Dichlorobenzamil, an analog of
amiloride, has been reported to inhibit Na-Ca exchange in sarcolemmal vesicles of guinea pig heart. To examine further the effect of the
drug on Na-Ca exchange in intact cardiac cells and the pharmacological specificity of this action, we determined in cultured chick heart cells the effects of
dichlorobenzamil on the following: contractile state, Nai-dependent Ca uptake, Ca uptake via slow Ca channels (defined as
verapamil-inhibitable Ca uptake), Ca efflux via the sarcolemmal Ca pump,
monovalent cation transport, and cellular Ca and Na content.
Dichlorobenzamil produced a concentration-dependent decrease in the amplitude of cell motion (EC50 = 5 X 10(-7) M) and abolished the development of
ouabain-induced rhythm disturbances and
contracture. In normal or Na-loaded cells,
dichlorobenzamil inhibited the Ca uptake rate, also in a concentration-dependent manner (EC50 = 6 X 10(-7) M).
Dichlorobenzamil (6 X 10(-7) M) also caused a significant inhibition of the
isoproterenol-induced elevation of Ca uptake. At 5 X 10(-5) M,
dichlorobenzamil blocked completely Ca influx via slow Ca channels. Ca efflux rate was also reduced by
dichlorobenzamil (EC50 = 10(-6) M). Replacement of Na with
choline in the efflux medium to prevent Ca efflux via Na-Ca exchange did not alter the ED50 of the
drug's inhibition of Ca efflux rate.
Dichlorobenzamil caused concentration-dependent inhibition of
sodium pump activity as judged by
ouabain-sensitive 42K uptake (EC50 approximately 2 X 10(-6) M), and, at concentrations above 5 X 10(-7) M), produced an increase in steady state cellular Na content. These results indicate that
dichlorobenzamil has several sites of action in intact heart cells and that the negative inotropic action of the
drug is due, in part, to inhibition of Ca influx via both Na-Ca exchange and slow Ca channels.