Effects of Bimakalim on Human Cardiac Action Potentials: Comparison with Guinea Pig and Nicorandil and Use-Dependent Study

Abstract

Electrophysiologic effects of K(ATP) channel openers (KCOs) are rarely studied for tissue and species specificity, and use-dependent investigations in human tissues are lacking. We therefore investigated in vitro the concentration-dependent effects of the KCO bimakalim [from 10 nM to 10 microM, at 1,000 ms of cycle length (CL) and 37 degrees C] on human (atrium, n = 4, and ventricle, n = 6) and guinea pig (atrium, n = 7, and ventricle, n = 6) transmembrane action potential (AP). The frequency relation (from CL 1,600 to 300 ms, 31 degrees C) of human atrial AP duration 90% (APD90) shortening (10 microM vs. baseline, n = 7) also was determined. A parallel study was performed with the KCO nicorandil (from 10 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); APD90 was shortened in all tissues (p < 0.01). Median effective concentration (EC50) for APD90 shortening at 37 degrees C was 0.54 and 2.74 microM in atrial and ventricular human tissue, respectively, and 8.55 and 0.89 microM in atrial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31 degrees C, EC50 with bimakalim was 0.39 microM; a much higher value was seen with nicorandil (210 microM). Bimakalim (10 microM)-induced APD90 shortening as a function of stimulation rate was greatest at longest CL. Evidence is provided for (a) species (human vs. guinea pig) and tissue (atrium vs. ventricle) differential AP sensitivity to bimakalim; (b) an approximately 500-fold higher efficacy of bimakalim versus nicorandil to shorten human atrial APD90; and (c) normal use-dependence of human atrial APD90 shortening with bimakalim at 10 microM.

Bimakalim: A Promising KATP Channel Activating Agent

“…The site of action of KCOs is likely to be at the level of the pore-forming protein of K ATP channel, most probably at the internal pore level. As recently reviewed (48), KCOs access their receptor at the inner surface of the cell membrane where a phosphorylation-dephosphorylation mechanism might be involved. However, it is not certain whether KCOs bind to the channel protein or to the SUR or whether they promote an indirect competition with the binding site for ATP on cyclic nucleotide-dependent protein kinases.…”

“…This is also true for bimakalim (12,20). At relatively high concentrations (> 1 mM), KCOs open K ATP channels in the normally oxygenated myocardium (15), causing a dramatic decrease in the APD (5,40,48). This effect on APD can be viewed as potentially toxic.…”

“…This effect on APD can be viewed as potentially toxic. It is important, however, to realize that at clinically used plasma concentrations of bimakalim (~50 nM) APD shortening (and, therefore, possibly arrhythmogenesis) was not seen in normoxic human atrial and ventricular fibers at 37°C (48). Under conditions of impaired cellular metabolism, such as ischemia, the situation is entirely different since cardiac K ATP channels become much more sensitive to KCOs (9,14,15,40).…”

“…Bimakalim is probably the most intensively investigated, potent, and pure activator of adenosine triphosphate sensitive potassium channels (K ATP ), both at plasmalemmal (42,48) and mitochondnal (18) levels. It survived the initial developmental scrutiny with a substantial amount of data, including studies with human tissues (42,48) and even initial clinical studies in volunteers (11,52). Bimakalim is in many respects similar to other potassium channel openers (KCOs) reviewed in other publications (4,27,34,58).…”

“…Some recent data, discussed in this review, are pointing to the intracellular site of action of bimakalim,pharmacological effect of the drug. We estimated the plasma concentration of bimakalim after the maximal oral dose of 1 mg to be~50 nM (48).…”