A pharmacologic activator of endothelial K_(Ca) channels enhances coronary flow in the hearts of type 2 diabetic rats

摘要

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 SICA-31, a positive modulator of endothelial Ca~(2+)-activated K~+ (K_(Ca)) 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 18-20 weeks of age compared with age-matched Wistar controls, consistent with the presence of endothelial dysfunction. In contrast, SKA-31 dose-dependently (0.01-5 mug) 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. 0.3 muM) rescued the impaired BK and ADO-evoked vasodilatory responses in diabetic hearts. Endothelial K_(Ca) channel activators may thus help to preserve coronary flow in diabetic myocardium.