Cyclic ADP-Ribose Does Not Regulate Sarcoplasmic Reticulum Ca sup 2 plus Release in Intact Cardiac Myocytes

Cyclic ADP-ribose (cADPR), an intracellular second messenger known to mobilize Ca² plus in sea urchin eggs, has been implicated in modulating Ca² plus release in a variety of mammalian tissues. On the basis of studies of isolated cardiac sarcoplasmic reticulum (SR) vesicles and single SR Ca² plus release channels, cADPR has also been proposed to be a modulator of SR Ca² plus release in heart. In the present study, we directly examined the ability of cADPR to trigger SR Ca sup 2 plus release and to modulate Ca² plus-induced Ca² plus release (CICR) in intact rat ventricular myocytes. Voltage-clamped myocytes were dialyzed with up to 100 micro mol/L caged cADPR and 0.6 micro mol/L calmodulin along with the Ca² plus-sensitive dye fluo 3. A step increase in the cADPR concentration induced by flash photolysis of caged cADPR neither directly triggered SR Ca² plus release nor modulated CICR in intact myocytes. In contrast, under similar conditions, extracellular application of caffeine (1 to 2.5 mmol/L) onto myocytes produced both effects. Under equivalent conditions, flash photolysis of caged cADPR-loaded sea urchin eggs resulted in large Ca² plus transients. Further, the sustained presence of high cytosolic concentrations of either cADPR or its antagonist, 8-amino-cADPR, was ineffective in altering normal CICR in myocytes. These findings indicate that cADPR does not regulate SR Ca² plus release in intact cardiac myocytes.

(Circ Res. 1996;79:147-151.)