EFFECTS OF DANTROLENE SODIUM ON INTRACELLULAR CA2-HANDLING IN NORMAL AND CA2+-OVERLOADED CARDIAC-MUSCLE()

We investigated the effects of dantrolene sodium on intracellular Ca2 homeostasis in normal and Ca2+ overloaded rat cardiac muscle. In isom etrically contracting rat papillary muscles loaded with the Ca2+ indic ator aequorin, dantrolene (50 mu M) Produced a mild negative inotropic effect (28 +/- 1.8 to 21 +/- 1.1 mN/mm(2); mean +/- S.E.; n = 6; P < 0.01), which was paralleled by a decrease in peak systolic [Ca2+](i) ( 0.81 +/- 0.04 to 0.67 +/- 0.04 mu M; P < 0.01). In isolated cardiac sa rcoplasmic reticulum, dantrolene (50 mu M) increased the initial Ca2uptake rate by 23% as compared to control preparations (at pCa 6.2: 46 .9 +/- 1.6 to 61.1 +/- 2,2 nmol/mg per min; n = 4; P < 0.001). Intrace llular Ca2+ overload was provoked in isoproterenol-pretreated (100 mu M) Preparations with [Ca2+](0) = 5.0 mM at a stimulation rate of 1.0 H z (n = 12). Diastolic Ca2+ oscillations and aftercontractions increase d mean diastolic [Ca2+](i) (0.33 +/- 0.1 to 0.56 +/- 0.1 mu M) and ten sion (9.5 +/- 1.8 to 15.3 +/- 2.1 mN/mm(2)), respectively. Addition of dantrolene (50 mu M) reduced the amplitude of Ca2+ oscillations and a ftercontractions; mean diastolic [Ca2+](i) decreased to 0.44 +/- 0.1 m u M and diastolic tension to 13.5 +/- 2.2 mN/mm(2). We conclude, there fore, that dantrolene sodium modifies Ca2+ handling by the myocardial sarcoplasmic reticulum, an effect that might be useful in cardiac diso rders with impaired [Ca2+](i) homeostasis.