The effect of external calcium concentration on the negative inotropic action of dantrolene in isolated hyperthyroid and euthyroid heart

The effect of altering external calcium concentration [Ca²⁺]_o on the negative inotropic action of dantrolene was tested in Langendorff-perfused hearts from euthyroid and hyperthyroid rats. Elevated contractility was demonstrated in the hyperthyroid hearts at all the [Ca²⁺]_otested. At a [Ca²⁺]_o of 1.25 mm (physiological),dantrolene (5×10^-5m) significantly reduced contractility (dP/df_max) in hyperthyroid but not in euthyroid hearts (-42% and -4% of zero-time values at 12 min perfusion, respectively). When hearts from both groups were paced at 375 beats/min, dantrolene again exerted a greater negative inotropic action in the hyperthyroid preparations, showing that the effect was not heart rate related. Elevating the [Ca²⁺]_o did not further affect the time course of dantrolene action in hyperthyroid hearts. In euthyroid hearts, however, raising the [Ca²⁺]_o to 2.5 and 3.75 mm caused a progressive increase in the negative inotropic action of dantrolene(-15% and -56% of zero-time values at 12 min perfusion, respectively). Our results demonstrate that dantrolene exerts a negative inotropic action which at physiological [Ca²⁺]_o is greater in the hyperthyroid than in the euthyroid heart thus indicating that calcium handling by the myocardium is altered in the hyperthyroid state. However, dantrolene action in the rat myocardium is more complex than was at first believed; as in euthyroid hearts, its negative inotropic action appears to be increased rather than reduced by increases in [Ca²⁺]_o.