Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice

ATP-sensitive potassium (K-ATP) channels were discovered in ventricular cel ls. but their roles in the heart remain mysterious. K-ATP channels have als o been found in numerous other tissues, including vascular smooth muscle. T wo pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of K-ATP channels. To determine which subunits are operative in the cardiovas cular system and their functional roles, we characterized the effects of ph armacological K+ channel openers (KCOs, ie, pinacidil, P-1075, and diazoxid e) in Kir6.2-deficient mice. Sarcolemmal K-ATP channels could be recorded e lectrophysiologically in ventricular cells from Kir6.2(+/+) (wild-type [WT] ) but not from Kir6.2(-/-) (knockout [KO]) mice. In WT ventricular cells, p inacidil induced an outward current and action potential shortening, effect s that were blocked by glibenclamide, a K-ATP channel blocker. KO ventricul ar cells exhibited no response to KCOs, but gene transfer of Kir6.2 into ne onatal ventricular cells rescued the electrophysiological response to P-107 5. In terms of contractile function, pinacidil decreased force generation i n WT but not KO hearts. Pinacidil and diazoxide produced concentration-depe ndent relaxation in both WT and KO aortas precontracted with norepinephrine . in addition, pinacidil induced a glibenclamide-sensitive current of simil ar magnitude in WT and KO aortic smooth muscle cells and comparable levels of hypotension in anesthetized WT and KO mice. In both WT and KO aortas, on ly Kir6.1 mRNA was expressed. These findings indicate that the Kir6.2 subun it mediates the depression of cardiac excitability and contractility induce d by KCOs: in contrast, Kir6.2 plays no discernible role in the arterial tr ee.