The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries

Abstract

Increased renal vascular resistance contributes to the pathogenesis of hypertension. The new Rho kinase (ROCK) inhibitor SAR407899 more potently lowers arterial pressure than the commercially available ROCK inhibitor Y27623. We tested whether ROCK inhibition more effectively reduced agonist-induced vasoconstriction in renal than in nonrenal resistance arteries and if SAR407899 more potently inhibits agonist-induced vasoconstriction than Y27632. The effects of the ROCK inhibitors on endothelin-1 (ET-1) induced vasoconstriction were investigated in isolated renal and coronary arteries from lean, normotensive Dark Agouti and obese, type 2 diabetic Zucker diabetic fatty (ZDF) rats as well as in isolated human resistance arteries from the kidney and thymus. Vascular ROCK mRNA abundance was studied by real-time PCR (RT-PCR). ET-1-induced constriction depended more on ROCK in rat and human renal resistance arteries than in rat coronary or human thymic arteries, respectively. SAR407899 was more effective than Y27632 in reducing ET-1-induced vasoconstriction in ZDF rat renal resistance arteries. Maximum ET-1-induced vasoconstriction in SAR407899-treated and Y27632-treated human renal resistance arteries was 23 ± 5 and 48 ± 6% of control values, respectively. Transcripts of both ROCK isoforms were detected in rat and human renal resistance arteries. In human thymic arteries, only the ROCK2 transcript was found. ET-1-induced vasoconstriction is more ROCK-dependent in renal than in nonrenal resistance arteries. SAR407899 causes a greater inhibition of ET-1-induced vasoconstriction in renal resistance arteries from ZDF rats and patients than Y27632. The greater efficacy in renal vessels may contribute to the higher antihypertensive potency of SAR407899 compared with Y27632.