SKA-31, a novel activator of SKCa and IKCa channels, increases coronary flow in male and female rat hearts

摘要

AimsEndothelial SKCa and IKCa channels play an important role in the regulation of vascular function and systemic blood pressure. Based on our previous findings that small molecule activators of SKCa and IKCa channels (i.e. NS309 and SKA-31) can inhibit myogenic tone in isolated resistance arteries, we hypothesized that this class of compounds may induce effective vasodilation in an intact vascular bed, such as the coronary circulation.Methods and resultsIn a Langendorff-perfused, beating rat heart preparation, acute bolus administrations of SKA-31 (0.01-5 μg) dose-dependently increased total coronary flow (25-30%) in both male and female hearts; these responses were associated with modest, secondary increases in left ventricular (LV) systolic pressure and heart rate. SKA-31 evoked responses in coronary flow, LV pressure, and heart rate were qualitatively comparable to acute responses evoked by bradykinin (1 μg) and adenosine (10 μg). In the presence of apamin and TRAM-34, selective blockers of SK Ca and IKCa channels, respectively, SKA-31 and bradykinin-induced responses were largely inhibited, whereas the adenosine-induced changes were blocked by ～40%; TRAM-34 alone produced less inhibition. Sodium nitroprusside (SNP, 0.2 μg bolus dose) evoked changes in coronary flow, LV pressure, and heart rate were similar to those induced by SKA-31, but were unaffected by apamin + TRAM-34. The NOS inhibitor L-NNA reduced bradykinin-and adenosine-evoked changes, but did not affect responses to either SKA-31 or SNP.ConclusionOur study demonstrates that SKA-31 can rapidly and reversibly induce dilation of the coronary circulation in intact functioning hearts under basal flow and contractility conditions.