Electrophysiological effects of bimoclomol in canine ventricular myocytes

Concentration-dependent effects of bimoclomol, a novel heat shack protein ( HSP) coinducer, were studied on the parameters of action potential and tran smembrane ionic currents in enzymatically dispersed canine ventricular card iomyocytes using conventional microelectrode and whole cell voltage clamp t echniques. Bimoclomol (10-100 mu M) decreased the maximum velocity of depol arization ((V) over dot(max)) and amplitude of action potentials in a conce ntration-dependent manner. These effects were fully reversible after a 5-mi n period of washout in drug-free medium. Action potential duration measured at 50% or 90% level of repolarization (APD-50 and APD-90, respectively) wa s markedly shortened by bimoclomol. Both APD-50 and APD-90 were decreased, but the reduction in APD-50 was more pronounced. The APD-shortening effect of bimoclomol was significantly reduced in the presence of 20 nM charybdoto xin (inhibitor of the Ca-dependent K current) or 0.5 mM anthracene-9-carbox ylic acid (inhibitor of the Ca-dependent Cl current) or 1 mu M glibenclamid e (inhibitor of the ATP-sensitive K current). In the presence of anthracene -9-carboxylic acid, APD-90 was lengthened by bimoclomol. The APD-shortening effect of bimoclomol was also partially antagonized by chelation of intrac ellular Ca2+ by application of the cell permeant form of BAPTA, or when usi ng 10 mM EGTA-containing patch pipettes to record action potentials. The (V ) over dot(max)-depressant effect of bimoclomol was not affected by charybd otoxin, anthracene-9-carboxylic acid, glibenclamide, or BAPTA load. In voltage clamped cardiomyocytes bimoclomol (100 mu M) had no effect all t he amplitude of I-Ca, but decreased significantly the inactivation time con stant of I-Ca (from 19.8+/-1.6 ms to 16.8+/-1.2 ms at 0 mV). Bimoclomol als o decreased significantly the amplitude of I-K1 (from -20.5+/-1.1 pA/pF to -16.6+/-0.8 pA/pF at -135 mV), causing reduction in slope of the negative b ranch of the I-V curve. At positive potentials, however, bimoclomol increas ed outward current. The bimoclomol-induced current, therefore, was studied in the presence of BaCl2, when I-K1 current was blocked. The bimoclomol-ind uced current had a reversal potential close to -90 mV. Bimoclomol (100 mu M ) had no effect on the amplitude or kinetic properties of the transient out ward K current (I-to) and the delayed rectifier K current (I-K). It is concluded that bimoclomol exerts both Ca-independent (inhibition of I -Na and I-K1, activation of the ATP-sensitive K current) and Ca-dependent e ffects (mediated by Ca-activated Cl and probably K currents) in canine vent ricular myocytes.