ca2+]i induced by prostaglandin F2 alpha (PGF2 alpha), a potent vasoconstrictor, or ionomycin, a Ca2+ ionophore. These results indicate that the suppressive effects of CV-11974 act on the binding of AII and its specific receptors. AII 10(-7) M increased the synthesis of DNA and protein to 1.5 and 1.7 times the control values, respectively. CV-11974 had no effect on synthesis of DNA or protein, but suppressed the AII-stimulated synthesis of DNA and protein dose dependently at concentrations > or = 10(-8) and 10(-10) M, respectively and completely at 10(-6) M. These results indicate that AII increases [Ca2+]i and synthesis of DNA and protein in VSMC through activation of AT1. CV-11974 showed no partial agonistic effects on AII. Thus, CV-11974 may act not only as an antihypertensive agent, but also as an inhibitor of vascular injury stimulated by AII.
authors.affiliation: Department of Geriatric Medicine, Osaka University Medical School, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Koh
authors.forename: S
authors.initials: S
authors.lastname: Morimoto
authors.forename: J
authors.initials: J
authors.lastname: Tomita
authors.forename: H
authors.initials: H
authors.lastname: Rakugi
authors.forename: B
authors.initials: B
authors.lastname: Jiang
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Nabata
authors.forename: K
authors.initials: K
authors.lastname: Fukuo
authors.forename: T
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D015237:Dinoprost / Q000494:pharmacology; D016257:Fura-2; D006965:Hyperplasia / Q000139:chemically induced; D006984:Hypertrophy / Q000139:chemically induced; D015759:Ionomycin / Q000494:pharmacology; D009124:Muscle Proteins / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009124:Muscle Proteins; D013777:Tetrazoles; D000804:Angiotensin II; D015759:Ionomycin; D004247:DNA; D015237:Dinoprost; C081643:candesartan; D002118:Calcium; D016257:Fura-2