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Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart
Author(s) -
Kojima Akiko,
Ito Yuki,
Kitagawa Hirotoshi,
Matsuura Hiroshi
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12936
Subject(s) - sinoatrial node , chronotropic , diastolic depolarization , propofol , bradycardia , chemistry , medicine , heart rate , anesthesia , cardiology , blood pressure
Background and Purpose 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. Experimental Approach 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 ( I f ), T ‐type and L ‐type Ca 2+ currents ( I Ca,T and I Ca,L , respectively) and the rapidly and slowly activating delayed rectifier K + currents ( I Kr and I K s , respectively). ECGs were recorded from L angendorff‐perfused, isolated guinea pig hearts. Key Results Propofol (≥5 μM ) reversibly decreased the firing rate of spontaneous action potentials and their diastolic depolarization rate. Propofol impaired I f 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 I Ca,T (≥3 μM ) and I Ca,L (≥1 μM ). Propofol suppressed I Ks (≥3 μM ), but had a minimal effect on I Kr . 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 Implications Micromolar concentrations of propofol suppressed the slow diastolic depolarization and firing rate of sinoatrial node action potentials by impairing I f activation and reducing I Ca,T , I Ca,L and I Ks . 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.