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

The effects of CV-11974, a potent nonpeptide antagonist of the angiote nsin II (AII) type-1 receptor (AT(1)), on cytosolic free calcium conce ntration ([Ca2+](i)), hyperplasia, and hypertrophy of cultured vascula r smooth muscle cells (VSMC) from rat aorta were studied. [Ca2+](i) wa s measured by fura 2, and hyperplasia and hypertrophy were determined by incorporation of [H-3]thymidine and [H-3]leucine, respectively. CV- 11974 had no effect on [Ca2+](i) itself, but suppressed 10(-7) M AII-i nduced increase in [Ca2+](i) dose dependently at concentrations from 1 0(-10) M and completely at 10(-7) M. CV-11974 suppressed both Ca2+ rel ease from intracellular Ca2+ stores and Ca2+ influx from the extracell ular space. However, CV-11974 had no effect on the increases in [Ca2+] (i) induced by prostaglandin F-2 alpha (PGF(2 alpha)), a potent vasoco nstrictor, 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 p rotein 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 Ail- stimulated synthesis of DNA and protein dose dependently at concentrat ions greater than or equal to 10(-8) and 10(-10) M, respectively and c ompletely at 10(-6) M. These results indicate that AII increases [Ca2](i) and synthesis of DNA and protein in VSMC through activation of AT (1). CV-11974 showed no partial agonistic effects on AII. Thus, CV-119 74 may act not only as an antihypertensive agent, but also as an inhib itor of vascular injury stimulated by AII.