Effects of bimakalim on human cardiac action potentials: Comparison with guinea pig and nicorandil and use-dependent study

Electrophysiologic effects of K-ATP channel openers (KCOs) are rarely studi ed for tissue and species specificity, and use-dependent investigations in human tissues are lacking. We therefore investigated in vitro the concentra tion-dependent effects of the KCO bimakalim [from 10 nM to 10 mu M, at 1,00 0 ms of cycle length (CL) and 37 degrees C] on human (atrium, n = 4, and ve ntricle, n = 6) and guinea pig (atrium, n = 7, and ventricle, n = 6) transm embrane action potential (AP). The frequency relation (from CL 1,600 to 300 ms, 31 degrees C) of human atrial AP duration 90% (APD(90)) shortening (10 mu M VS. baseline, n = 7) also was determined. A parallel study was perfor med with the KCO nicorandil (from 18 nM to 1 mM, n = 3) in human atrial APs , at 31 degrees C. Resting membrane potential and maximal upstroke velocity of AP were not modified by bimakalim at maximal concentration, whereas AP amplitude was decreased in both guinea pig preparations (p < 0.05); APD(90) was shortened in all tissues (p < 0.01). Median effective concentration (E C50) for APD(90) Shortening at 37 degrees C was 0.54 and 2.74 mu M in atria l and ventricular human tissue, respectively, and 8.55 and 0.89 mu M in atr ial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31 degrees C, EC50 With bimakalim was 0.39 mu M; a much higher value wa s seen with nicorandil (210 mu M). Bimakalim (10 mu M)-induced APD(90) shor tening as a function of stimulation rate was greatest at longest CL. Eviden ce is provided for (a) species (human vs, guinea pig)and tissue (atrium vs, ventricle) differential AP sensitivity to bimakalim; (b) an approximate to 500-fold higher efficacy of bimakalim versus nicorandil to shorten human a trial APD(90); and (c) normal use-dependence of human atrial APD(90) shorte ning with bimakalim at 10 mu M.