Cardioprotection in mice lacking cardiovascular KATP channels

Adenosine triphosphate sensitive potassium (K ATP ) channels are thought to mediate stress response by sensing intracellular ATP concentration. Cardiomyocyte K ATP channels are composed of the pore‐forming Kir6.2 subunit and the regulatory sulfonylurea receptor SUR2. Mice lacking Kir6.2 have an impaired response to sympathetic stress with arrhythmia and death (Zingman et al. 2002). We studied adrenergic stress response in SUR2 null mice by injecting isoproterenol (5 μg/g, i.p.). Surprisingly, the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated during isoproterenol‐induced tachycardia. In SUR2 null mice, adrenergic stress did not have an adverse effect on survival, nor did it elicit ECG abnormalities. Ischemic stress experiments on Langendorff‐perfused hearts isolated from SUR2 null exhibited significantly reduced infarct size (54±4 vs 30±3%) and improved cardiac function after 40 min of no flow ischemia compared to control mice. SUR2 null mice were administered nifedipine (3 mg/kg/day for 10 days) to block baseline coronary vasospasm, and hearts from nifedipine‐treated SUR2 null mice exhibited increased infarct size similar to control wildtype mice (47±3 % vs 54±3%). We conclude that coronary vasospasm in SUR2 null mice generates a cardioprotective response, and this response does not require conventional cardiomyocyte K ATP channels. Supported by NIH RO1HL078926.