Effect of dantrolene sodium on calcium-overloaded heart

Spontaneous asynchronous contractile activity caused by spontaneous release of calcium ions (Ca²⁺) from the sarcoplasmic reticulum (SR) is thought 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 systolic and diastolic function of calcium-overloaded hearts. In isolated hamster left ventricles, the concentration of Ca²⁺ in the perfusate ([Ca²⁺](o)) was increased from 1 mmol/L to 7 mmol/L in 1-mmol/L steps in the absence (control, n=6) and presence of dantrolene sodium (11.8 μmol/L, n=5). Left ventricular developed pressure and its maximum rate of rise (max dP/dt) increased with an increase in [Ca²⁺]o up to 4 mmol/L, and decreased with a further increase in [Ca²⁺](o). In the presence of dantrolene sodium, developed pressure and max dP/dt increased up to 5 mmol/L [Ca²⁺](o). Thus, dantrolene sodium improves Ca²⁺ tolerance. In isolated ventricles perfused with l mmol/L [Ca²⁺](o), dantrolene sodium decreased developed pressure by 33.7±7.4% and max dP/dt by 37.4±5.6% (mean±SEM, n=8) at 1 mmol/L [Ca²⁺](o). In contrast, at 5 mmol/L [Ca²⁺](o) ('calcium-overloaded state'), dantrolene sodium increased developed pressure by 6.8±2.6% and max dP/dt by 14.4±5.7%, and decreased the end-diastolic pressure by 5.3±1.9% (n=8). Dantrolene sodium partially suppressed the spontaneous contractile activities observed microscopically on the epicardium of ventricles perfused with 5 mmol/L [Ca²⁺](o). Dantrolene sodium improved the Ca²⁺ tolerance of left ventricles and exerted positive inotropic effects and decreased diastolic stiffness in calcium-overloaded hamster left ventricles by suppressing spontaneous contractile activity.