The concentration-dependent effects of propofol on rat ventricular myocytes

Whether propofol contributes a direct negative inotropic effect is controve rsial. Our principal aim in this study was to determine whether negative in otropic effects of propofol occur at clinically relevant concentrations. We constructed the concentration-response relationship for the negative inotr opic effects on intact isolated, stimulated rat ventricular myocytes. Contr action was measured as cell shortening by using an optical system. Propofol was applied as dilutions of the commercial preparation in physiological sa line solution. The drug vehicle had a minimal effect on myocyte contractili ty. Propofol produced a concentration-dependent reduction in evoked contrac tion at concentrations greater than 5 mu M. The maximum effect was observed at >100 mu M, with the K-0.5 calculated to be 345 mu M (95% CI, 21.8-54.7 mu M). In further experiments, we investigated the relationship between cha nges in contractility and changes in Ca2+ transient (measured by using fura -2 fluorescence) after the application of propofol. By using the shift in t he relationship of the cell length to fura-2 fluorescence ratio in the rela xation phase of a contraction as an index of Ca2+ response of the myofilame nts, we demonstrated that some of the negative inotropic effect of propofol may be caused by a reduction in myofilament Ca2+ sensitivity. We confirmed this by comparing the reduction in contractility in the presence of propof ol, with that caused by reducing the extracellular Ca2+ concentration. We o bserved that, for a decrease in the fura-2 fluorescence ratio of 21%, propo fol caused a 12% (95% CT, 2% to 22%) greater reduction in contractility tha n predicted from reducing the extracellular Ca2+ concentration. However, th e K-0.5 for the negative inotropic effect of propofol we observed is more t han 80 times the 50% effective concentration value for anesthesia. The pote ntial relevance of these findings for clinical use of propofol in humans is discussed.