Rho kinase inhibitors prevent endothelium-dependent contractions in the rat aorta.
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-isoquinolinesulfonyl)-homopiperazine (fasudil)] and Y27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride], 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 N(omega)-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 F(1alpha). 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 F(2alpha), 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.
Chan
Calvin K Y
CK
Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
Mak
Judith C
JC
Man
Ricky Y K
RY
Vanhoutte
Paul M
PM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000577:Amides; D000959:Antihypertensive Agents; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil