© 1997 American Heart Association, Inc.
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Increased Myogenic Tone and Diminished Responsiveness to ATP-Sensitive K+ Channel Openers in Cerebral Arteries From Diabetic Rats
From the Department of Pharmacology (A.S.S., H.J.K., M.T.N.) and the Division of Cardiology (P.A.Z.), The University of Vermont, Burlington.
Correspondence to Dr Mark T. Nelson, Department of Pharmacology, The University of Vermont, Given Building, Room B303, Burlington, VT 05405-0068. E-mail nelson{at}northpole.med.uvm.edu
Abstract Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel openers. In this study, we explored the effects of diabetes induced in rats by streptozotocin on cerebral artery (250 to 300 µm) myogenic tone and on vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim. Elevation of intravascular pressure caused a graded membrane potential depolarization and constriction, which was greater in arteries from diabetic rats compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 µm more constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15-fold less sensitive to pinacidil and levcromakalim than were control arteries (EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 µmol/L, respectively, in diabetic animals and 0.3 and 0.04, respectively, in control animals; P<.05). Removal of the endothelium or addition of a NO synthase inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the sensitivity to KATP channel openers and depolarized and constricted control arteries to levels similar to those observed in arteries from diabetic animals. Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals. Removal of the endothelium or LNNA had little effect on the apparent KATP channel opener sensitivity, the membrane potential, and pressure-induced constrictions of arteries from diabetic animals. The results are consistent with the hypothesis that this type of diabetes leads to a decrease in tonic NO release from the endothelium, which in turn causes membrane potential depolarization and vasoconstriction, resulting in a diminished response to KATP channel openers.
Key Words: diabetes • K+ channel • endothelium • vascular smooth muscle • nitric oxide
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