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

1. 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. 2. Pretreatment with DCB (10-100 microM) 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 contractures 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. 3. DCB (10-100 microM) 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 failed to substantially inhibit the Ca2+ influx mediated by Na-Ca exchange. 4. The duration of the plateau of the action potentials of atrial cells equilibrated with Ca2+-free saline was reduced from 1.42 +/- 0.27 s to 0.61 +/- 0.13 s by 50 microM DCB (P less than 0.001). This was attributed to blockade of Na+ currents through modified L-type Ca2+ channels. 5. It is proposed that the 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. 6. The results of this study support the conclusion that DCB 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 is unwarranted.