title: Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart.
abstract: OBJECTIVE
  Propofol is a widely used intravenous anaesthetic agent, but has undesirable cardiac side effects, including bradyarrhythmia and its severe form asystole. This study examined the ionic and cellular mechanisms underlying propofol-induced bradycardia.
  
  
  METHODS
  Sinoatrial node cells, isolated from guinea pig hearts, were current- and voltage-clamped to record action potentials and major ionic currents involved in their spontaneous activity, such as the hyperpolarization-activated cation current (If ), T-type and L-type Ca(2+) currents (ICa,T and ICa,L , respectively) and the rapidly and slowly activating delayed rectifier K(+) currents (IKr and IK s , respectively). ECGs were recorded from Langendorff-perfused, isolated guinea pig hearts.
  
  
  RESULTS
  Propofol (≥5 μM) reversibly decreased the firing rate of spontaneous action potentials and their diastolic depolarization rate. Propofol impaired If activation by shifting the voltage-dependent activation to more hyperpolarized potentials (≥1 μM), slowing the activation kinetics (≥3 μM) and decreasing the maximal conductance (≥10 μM). Propofol decreased ICa,T (≥3 μM) and ICa,L (≥1 μM). Propofol suppressed IKs (≥3 μM), but had a minimal effect on IKr . Furthermore, propofol (≥5 μM) decreased heart rates in Langendorff-perfused hearts. The sinoatrial node cell model reasonably well reproduced the negative chronotropic action of propofol.
  
  
  CONCLUSIONS
  Micromolar concentrations of propofol suppressed the slow diastolic depolarization and firing rate of sinoatrial node action potentials by impairing If activation and reducing ICa,T , ICa,L and IKs . These observations suggest that the direct inhibitory effect of propofol on sinoatrial node automaticity, mediated via multiple channel inhibition, underlies the propofol-induced bradycardia observed in clinical settings.
authors.affiliation: Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kojima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D015742:Propofol