Role of calcium-activated potassium channels in impaired acetylcholine vasodilatory responses in diabetic rats.
Muscarinic agonists produce endothelium-dependent vasodilatation in the presence of nitric oxide synthase (NOS) inhibition. The importance of this mechanism was assessed in the methoxamine-preconstricted perfused mesenteric vascular bed (MVB) of streptozotocin diabetic Sprague-Dawley rats. At 9 weeks of age, male rats were treated with streptozotocin (55 mg/kg in citrate buffer) or with citrate buffer alone. The superior mesenteric artery was cannulated and the MVB was detached from its intestinal borders. Concentration-response curves to acetylcholine were determined in the presence and in the absence of indomethacin, tetrabutylammonium (a calcium-activated potassium channel blocker), high extracellular potassium, or NOS inhibition with Nomega-nitro-l-arginine and l-NG-nitro-l-arginine. There was a rightward shift in the concentration-response curve with an increase in median inhibitory concentration (p < 0.05) and a reduction in acetylcholine IMAX (p < 0.05) values in 14-week streptozotocin rats. The ability of NOS inhibition to attenuate vasodilatation was reduced in the 14-week streptozotocin group relative to the 2-week streptozotocin treatment group (p < 0.05). However, the ability of tetrabutylammonium to block acetylcholine-mediated vasodilatation remained consistent in streptozotocin rats at both stages. The results demonstrate that an alternate pathway involving calcium-activated potassium channels may compensate for diminished nitric oxide bioactivity. This effect is contingent on the duration of diabetes. This study provides insight into the development and progression of altered diabetic vascular responses.
Misurski
Derek A
DA
Department of Pharmacology and the Cardiovascular Risk Factor Reduction Unit, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Gopalakrishnan
Venkat
V
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000109:Acetylcholine