The concentration-dependent effects of propofol on rat ventricular myocytes.
Whether propofol contributes a direct negative inotropic effect is controversial. Our principal aim in this study was to determine whether negative inotropic effects of propofol occur at clinically relevant concentrations. We constructed the concentration-response relationship for the negative inotropic effects on intact, isolated, stimulated rat ventricular myocytes. Contraction was measured as cell shortening by using an optical system. Propofol was applied as dilutions of the commercial preparation in physiological saline solution. The drug vehicle had a minimal effect on myocyte contractility. Propofol produced a concentration-dependent reduction in evoked contraction at concentrations greater than 5 microM. The maximum effect was observed at >100 microM, with the K(0.5) calculated to be 34.5 microM (95% CI, 21.8-54.7 microM). In further experiments, we investigated the relationship between changes in contractility and changes in Ca(2+) transient (measured by using fura-2 fluorescence) after the application of propofol. By using the shift in the relationship of the cell length to fura-2 fluorescence ratio in the relaxation phase of a contraction as an index of Ca(2+) response of the myofilaments, we demonstrated that some of the negative inotropic effect of propofol may be caused by a reduction in myofilament Ca(2+) sensitivity. We confirmed this by comparing the reduction in contractility in the presence of propofol with that caused by reducing the extracellular Ca(2+) concentration. We observed that, for a decrease in the fura-2 fluorescence ratio of 21%, propofol caused a 12% (95% CI, 2% to 22%) greater reduction in contractility than predicted from reducing the extracellular Ca(2+) concentration. However, the K(0.5) for the negative inotropic effect of propofol we observed is more than 80 times the 50% effective concentration value for anesthesia. The potential relevance of these findings for clinical use of propofol in humans is discussed.


CONCLUSIONS
By using intact, isolated rat heart ventricle cells, we investigated the mechanisms and concentration dependence of the depressant effect of propofol on contractility of the heart. We conclude that direct effects of propofol on the heart are unlikely to be of significance at the clinical dosage usually given.
School of Biomedical Sciences and Academic Unit of Anaesthesia, University of Leeds, United Kingdom.
D L
DL
Hamilton
M R
MR
Boyett
S M
SM
Harrison
L A
LA
Davies
P M
PM
Hopkins
D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D016257:Fura-2; D006352:Heart Ventricles / Q000166:cytology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats
D018686:Anesthetics, Intravenous; D005456:Fluorescent Dyes; D002118:Calcium; D016257:Fura-2; D015742:Propofol