MODULATION OF SARCOPLASMIC-RETICULUM CA-2+-RELEASE CHANNELS BY CAFFEINE, CA-2+, AND MG-2+ IN SKINNED MYOCARDIAL FIBERS OF FETAL AND ADULT-RATS

Ryanodine causes depression of the caffeine-induced tension transient (ryanodine depression) in skinned muscle fibers, because it blocks the sarcoplasmic reticulum (SR) Ca2+-release channels [Su, J. Y (1988) Pflugers Arch 411:132-136, 371-377; (1992) Pflugers Arch 421:1-6]. This study was performed to examine the sensitivity of SR Ca2+-release channels to ryanodine in fetal compared to adult myocardium and to investigate the influence of Ca2+, caffeine, and Mg2+ on ryanodine depression in skinned fibers. Ryanodine (0.3 nM-1 muM) caused a dose-dependent depression in skinned myocardial fibers of the rat, and the fetal fibers (IC50 almost-equal-to 74 nM) were 26-fold less sensitive than those of the adult (IC50 almost-equal-to 2.9 nM). The depression induced by 0.1 muM or 1 muM ryanodine was a function of [caffeine], or [Ca2+] (pCa < 6.0), which was potentiated by caffeine, and an inverse function of [Mg2+]. At pCa > 8.0 plus 25 mM caffeine, a 20 % ryanodine depression was observed in both the fetal and adult fibers, indicating independence from Ca2+. Ryanodine depression in skinned fibers of the fetus was less affected than that seen in the adult by pCa(i), [caffeine]i, or 25 mM caffeine plus pCa(i) or plus pMg(i) (IC50 almost-equal-to pCa 4.5 versus 5.1; caffeine 12.7 mM versus 2 mM; pCa 6.7 versus 7.3; and pMg 3.9 versus 3.3 respectively). The results show that the SR Ca2+-release channel in both fetal and adult myocardium is modulated by Ca2+, caffeine, and Mg2+. It is concluded that less ryanodine depression seen in the skinned fibers of the fetus, indicating a relatively insensitive SR Ca2+-release channel, could contribute to the resistance of intact myocardium to ryanodine.