title: The effects of propofol on the contractility of failing and nonfailing human heart muscles.
abstract: We determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles. Atrial and ventricular trabecular muscles were obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass surgery. Isometric contraction variables were recorded before and after propofol was added to the bath in concentrations between 0.056 and 560 microM. The effects of propofol were compared with its commercial vehicle intralipid. To test beta-adrenergic effects in the presence of propofol, 1 microM isoproterenol was added at the end of each experiment. To determine the cellular mechanisms responsible for the actions of propofol, we examined its effects on actomyosin ATPase activity and sarcoplasmic reticulum (SR) Ca(2+) uptake in nonfailing atrial tissues. Propofol caused a concentration-dependent decrease in maximal developed tension in all muscles, which became significant (P < 0.05) at concentrations exceeding the clinical range (> or =56 microM). Isoproterenol restored contractility to the level achieved before exposure to propofol (P > 0.05 compared with baseline). 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 Ca(2+) into SR vesicles. At the same time, in the presence of 56 microM propofol, the Ca(2+)-activated actomyosin ATPase activity was shifted leftward, demonstrating an increase in myofilament sensitivity to Ca(2+). We conclude that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with beta-adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by decreased Ca(2+) uptake into the SR; however, the net effect of propofol on contractility is insignificant at clinical concentrations because of a simultaneous increase in the sensitivity of the myofilaments to activator Ca(2+).
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, USA. sprung.juraj@mayo.edu
authors.forename: J
authors.initials: J
authors.lastname: Sprung
authors.forename: M L
authors.initials: ML
authors.lastname: Ogletree-Hughes
authors.forename: B K
authors.initials: BK
authors.lastname: McConnell
authors.forename: D R
authors.initials: DR
authors.lastname: Zakhary
authors.forename: S M
authors.initials: SM
authors.lastname: Smolsky
authors.forename: C S
authors.initials: CS
authors.lastname: Moravec
mesh_terms: D000368:Aged; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D009210:Myofibrils / Q000187:drug effects / Q000201:enzymology; D009218:Myosins / Q000378:metabolism; D015742:Propofol / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology
chemical_list: D018686:Anesthetics, Intravenous; D009218:Myosins; D002118:Calcium; D015742:Propofol