Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signalling system in vascular smooth muscle cells

Abstract

2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt (Losartan) (previous name, DuP 753 or MK 954) is a nonpeptide angiotensin II receptor antagonist. This study was performed to investigate the ability of Losartan to inhibit the angiotensin II-induced stimulation of the phospoinositide signalling system and the angiotensin II-induced hypertrophy in aortic vascular smooth muscle cells of normotensive Wistar-Kyoto rats. 10 −7 M Losartan abolished the angiotensin II-induced formation of inositol 1,4,5-trisphosphate in vascular smooth muscle cells. 10 −6 M Losartan completely abolished the angiotensin II-induced elevation of the intracellular free Ca 2+ concentration ([Ca 2+] i). 10 −6 M Losartan lacked effects on the [Arg 8]vasopressin-induced elevation of [Ca 2+] i. In addition, 10 −6 M completely inhibited the angiotensin II-induced stimulation of Na +/H + exchange in the vascular smooth muscle cells. 10 −10 to 10 −6 M Losartan inhibited the angiotensin II-induced cell protein synthesis in a concentration-dependent manner, yielding to an effective concentration (ED 50) of 6.2 ± 1.8 × 10 −8 M (n = 4). Losartan did not affect the platelet-derived growth factor-BB-induced increase in cell protein. These results show that Losartan is a highly specific angiotensin II receptor antagonist which inhibits angiotensin II-induced cell growth and thus may have beneficial effects on the development and regression of vascular hypertrophy.