title: Concentration-dependent inotropic effects of halothane, isoflurane and sevoflurane on rat ventricular myocytes.
abstract: We have described the concentration-dependent inotropic effects of halothane, isoflurane and sevoflurane on rat ventricular cells and investigated the role of the sarcoplasmic reticulum (SR) in these inotropic actions. Single ventricular myocytes, isolated from rat hearts, were stimulated electrically at 1 Hz and contractions recorded optically. Cells were exposed to a range of concentrations of halothane, isoflurane or sevoflurane for a period of 1 min to determine the concentration-dependency of their inotropic actions. For each anaesthetic, the peak negative inotropic action was determined early during an exposure, and sustained negative inotropic action was measured at steady-state just before wash-off. In some experiments, cells were equilibrated with ryanodine 1 mumol litre-1 to investigate the role of the SR in these intropic effects. Halothane caused a concentration-dependent initial increase in contractions (to mean 130 (SEM 28)% at 10 mmol litre-1) followed by rapid onset of a negative inotropic effect (K0.5 0.34 mmol litre-1 for peak effect; K0.5 0.46 mmol litre-1 for sustained effect). Exposure to isoflurane induced a small potentiation of contractions in some cells, followed by a concentration-dependent decrease in contraction in all cells (K0.5 0.85 mmol litre-1 for peak effect; K0.5 1.92 mmol litre-1 for sustained effect); contractions recovered partially during a 1-min exposure. On wash-off, contractions were increased transiently above control. Sevoflurane caused a large initial decrease in contraction which then returned rapidly towards control (K0.5 0.2 mmol litre-1 for peak effect; K0.5 2.57 mmol litre-1 for sustained effect). In common with isoflurane, removal of sevoflurane caused a transient increase in contractions above control. After exposure to ryanodine, the positive inotropic effects of halothane and isoflurane did not occur, and recovery of contractions during exposure to isoflurane and sevoflurane was abolished as was the transient increase in contractions seen on wash-off, indicating that these effects were mediated via the SR. Halothane had the most potent sustained negative inotropic effect but there was little difference between the negative inotropic effects of isoflurane and sevoflurane at clinically relevant concentrations. At higher concentrations, sevoflurane caused a less potent negative inotropic effect than isoflurane. The SR plays a major role in the effects of all three anaesthetics. One possible mechanism underlying the initial potentiation of contraction by halothane (and isoflurane) may be sensitization of the Ca(2+)-induced Ca(2+)-release process of the SR.
authors.affiliation: School of Biomedical Sciences, University of Leeds, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Davies
authors.forename: D L
authors.initials: DL
authors.lastname: Hamilton
authors.forename: P M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: M R
authors.initials: MR
authors.lastname: Boyett
authors.forename: S M
authors.initials: SM
authors.lastname: Harrison
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D006221:Halothane / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology; D008738:Methyl Ethers / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D012433:Ryanodine; D000077149:Sevoflurane; D007530:Isoflurane; D006221:Halothane