Dantrolene sodium improves the force-frequency relationship and beta-adregenic responsiveness in failing human myocardium.
BACKGROUND
Failing human myocardium is characterized by a negative force-frequency relationship and impaired beta-adrenergic responsiveness which have been related to alterations of the intracellular Ca2+ homeostasis. Dantrolene sodium is a clinically used drug that modulates myocardial [Ca2+]i handling in animal models. This study investigated the effects of dantrolene sodium on intracellular Ca2+ handling and contractile function in failing human myocardium.


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 Ca2+ transients (Ca2+ indicator: aequorin) were recorded simultaneously. The experiments were performed in three separate groups exposed to control condition (n = 8), addition of dantrolene (10 micromol/l; n = 8), or addition of verapamil (1 micromol/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/mm2 and a parallel rise in peak systolic [Ca2+]i to a maximum of 1.36 +/- 0.20 micromol/l. Dantrolene significantly improved (10.2 +/- 3.8 to 32.4 +/- 0.9 mN/mm2) and verapamil blunted (8.3 +/- 2.8 to 17.1 +/- 4.3 mN/mm2) the inotropic response to isoproterenol. The diastolic and systolic [Ca2+]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 [Ca2+]i was almost identical.


CONCLUSIONS
Dantrolene improves the negative force-frequency relationship and beta-adrenergic responsiveness in failing human myocardium. These effects are not accompanied by an additional increase in intracellular [Ca2+]i but might be related to modifications of the diastolic [Ca2+]i homeostasis.
Meissner
A
A
Department of Cardiology, University of Kiel, Germany. meissner@cardio.uni-kiel.de
Min
J Y
JY
Haake
N
N
Hirt
S
S
Simon
R
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D002121:Calcium Channel Blockers; D009125:Muscle Relaxants, Central; D011943:Receptors, Adrenergic, beta; D014700:Verapamil; D003620:Dantrolene; D007545:Isoproterenol; D002118:Calcium