Dantrolene sodium improves the force-frequency relationship and beta-adrenergic responsiveness in failing human myocardium

Background: Failing human myocardium is characterized by a negative force-f requency relationship and impaired P-adrenergic responsiveness which have b een related to alterations of the intracellular Ca2+ homeostasis. Dantrolen e sodium is a clinically used drug that modulates myocardial [Ca2+](i) hand ling in animal models. This study investigated the effects of dantrolene so dium on intracellular Ca2+ handling and contractile function in failing hum an myocardium. Methods and Results Twenty-three muscle strips from human le ft ventricular trabeculae were obtained from patients undergoing heart tran splantation for end-stage heart failure caused by idiopathic dilated cardio myopathy (n = 15). Isometric contraction and intracellular Ca2+ transients (Ca2+ indicator: aequorin) were recorded simultaneously. The experiments we re performed in three separate groups exposed to control condition (n = 8), addition of dantrolene (10 mu mol/l; n = 8), or addition of verapamil (1 m u mol/l; n = 7). Isoproterenol induced a moderate positive inotropic effect in the control group with a maximal increase of developed tension from 10. 8 +/- 2.9 to 23.4 +/- 4.7 mN/mm(2) and a parallel rise in peak systolic [Ca 2+](i) to a maximum of 1.36 +/- 0.20 mu mol/l. Dantrolene significantly imp roved (10.2 +/- 3.8 to 32.3 +/- 0.9 mN/mm(2)) and verapamil blunted (8.3 +/ - 2.8 to 17.1 +/- 4.3 mN/mm(2)) the inotropic response to isoproterenol. Th e diastolic and systolic [Ca2+](i) during isoproterenol stimulation were sl ightly lower in the dantrolene group but significantly depressed in the ver apamil group as compared to the control group. Similarly, analyses of force -frequency relationships revealed an improvement of developed tension in da ntrolene-treated as compared to control preparations whereas the peak systo lic [Ca2+](i) was almost identical. Conclusion: Dantrolene improves the neg ative force-frequency relationship and beta-adrenergic responsiveness in fa iling human myocardium. These effects are not accompanied by an additional increase in intracellular [Ca2+](i) but might be related to modifications o f the diastolic [Ca2+](i) homeostasis, (C) 1999 European Society of Cardiol ogy. All rights reserved.