Objectives: 

Increased renal vascular resistance contributes to the pathogenesis of hypertension. The new Rho kinase (ROCK) inhibitor SAR407899 lowers arterial pressure more potently than the commercially available ROCK inhibitor Y27623. We tested if ROCK inhibition more effectively reduced agonist-induced vasoconstriction in renal than in non-renal resistance arteries and if SAR407899 more potently inhibits agonist-induced vasoconstriction than Y27632.

Methods: 

The effects of ROCK inhibitors on endothelin-1 (ET-1)-induced vasoconstriction were investigated in isolated human renal and thymic resistance arteries as well as in small renal and coronary arteries from lean, normotensive Dark Agouti (DA) and obese, Zucker diabetic fatty (ZDF) rats. Vascular ROCK mRNA abundance was studied by real-time RT-PCR.

Results: 

ET-1-induced vasoconstriction depended more on ROCK in human and rat renal resistance arteries than in human thymic and rat coronary arteries, respectively. SAR407899 and Y27632 reduced maximum ET-1-induced vasoconstriction to 23 ± 5 and 48 ± 6% of control values, respectively (p < 0.05). Similar results were obtained in ZDF rat small intrarenal arteries. Transcripts of both ROCK isoforms were detected in human renal, rat renal and rat coronary resistance arteries. In human thymic arteries only the ROCK2 transcript was found.

Conclusion: 

ET-1-induced vasoconstriction is more ROCK-dependent in renal than in non-renal resistance arteries. SAR407899 more potently inhibits ET-1-induced vasoconstriction in renal resistance arteries from patients and ZDF rats than Y27632. By efficiently reducing renal vascular resistance, SAR407899 may add valuable therapeutic options for the management of arterial hypertension.