Abstract

The RhoA-Rho kinase (ROCK) pathway contributes to a number of diabetic complications including cardiomyopathy and nephropathy. In this study, we investigated whether it contributes to elevated blood pressure and vascular contractile dysfunction in type 2 diabetes. Blood pressure was measured in Goto-Kakizaki rats, a nonobese model of type 2 diabetes, before and after treatment with the ROCK inhibitor fasudil. Vasoconstrictor responsiveness in the absence and presence of ROCK inhibitors as well as ROCK pathway activity was measured in isolated mesenteric resistance vessels from these animals. Blood pressure was elevated in diabetic rats compared with age-matched Wistar controls, and was normalized by treatment with fasudil. Contractile responses of mesenteric arteries from diabetic rats to phenylephrine and U-46619, as well as relaxant responses to acetylcholine, were unaltered. However, vasoconstrictor responses were more sensitive to ROCK inhibition with either Y-27632 or H-1152 than were responses of control arteries. No differences were found in expression of RhoA, ROCK1, or ROCK2 or in basal ROCK activity between arteries from control and diabetic rats. U-46619 produced a similar magnitude of increase in ROCK activity that was completely blocked by H-1152 in arteries from both groups of animals. These data suggest that ROCK contributes to the increase in blood pressure in type 2 diabetic Goto-Kakizaki rats, and that vasoconstrictor responses of small mesenteric arteries from these animals are more dependent on ROCK than are responses of control arteries.

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