EFFECTS OF R-56865 ON TRANSIENT INWARD CURRENT, NA-CA2+ EXCHANGE, ANDCA2+ RELEASE FROM SR IN CARDIAC MYOCYTES()

Voltage-clamp studies were performed on guinea pig ventricular myocyte s to clarify the action of butyl]-4-piperidinyl)-N-methyl-2-benzothiaz olamine (R-56865), an inhibitor of cardiac glycoside-induced arrhythmi as. Transient inward current (I-ti) was induced using low-K+/high-Ca2 Tyrode solution. R-56865 (1 mM) was found to abolish I-ti. R-56865 ha d no influence on the peak Ca2+ current, steady-state current during t he clamp, holding current, or the Ni2+-sensitive electrogenic Na+-Ca2 exchange current. Fluorescence transients after repolarization (tempo rally related to the I-ti) were abolished by R-56865 without affecting the fluorescence transients during depolarization. In separate experi ments, the threshold of Ca2+ release from sarcoplasmic reticulum (SR) by the Ca2+ current was found to be unchanged, whereas Ca2+ transients (presumably triggered by Ca2+ entry through the Na+-Ca2+ exchanger) w ere depressed. Our results suggest that R-56865 inhibits spontaneous C a2+ release from the SR when it is mediated by Ca2+ entry through the Na+-Ca2+ exchanger but that it has no direct effect on the well-known ''physiological'' Ca2+-induced Ca2+-release mechanism from SR.