Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart. (15th December 2014)

• Record Type: Journal Article
• Authors: Kojima, Akiko; Ito, Yuki; Kitagawa, Hirotoshi; Matsuura, Hiroshi
• Is Part Of: British journal of pharmacology. Volume 172:Number 3(2015:Feb.)
• Page Start: 799
• Page End: 814
• Publication Date: 2014-12-15
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12936
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12936-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12936-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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 (<italic>I</italic><sub>f</sub>), T‐type and L‐type Ca<sup>2+</sup> currents (<italic>I</italic><sub>Ca, T</sub> and <italic>I</italic><sub>Ca, L</sub>, respectively) and the rapidly and slowly activating delayed rectifier K<sup>+</sup> currents (<italic>I</italic><sub>Kr</sub> and <italic>I</italic><sub>K</sub><sub>s</sub>, respectively). ECGs were recorded from Langendorff‐perfused, isolated guinea pig hearts.</p> </sec> <sec id="bph12936-sec-0003" sec-type="section"> <title>Key Results</title> <p>Propofol (≥5 μM) reversibly decreased the firing rate of spontaneous action potentials and their diastolic depolarization rate. Propofol impaired <italic>I</italic><sub>f</sub> 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 <italic>I</italic><sub>Ca, T</sub> (≥3 μM) and <italic>I</italic><sub>Ca, L</sub> (≥1 μM). Propofol suppressed <italic>I</italic><sub>Ks</sub> (≥3 μM), but had a minimal effect on <italic>I</italic><sub>Kr</sub>. 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.</p> </sec> <sec id="bph12936-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Micromolar concentrations of propofol suppressed the slow diastolic depolarization and firing rate of sinoatrial node action potentials by impairing <italic>I</italic><sub>f</sub> activation and reducing <italic>I</italic><sub>Ca, T</sub>, <italic>I</italic><sub>Ca, L</sub> and <italic>I</italic><sub>Ks</sub>. 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.</p> </sec> </abstract>