Reduced vasorelaxant effect of carbon monoxide in diabetes and the underlying mechanisms.
Carbon monoxide (CO) is an endogenous gaseous factor that relaxes vascular tissues by acting on both the cGMP pathway and calcium-activated K+ (K(Ca)) 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 K(Ca) channels in diabetic smooth muscle cells (SMCs) was not different from that of normal SMCs. However, the sensitivity of K(Ca) channels to CO in diabetic SMCs was significantly reduced. CO (10 micromol/l) induced an 81 +/- 24% increase in the mean open probability of single K(Ca) 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 K(Ca) channels to CO. On the other hand, the sensitivity of K(Ca) 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 K(Ca) channels in diabetic vascular SMCs.
Wang
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Department of Physiology, University of Saskatchewan, Saskatoon, Canada. wangrui@duke.usask.ca
Wang
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Wu
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Hanna
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Peterson-Wakeman
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D019325:3-O-Methylglucose / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D002248:Carbon Monoxide / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013623:Tail / Q000098:blood supply; D013997:Time Factors; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D015221:Potassium Channels; D011810:Quinoxalines; D014665:Vasodilator Agents; D019325:3-O-Methylglucose; D002248:Carbon Monoxide; D006152:Cyclic GMP; D005947:Glucose; D002118:Calcium