Potassium ATP (KATP) channels are composed of a sulfonylurea subunit, SUR1 or SUR2, and a pore forming potassium channel, Kir6.1 or Kir6.2. KATP channels regulate cellular membrane potential by responding to the intracellular energy state through ADP levels. Because KATP channels are pharmacologically accessible, KATP channels have been implicated in ischemic preconditioning, cardiac stress response, and in the generation of electrocardiographic evidence of cardiac ischemia and injury. We studied mice lacking SUR2, a protein normally found in vascular smooth and striated muscle. The cardiovascular phenotype in SUR2 mutant mice is multifold reflecting the importance of KATP channels to normal cardiovascular function. First, SUR2 mutant mice develop hypertension. Additionally, SUR2 mutant mice display episodic coronary artery vascular spasm that can be visualized by electrocardiographic monitoring and by direct visualization of coronary arteries. Coronary artery vascular spasm leads to enhanced mortality in SUR2 null mice by producing lethal bradycardic arrhythmias that arise as a result of coronary artery vasospasm. Lethality is more profound in male versus female SUR2 mutant mice. Therefore, we propose experiments designed to understand the tissue of origin responsible for aspects of the SUR2 mutant phenotype. We propose to restore the vascular smooth muscle sulfonylurea component in SUR2 mutant mice to demonstrate that an intrinsic vascular smooth muscle defect is responsible for both hypertension and coronary artery vascular spasm. We will use a transgenic rescue strategy where SUR2 will be expressed under the control of the SM22alpha, smooth muscle promoter. Similarly, we propose to express SUR2 under the control of a cardiomyocyte-specific promoter and breed these transgenic mice to SUR2 null mice. These experiments will help determine the origin of vascular spasm as well as the role of cardiomyocyte KATP channels. We will examine whether the enhanced lethality seen in male SUR2 mutant mice derives from increased vascular spasm. We will also study the role of cardiac and vascular smooth muscle KATP channels in mediating the response to acute adrenergically mediated stress.
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