title: Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes.
abstract: The mechanisms contributing to the negative inotropic effect of halothane were studied in isolated rate ventricular myocytes. Contraction and intracellular Ca2+ transients were measured optically in these cells. The initial application of halothane (2% or 0.5 mmol litre-1) led to short-lived increases in the Ca2+ transient and contraction, which were abolished by ryanodine. Continued application of halothane led to a sustained decrease in contraction: this resulted from: (i) a decrease in myofilament Ca2+ sensitivity; (ii) a decrease in the Ca2+ transient; and (iii) a decrease in the Ca2+ content of the sarcoplasmic reticulum. Although halothane reduced action potential duration, the sustained negative inotropic effect was similar when action potentials or voltage clamp pulses of constant duration were used to trigger contractions. In cells exposed to nifedipine 0.5 mumol litre-1 (which decreases the L-type Ca2+ current, ICa), Ca2+ transients, sarcoplasmic reticulum Ca2+ content and fractional release (the fraction of sarcoplasmic reticulum Ca2+ content released during each stimulus) were reduced. Halothane 0.5 mmol litre-1 (which also decreases ICa) decreased Ca2+ transients to a lesser extent and reduced sarcoplasmic reticulum Ca2+ content to a greater extent than nifedipine, whereas fractional release was unchanged compared with control. These data suggest that halothane sensitizes Ca(2+)-induced Ca2+ release from the sarcoplasmic reticulum in addition to reducing ICa.
authors.affiliation: School of Biomedical Sciences, University of Leeds, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Harrison
authors.forename: M
authors.initials: M
authors.lastname: Robinson
authors.forename: L A
authors.initials: LA
authors.lastname: Davies
authors.forename: P M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: M R
authors.initials: MR
authors.lastname: Boyett
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D002118:Calcium; D006221:Halothane