Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signalling system in vascular smooth muscle cells.
2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-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 Ca2+ concentration ([Ca2+]i). 10(-6) M Losartan lacked effects on the [Arg8]vasopressin-induced elevation of [Ca2+]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 (ED50) of 6.2 +/- 1.8 x 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.
Ko
Y
Y
Medizinische Universitäts-Poliklinik, Bonn, Germany.
Görg
A
A
Appenheimer
M
M
Wieczorek
A J
AJ
Düsing
R
R
Vetter
H
H
Sachinidis
A
A
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; D019808:Losartan; D002118:Calcium