The effects of propofol on the contractility of failing and nonfailing human heart muscles

We determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles. Atrial and ve ntricular trabecular muscles were obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coron ary artery bypass surgery. Isometric contraction variables were recorded be fore and after propofol was added to the bath in concentrations between 0.0 56 and 560 muM. The effects of propofol were compared with its commercial v ehicle intralipid. To test beta -adrenergic effects in the presence of prop ofol, 1 muM isoproterenol was added at the end of each experiment. To deter mine the cellular mechanisms responsible for the actions of propofol, we ex amined its effects on actomyosin ATPase activity and sarcoplasmic reticulum (SR) Ca2+ uptake in nonfailing atrial tissues. Propofol caused a concentra tion-dependent decrease in maximal developed tension in all muscles, which became significant (P < 0.05) at concentrations exceeding the clinical rang e (greater than or equal to 56 muM). Isoproterenol restored contractility t o the level achieved before exposure to propofol (P > 0.05 compared with ba seline). Failing ventricular muscle exposed to propofol exhibited somewhat diminished ability to recover contractility in response to isoproterenol (P < 0.05 versus failing muscle exposed to intralipid only). Propofol induced a concentration-dependent decrease in the uptake of Ca2+ into SR vesicles. At the same time, in the presence of 56 muM propofol, the Ca2+-activated a ctomyosin ATPase activity was shifted leftward, demonstrating an increase i n myofilament sensitivity to Ca2+. We conclude that propofol exerts a direc t negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negati ve inotropic effects are reversible with beta -adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by dec reased Ca2+ uptake into the SR; however, the net effect of propofol on cont ractility is insignificant at clinical concentrations because of a simultan eous increase in the sensitivity of the myofilaments to activator Ca2+.