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 mumol/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 1 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.
Satoh
M
M
First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Ishide
N
N
Shinozaki
T
T
Kagaya
Y
Y
Shirato
K
K
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D003620:Dantrolene / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects*; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism
D003620:Dantrolene; D002118:Calcium