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-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 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.
Footnotes
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This work was supported by the Research Grant Council of Hong Kong and the Research Centre of Heart, Brain, Hormone and Healthy Aging [Grant University of Hong Kong–777507M].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.148247.
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ABBREVIATIONS: SHR, spontaneously hypertensive rat; EC, endothelial cells; EDCF, endothelium-dependent contracting factor; TP, thromboxane-prostanoid; HA1077 (fasudil), 1-(5-isoquinolinesulfonyl)-homopiperazine; WKY, Wistar Kyoto rat(s); 6-keto PGF1α, 6-keto prostaglandin F1α; l-NAME, Nω-nitro-l-arginine methyl ester; A23187, 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; Y27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride; U46619, (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid; S18886, terutroban, Triplion.
- Received November 6, 2008.
- Accepted February 3, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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