Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes

The mechanisms contributing to the negative inotropic effect of halothane w ere studied in isolated rat ventricular myocytes. Contraction and intracell ular Ca2+ transients were measured optically in these cells. The initial ap plication of halothane (2% or 0.5 mmol litre(-1)) led to short-lived increa ses in the Ca2+ transient and contraction, which were abolished by ryanodin e. Continued application of halothane led to a sustained decrease in contra ction: this resulted from: (i) a decrease in myofilament Ca2+ sensitivity; (ii) a decrease in the Ca2+ transient; and (iii) a decrease in the Ca2+ con tent of the sarcoplasmic reticulum. Although halothane reduced action poten tial duration, the sustained negative inotropic effect was similar when act ion potentials or voltage clamp pulses of constant duration were used to tr igger contractions. In cells exposed to nifedipine 0.5 mu mol litre(-1) (wh ich decreases the L-type Ca2+ current, I-Ca), Ca2+ transients, sarcoplasmic reticulum Ca2+ content and fractional release (the fraction of sarcoplasmi c reticulum Ca2+ content released during each stimulus) were reduced. Halot hane 0.5 mmol litre(-1) (which also decreases Ic,) decreased Ca2+ transient s to a lesser extent and reduced sarcoplasmic reticulum Ca2+ content to a g reater extent than nifedipine, whereas fractional release was unchanged com pared with control. These data suggest that halothane sensitizes Ca2+-induc ed Ca2+ release from the sarcoplasmic reticulum in addition to reducing I-C a.