FRACTIONAL SR CA RELEASE IS REGULATED BY TRIGGER CA AND SR CA CONTENTIN CARDIAC MYOCYTES

The release of sarcoplasmic reticulum (SR) Ca in cardiac muscle during excitation-contraction coupling is known to be graded by the amount o f activating Ca outside the SR (i.e., Ca-induced Ca release). However, little is known about how intra-SR Ca affects the release process. In this study we assessed how the fractional SR Ca release as described by Bassani et al. [Am. J. Physiol. 265 (Cell Physiol. 34): C533-C540, 1993] is affected by alteration of trigger Ca and of SR Ca content. Ex periments were done with isolated ferret ventricular myocytes using in do 1 to measure Ca concentration, perforated patch to measure Ca curre nt (I-Ca), caffeine application to release SR Ca, and thapsigargin to completely block SR Ca uptake. For what we consider a Normal SR Ca loa d and trigger Ca [action potential at 0.5 Hz with 2 mM extracellular C a concentration ([Ca](o))], 35 +/- 3% of the SR Ca content was release d at a twitch. Changing trigger Ca by altering [Ca](o) (to 0.5 and 8 m M) at a test twitch changed this fractional SR Ca release to 10 +/- 2 and 59 +/- 6%, with the same SR Ca load (and peak I-Ca changed in a pa rallel manner in separate voltage-clamp experiments). Three different levels of SR Ca load were studied (Low, Normal, and High; by action po tential stimulation at different frequencies from 0.05 to 0.8 Hz) usin g the same standard test trigger Ca (2 mM). Surprisingly, the High-loa d condition only increased SR Ca content by similar to 4% but appeared to be very close to the limiting SR Ca capacity. The fractional SR Ca release increased from 3.6 +/- 0.8 to 35 +/- 3 to 59 +/- 8% for Low-, Normal-, and High-loading conditions. Thus a small increase in SR Ca content from the control value produced a large increase in fractional SR Ca release. This demonstrates a novel and important regulatory rol e of intra-SR Ca. This regulatory effect may be at least as quantitati vely important as changes in trigger Ca in controlling the amount of C a released and can also explain spontaneous SR Ca release during Ca ov erload.