Abstract

Angiotensin II (AII), an important hypertrophic factor in the cardiovascular system, exerts most of its known effects in vivo through the AII receptor type 1 (AT₁) subclass of AII receptors. These receptors are also responsible for the growth-related effects of AII in cultured vascular smooth muscle cells (VSMCs). We presently investigated the effects of BAY 10–6734 (Embusartan), a new orally active AT₁ antagonist, on VSMC growth and proliferation of cultured VSMCs isolated from the aortae of Wistar Kyoto rats and spontaneously hypertensive rats. BAY 10–6734 and losartan (considered as AT₁ receptor antagonist of reference), as well as their respective active metabolites, were studied for their inhibition of: 1) [¹²⁵I]AII binding to its receptors, 2) AII-induced DNA and protein synthesis (by measuring the incorporation of 5-bromo-2′-deoxyuridine and [³H]l-leucine, respectively), and 3) AII-induced variations in intracellular Ca²⁺ concentration, using cells labeled with Fura-2. All of the tested compounds inhibited the aforementioned parameters in a concentration-dependent manner. Half-maximal inhibitory concentration values indicated that BAY 10–6734 was significantly more potent than losartan and that spontaneously hypertensive rat-derived VSMCs were more sensitive than Wistar Kyoto rat-derived ones. Neither BAY 10–6734 nor losartan affected the intracellular Ca²⁺ concentration of unstimulated VSMCs but both compounds inhibited both AII-induced Ca²⁺ mobilization from internal stores and Ca²⁺influx. Neither compound affected arginine-vasopressin-, basic fibroblast growth factor-, or serum-induced DNA and protein synthesis. BAY 10–6734 appears therefore as a potent and specific new inhibitor of AII-induced growth-related events in VSMCs.