Aprikalim reduces the Na+-Ca2+ exchange outward current enhanced by hyperkalemia in rat ventricular myocytes

Abstract Bacground . Aprikalim, an adenosine triphosphate (ATP) sensitive K + (K ATP ) channel opener, attenuates the elevation of intracellular Ca 2+ concentration ([Ca 2+ ] i ) and improves the contractile functions after hyperkalemic and hypothermic cardioplegia. There is evidence that cardioplegia increases the Na + -Ca 2+ exchange activity without affecting Ca 2+ influx through L-type Ca 2+ channels or Ca 2+ content in the sarcoplasmic reticulum, the intracellular Ca 2+ store. Methods . We measured the Na + -Ca 2+ exchange outward current with the patch-clamp technique in single rat ventricular myocytes exposed to hyperkalemia and hypothermia in the presence of aprikalim. The intracellular calcium concentration ([Ca 2+ ] i ) during cardioplegia, and the contractile function and [Ca 2+ ] i transients induced by electrical stimulation or caffeine during rewarming and reperfusion in single ventricular myocytes were also determined. Contraction and [Ca 2+ ] i were determined with video tracking and spectrofluorometry, respectively. Results . Aprikalim, 100 μmol/L, the effect of which was blocked by glibamclamide, a K ATP inhibitor, significantly attenuated the hyperkalemia-elevated Na + -Ca 2+ exchange current by 26% and 11% at 22°C and 4°C, respectively. Aprikalim also attenuated significantly the [Ca 2+ ] i elevated during cardioplegia. Furthermore aprikalim significantly attenuated the reduction in amplitude and prolongation in duration of contraction of myocytes after cardioplegia. The effects of aprikalim mimicked those of nickle (Ni 2+ ), a Na + -Ca 2+ exchange blocker. The electrically or caffeine-induced [Ca 2+ ] i transients were unaltered by cardioplegia or aprikalim. Conclusions . Aprikalim attenuates the Na + -Ca 2+ exchange outward current elevated by hyperkalemia, which may attenuate the [Ca 2+ ] i elevation during hyperkalemia and improve the contractile function after cardioplegia in the ventricular myocyte. The study provides further support that addition of a K ATP channel opener to the cardioplegic solution may produce beneficial effects in open heart surgery.