Vol. 289, Issue 1, 181-187, April 1999

Effects of Bay 10-6734 (Embusartan), a New Angiotensin II Type I Receptor Antagonist, on Vascular Smooth Muscle Cell Growth^1,2

L. Iouzalen, O. Stepien and P. Marche

Department of Pharmacology, CNRS URA 1482, University René Descartes, Necker Medical School, Paris, France

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.