PHARMACOLOGICAL EVIDENCE FOR 2 TYPES OF MYOCARDIAL SARCOPLASMIC-RETICULUM CA-2+ RELEASE

Contractions of guinea pig papillary muscles were studied at 37-degrees-C under a variety of conditions and stimulation rates that markedly alter the pattern of tension development. When rested-state contractions (RSCs) were enhanced by treatments that increase intracellular adenosine 3',5'-cyclic monophosphate (0.1-1-mu-M) isoproterenol, 1-10-mu-M forskolin), a markedly enhanced late peak tension developed after a 100-ms delay. Such late peak tension was selectively depressed by local anesthetics (200-400-mu-M procaine, 4-10-mu-M tetracaine, or 0.5-1 mM ethyl amino-benzoate). In contrast, 0.1-1-mu-M ryanodine had little effect on late peak tension, whereas 5 mM caffeine reduced the delay before tension development. Inotropic interventions such as increased external Ca2+ concentration or the Ca2+ channel agonist BAY K 8644 did not elicit such distinct late peaking RSCs. Rapid initial tension development observed under a variety of situations (short cycle lengths, stimualtion rates of 0.25 Hz plus isoproterenol, decreased external Na+ concentration) was markedly depressed by 0.01-1-mu-M ryanodine and by caffeine, whereas local anesthetics had little effects. These results suggests two pharmacologically distinct types of sarcoplasmic reticulum Ca2+ release: 1) Ca2+ that accumulates during prior depolarizations is released immediately upon depolarization and decreased by ryanodine and caffeine; 2) extracellular Ca2+ that enters the myocyte is accumulated and released after an initial delay and is selectively depressed by low concentrations of local anesthetics.