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© 2001 by the American Diabetes Association, Inc.
Reduced Vasorelaxant Effect of Carbon Monoxide in Diabetes and the Underlying Mechanisms
From the Departments of Physiology (R.W., S.T.H., R.P.-W.) and Anatomy and Cell Biology (L. W.), University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and the Laboratory of Cellular Morphology (Z. W.), Weifang Medical College, Weifang, China.
Address correspondence and reprint requests to Dr. Rui Wang, Department of Physiology, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, SK, Canada S7N 5E5. Email: wangrui{at}duke.usask.ca .
Carbon monoxide (CO) is an endogenous gaseous factor that relaxes vascular tissues by acting on both the cGMP pathway and calcium-activated K+ (KCa) channels. Whether the vascular effect of CO is altered in diabetes had been unknown. It was found that the CO-induced relaxation of tail artery tissues from streptozotocin-induced diabetic rats was significantly decreased as compared with that of nondiabetic control rats. The blockade of the cGMP pathway with ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one) completely abolished the CO-induced relaxation of diabetic tissues but only partially inhibited the CO effect in normal tissues. Single-channel conductance of KCa channels in diabetic smooth muscle cells (SMCs) was not different from that of normal SMCs. However, the sensitivity of KCa channels to CO in diabetic SMCs was significantly reduced. CO (10 µmol/l) induced an 81 ± 24% increase in the mean open probability of single KCa channels in normal SMCs but had no effect in diabetic SMCs. Longterm culture of normal vascular SMCs with 25 mmol/l glucose or 25 mmol/l 3-OMG (3-O-methylglucose) but not 25 mmol/l mannitol significantly reduced the sensitivity of KCa channels to CO. On the Other hand, the sensitivity of KCa channels to CO was regained in diabetic SMCs that were cultured with 5 mmol/l glucose for a prolonged period. The decreased vasorelaxant effect of CO in diabetes represents a novel mechanism for the vascular complications of diabetes, which could be closely related to the glycation of KCa channels in diabetic vascular SMCs.
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