Vol. 304, Issue 3, 1236-1242, March 2003

Minalrestat, an Aldose Reductase Inhibitor, Corrects the Impaired Microvascular Reactivity in Diabetes

Eliana H. Akamine, Thomas C. Hohman, Dorothy Nigro, Maria Helena C. Carvalho, Rita de Cássia Tostes and Zuleica B. Fortes

Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil (E.H.A., D.N., M.H.C.C., R.C.T., Z.B.F.); and Pharmacia & Upjohn, Peapack, New Jersey (T.C.H.)

We demonstrated that aldose reductase inhibition corrects the impaired microvascular responses to inflammatory mediators in diabetic rats. To study the mechanism involved in the restoring effect of aldose reductase inhibition, we examined the effects of minalrestat, another aldose reductase inhibitor, on the responses of mesenteric microvessels studied in vivo to permeability-increasing agents in diabetic and galactosemic rats. The diabetic group was treated from 3 days after the alloxan injection with minalrestat (10 mg/kg/day) for 30 days and the minalrestat treatment (10 mg/kg/day/7 days) of galactosemic rats started concomitantly with the induction of galactosemia. The mesenteric microvessel reactivity was studied using intravital microscopy and changes in vessel diameters were estimated after the topical application of vasoactive agents. The impaired responses to bradykinin, histamine, and platelet-activating factor of arterioles and venules observed in diabetic and galactosemic rats were completely prevented by minalrestat. Neither diabetes nor galactosemia affected responses to acetylcholine and sodium nitroprusside. Responses to these agents were not modified by aldose reductase inhibition. The restoring effect of minalrestat was reversed by inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine methyl ester, by blocking K⁺ channel with tetraethylammonium but not by cyclooxygenase inhibition with diclofenac. Therefore, we concluded that NO, membrane hyperpolarization, but not cyclooxygenase products are involved in the beneficial effect of minalrestat on the microvascular reactivity in diabetes. Together, these findings led us to suggest that aldose reductase inhibition might ameliorate diabetic complications through the correction of the altered microvascular reactivity by a mechanism that involves NO and membrane hyperpolarization.