Rho kinase inhibitors prevent endothelium-dependent contractions in the Rat Aorta

Abstract

Rho kinase is involved in the pathogenesis of hypertension, which favors the occurrence of endothelium-dependent contractions. The present study was designed to determine the effects of two Rho kinase inhibitors, HA1077 [1-(5-isoquinoline-sulfonyl)-homopiperazine (fasudil)] and Y27632 [(+)-(R]-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihy-drochloride], on endothelium-dependent and -independent contractions. Isometric tension of 1-year-old spontaneously hypertensive rat and Wistar Kyoto aortae were measured. In the presence of Nω-nitro-L-arginine methyl ester, HA1077, and Y27632 reduced endothelium-dependent contractions caused by acetylcholine and the calcium ionophore 5-(methylamino)2-[[2R,3R,6S,8S,9R,11R)- 3,9,11-trimethyl-8-[(1S)-1-methyl-2- oxo-2-(1H-pyrrol-2-yl)-ethyl]-1,7- dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid (A23187). The Rho kinase inhibitors did not significantly affect prostacyclin production measured as 6-keto prostaglandin F1α,. They nearly abolished endothelium-independent contractions to (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3- hydroxy-1-octenyl]-2-oxabicyclo-[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), prostaglandin F2α, and phenylephrine. Western blotting revealed a comparable expression of Rho kinase in the aortae of the two strains. The reduction by Rho kinase inhibitors of endothelium-dependent contractions is mainly because of their direct effect on the vascular smooth muscle cells. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.