Effects of dichlorobenzamil, a sodium-calcium exchange inhibitor, on the calcium paradox and the sodium withdrawal contractures of frog atrial muscle

The effects of dichlorobenzamil (DCB), an amiloride derivative and potent inhibitor of Na-Ca exchange in cardiac sarcolemmal vesicles and isolated cardiac myocytes, were investigated in two paradigms involving Na-Ca exchange, namely the Ca2+ paradox and the Na + - withdrawal contractures of frog atrial muscle strips. Pretreatment with DCB (10-100 micronM) inhibited in a dose-dependent manner the contractures elicited by reexposure of the atrial strips to the control Ringer solution after a 5-20 min equilibration with a Ca2 + - free saline (Ca2 + - readmission contractures; Ca2 + paradox). These contracture were not inhibited, however, when DCB was applied after the preparation had been exposed to the Ca2 + - free saline, but before the reexposure to the control Ringer solution. DCB (10-100 micronM) did not inhibit the contractures elicited by Na + - deficient saline (Na + - withdrawal contractures) in atrial strips pretreated or not with acetylstrophantydin. This result suggests that, under our experimental conditions, DCB falied to substantially inhibit the Ca2 + influx mediated by Na-Ca exchange. The duration of the plateu of the action potentials of atrial cells equilibrated with Ca2 + - free saline was reduced from 1,42 ñ 0,27 s to 0,61 ñ 0,13 s by 50 micronM DCB (P<0.001). This was atributed to blockade of Na + currents through modified L-type Ca2 + channels. It is proposed that shortening of the Na + - dependent action potentials can account for the inhibition of the Ca2 + - readmission contractures, because these contractures have a steep dependence on the Na + influx and intracellular Na + accumulation that occurs during the Ca2 + - free period. The results of this study support the conclusion thatDCB has multiple effects on heart muscle, including a potent blockade of Ca2 + channels, and its use as a selective inhibitor of Na-Ca exchange in cellular systems in un unwarranted