• Akiko Kojima, Yuki Ito, Hirotoshi Kitagawa, and Hiroshi Matsuura.
• Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, Japan.
• Br. J. Pharmacol. 2015 Feb 1; 172 (3): 799-814.

Background And PurposePropofol 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.Experimental ApproachSinoatrial 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.Key ResultsPropofol (≥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 And ImplicationsMicromolar 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.© 2014 The British Pharmacological Society.

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