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 isometrically contracting rat papillary muscles loaded with the Ca2+ indicator aequorin, dantrolene (50 microM) produced a mild negative inotropic effect (28 +/- 1.8 to 21 +/- 1.1 mN/mm2; 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 microM; P < 0.01). In isolated cardiac sarcoplasmic reticulum, dantrolene (50 microM) increased the initial Ca2+ uptake 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). Intracellular Ca2+ overload was provoked in isoproterenol-pretreated (100 microM) preparations with [Ca2+]o = 5.0 mM at a stimulation rate of 1.0 Hz (n = 12). Diastolic Ca2+ oscillations and aftercontractions increased mean diastolic [Ca2+]i (0.33 +/- 0.1 to 0.56 +/- 0.1 microM) and tension (9.5 +/- 1.8 to 15.3 +/- 2.1 mN/mm2), respectively. Addition of dantrolene (50 microM) reduced the amplitude of Ca2+ oscillations and aftercontractions; mean diastolic [Ca2+]i decreased to 0.44 +/- 0.1 microM and diastolic tension to 13.5 +/- 2.2 mN/mm2. We conclude, therefore, that dantrolene sodium modifies Ca2+ handling by the myocardial sarcoplasmic reticulum, an effect that might be useful in cardiac disorders with impaired [Ca2+]i homeostasis.