In isolated left atria of guinea pigs, we investigated the effects of four different calcium antagonists on the adaptation of force of contraction, action potential duration (APD), and calcium (Ca) content to a sudden change in the extracellular Ca2+ concentration ([Ca2+]0) from 0.9 to 3.6 mM. Under control conditions (rate of stimulation, 1 Hz), force of contraction rapidly adapted to an increase in [Ca2+]0 from 0.9 to 3.6 mM, reaching a transient maximum within 5 min ("hypercontractility"). The accompanying prolongation in APD also had a biphasic time course, but only when [Ca2+]0 was increased within the 1st hour of an experiment. The Ca antagonists investigated were gallopamil (0.2 microM), nifedipine (75 nM), Ni2+ (0.5 mM), and La3+ (1 mM). The negative inotropic effect of La3+ was complicated by an increase in resting tension after prolonged exposure (greater than 30-60 min). With the exception of Ni2+, the Ca antagonists depressed the maximum and the steady-state force of contraction after the increase in [Ca2+]0. The biphasic nature of force adaptation was attenuated by gallopamil, Ni2+, and La3+, but not by nifedipine. Gallopamil and La3+ slowed the time course of adaptation. The Ca content of the tissue was determined with the 45Ca method. Gallopamil, nifedipine, and Ni2+ had no effect on the Ca content nor on the time course of Ca uptake after the increase in [Ca2+]0, but La3+ profoundly slowed the time course of Ca uptake. Although inhibition of the Ca current by Ca antagonists modifies the functional adaptation to elevated [Ca2+]0, the Ca antagonists with the exception of La3+, do not influence the change in total Ca content. It is concluded that calcium channels are not the only pathway by which calcium is taken up by the tissue when [Ca2+]0 is increased.