SUR2A C‐terminal fragments reduce K ATP currents and ischaemic tolerance of rat cardiac myocytes

C‐terminal fragments of the sulphonylurea receptor SUR2A can alter the functional expression of cloned ATP‐sensitive K + channels (K ATP ). To investigate the protective role of K ATP channels during metabolic stress we transfected SUR2A fragments into adult rat cardiac myocytes. A fragment comprising residues 1294–1358, the A‐fragment, reduced sarcolemmal K ATP currents by over 85% after 2 days (pinacidil‐activated current densities were: vector alone 7.04 ± 1.22; and A‐fragment 0.94 ± 0.07 pA pF −1 , n = 6,6, P < 0.001). An inactive fragment (1358–1545, current density 6.30 ± 0.85 pA pF −1 , n = 6) was used as a control. During metabolic inhibition (CN and iodoacetate) of isolated myocytes stimulated at 1 Hz, the A‐fragment delayed action potential shortening and contractile failure, but accelerated rigor contraction and increased Ca 2+ loading. On reperfusion, A‐fragment‐transfected cells also showed increased intracellular Ca 2+ and the proportion of cells recovering contractile function was reduced from 40.0 to 9.5% ( P < 0.01). The protective effect of pretreatment with 2,4‐dinitrophenol, measured from increased functional recovery and reduced Ca 2+ loading, was abolished by the A‐fragment. Our data are consistent with a role for K ATP channels in causing action potential failure and reduced Ca 2+ loading during metabolic stress, and with a major role in protection by preconditioning. The effects of the A‐fragment may arise entirely from reduced expression of the sarcolemmal K ATP channel, but we also discuss the possibility of mitochondrial effects.