Effects of FPL 64176 on Ca transients in voltage‐clamped rat venticular myocytes

The L‐type Ca channel agonist FPL 64176 increased the amplitude of both Ca currents and Ca transients elicited from isolated voltage clamped rat ventricular myocytes far more than it increased the rate of rise of the Ca transients. Consequently, the gain function relating the amplitude of peak Ca current to Ca transient rate of rise was greatly reduced at all potentials. Furthermore, an increase in this gain function normally observed at negative potentials is abolished by FPL 64716. Despite slowing the rate of decline of Ca transients, FPL 64176, at the concentration of 1 μ M used throughout, had no direct effect on sarcoplasmic reticulum (SR) Ca uptake or release using isolated cardiac membranes. Arguments based on results presented here and elsewhere suggest that decreased gain was not due to increased ryanodine receptor adaptation or inactivation, to decreased L‐type single channel current, to decreased SR Ca content, or to decreased synchronization of release. Decreased gain instead appears to reflect a form of decrease in coupling efficiency due either to differential effects of long openings on whole cell currents as opposed to the Ca release the long openings trigger or to some compensatory mechanism activated by the increased Ca trigger or resting free [Ca 2+ ] i . Abolition by FPL 64176 of the increased gain normally seen at negative potentials rendered it impossible to confirm or refute the claim that a single Ca ion suffices to activate ryanodine receptors.British Journal of Pharmacology (2002) 135 , 1495–1504; doi: 10.1038/sj.bjp.0704598