EFFECT OF DANTROLENE SODIUM ON CALCIUM-OVERLOADED HEART

Spontaneous asynchronous contractile activity caused by spontaneous re lease of calcium ions (Ca2+) from the sarcoplasmic reticulum (SR) is t hought to be the cause of deterioration of ventricular function under conditions of calcium overload. We examined whether dantrolene sodium, which can inhibit Ca2+ release from the skeletal SR, improves the sys tolic and diastolic function of calcium-overloaded hearts. In isolated hamster left ventricles, the concentration of Ca2+ in the perfusate ( [Ca2+](0)) was increased from 1 mmol/L to 7 mmol/L in 1-mmol/L steps i n the absence (control, n = 6) and presence of dantrolene sodium (11.8 mu mol/L, n = 5). Left ventricular developed pressure and its maximum rate of rise (max dP/dt) increased with an increase in [Ca2+](0) up t o 4 mmol/L, and decreased with a further increase in [Ca2+](0). In the presence of dantrolene sodium? developed pressure and max dP/dt incre ased up to 5 mmol/L [Ca2+](0). Thus, dantrolene sodium improves Ca2+ t olerance. In isolated ventricles perfused with 1 mmol/L [Ca2+](0), dan trolene sodium decreased developed pressure by 33.7 +/- 7.4% and max d P/dt by 37.4 +/- 5.6% (mean +/- SEM, n = 8) at 1 mmol/L [Ca2+](0). In contrast, at 5 mmol/L [Ca2+](0) ('calcium-overloaded state'), dantrole ne sodium increased developed pressure by 6.8 +/- 2.6% and max dP/dt b y 14.4 +/- 5.7%, and decreased the end-diastolic pressure by 5.3 +/- 1 .9% (n = 8). Dantrolene sodium partially suppressed the spontaneous co ntractile activities observed microscopically on the epicardium of ven tricles perfused with 5 mmol/L [Ca2+](0). Dantrolene sodium improved t he Ca2+ tolerance of left ventricles and exerted positive inotropic ef fects and decreased diastolic stiffness in calcium-overloaded hamster left ventricles by suppressing spontaneous contractile activity.