Biphasic effect of bimoclomol on calcium handling in mammalian ventricularmyocardium

1 Concentration-dependent effects of bimoclomol, the novel heat shock prote in coinducer, on intracellular calcium transients and contractility were st udied in Langendorff-perfused guinea-pig hearts loaded with the fluorescent calcium indicator dye Fura-2. Bimoclomol had a biphasic effect on contract ility: both peak left ventricular pressure and the rate of force developmen t significantly increased at a concentration of 10 nM or higher. The maxima l effect was observed between 0.1 and 1 mu M, and the positive inotropic ac tion disappeared by further increasing the concentration of bimoclomol. The drug increased systolic calcium concentration with a similar concentration -dependence. In contrast, diastolic calcium concentration increased monoton ically in the presence of bimoclomol. Thus low concentrations of the drug ( 10-100 nM) increased, whereas high concentrations (10 mu M) decreased the a mplitude of intracellular calcium transients. 2 Effects of bimoclomol on action potential configuration was studied in is olated canine ventricular myocytes. Action potential duration was increased at low (10 nM), unaffected at intermediate (0.1-1 mu M) and decreased at h igh (10-100 mu M) concentrations of the drug. 3 In single canine sarcoplasmic calcium release channels (ryanodine recepto r), incorporated into artificial lipid bilayer, bimoclomol significantly in creased the open probability of the channel in the concentration range of 1 -10 mu M. The increased open probability was associated with increased mean open time. The effect of bimoclomol was again biphasic: the open probabili ty decreased below the control level in the presence of 1 mM bimoclomol. 4 Bimoclomol (10 mu M-1 mM) had no significant effect on the rate of calciu m uptake into sarcoplasmic reticulum vesicles of the dog, indicating that i n vivo calcium reuptake might not substantially be affected by the drug. 5 In conclusion, the positive inotropic action of bimoclomol is likely due to the activation of the sarcoplasmic reticulum calcium release channel in mammalian ventricular myocardium.