A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats.
Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D) who exhibit cardiovascular disease. In the present study, we have examined the effect of SKA-31, a positive modulator of endothelial Ca(2+)-activated K(+) (KCa) channels, on total coronary flow in isolated hearts from Goto-Kakizaki rats, a non-obese model of T2D exhibiting metabolic syndrome. Total coronary flow and left ventricular developed pressure were monitored simultaneously in isolated, spontaneously beating Langendorff-perfused hearts. Acute administrations of bradykinin (BK) or adenosine (ADO) increased coronary flow, but responses were significantly blunted in diabetic hearts at 10-12 and 18-20weeks of age compared with age-matched Wistar controls, consistent with the presence of endothelial dysfunction. In contrast, SKA-31 dose-dependently (0.01-5μg) increased total coronary flow to comparable levels in both control and diabetic rat hearts at both ages. Flow responses to sodium nitroprusside were not different between control and diabetic hearts, suggesting normal arterial smooth muscle function. Importantly, exposure to a sub-threshold concentration of SKA-31 (i.e. 0.3μM) rescued the impaired BK and ADO-evoked vasodilatory responses in diabetic hearts. Endothelial KCa channel activators may thus help to preserve coronary flow in diabetic myocardium.
Dept of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, T2N 4 N1 Canada.
Ramesh C
RC
Mishra
Dept of Pharmacology, University of California-Davis, Davis, CA 95616, USA.
Heike
H
Wulff
Dept of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, T2N 4 N1 Canada.
William C
WC
Cole
Dept of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, T2N 4 N1 Canada. Electronic address: abraun@ucalgary.ca.
Andrew P
AP
Braun
D000241:Adenosine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007260:Infusion Pumps; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D009924:Organ Culture Techniques; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D052160:Benzothiazoles; D024681:Potassium Channels, Calcium-Activated; C535212:naphtho(1,2-d)thiazol-2-ylamine; D009599:Nitroprusside; D000241:Adenosine; D001920:Bradykinin
Calcium-activated K(+) channel; Coronary circulation; Endothelium; Type 2 diabetes; Vasodilation