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Dantrolene sodium improves the force–frequency relationship and β‐adrenergic responsiveness in failing human myocardium
Author(s) -
Meissner Achim,
Min JiangYong,
Haake Nils,
Hirt Stephan,
Simon Rüdiger
Publication year - 1999
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1016/s1388-9842(99)00017-3
Subject(s) - dantrolene sodium , inotrope , dantrolene , verapamil , medicine , isometric exercise , endocrinology , heart failure , cardiomyopathy , lusitropy , cardiology , diastole , calcium , blood pressure
Background: Failing human myocardium is characterized by a negative force–frequency relationship and impaired β‐adrenergic responsiveness which have been related to alterations of the intracellular Ca 2 homeostasis. Dantrolene sodium is a clinically used drug that modulates myocardial Ca 2 i handling in animal models. This study investigated the effects of dantrolene sodium on intracellular Ca 2 handling and contractile function in failing human myocardium. Methods and Results: Twenty‐three muscle strips from human left ventricular trabeculae were obtained from patients undergoing heart transplantation for end‐stage heart failure caused by idiopathic dilated cardiomyopathy ( n =15). Isometric contraction and intracellular Ca 2 transients (Ca 2 indicator: aequorin) were recorded simultaneously. The experiments were performed in three separate groups exposed to control condition ( n =8), addition of dantrolene (10 μmol/l; n =8), or addition of verapamil (1 μmol/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 μmol/l. Dantrolene significantly improved (10.2±3.8 to 32.4±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. The diastolic and systolic Ca 2 i during isoproterenol stimulation were slightly lower in the dantrolene group but significantly depressed in the verapamil group as compared to the control group. Similarly, analyses of force–frequency relationships revealed an improvement of developed tension in dantrolene‐treated as compared to control preparations whereas the peak systolic Ca 2 i was almost identical. Conclusion: Dantrolene improves the negative force–frequency relationship and β‐adrenergic responsiveness in failing human myocardium. These effects are not accompanied by an additional increase in intracellular Ca 2 i but might be related to modifications of the diastolic Ca 2 i homeostasis.