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.