Effects of propofol and enflurane on action potentials, membrane currents and contraction of guinea‐pig isolated ventricular myocytes

Abstract

1 The effects of two general anaesthetics, propofol and enflurane, on electrical activity and contractions were investigated in single myocytes isolated from guinea-pig ventricles. 2 Propofol and enflurane depressed the plateau and shortened the duration of action potentials. 3 Under voltage-clamp conditions, propofol and enflurane reduced the amplitude of inward calcium current and of additional inward current activated by cytosolic calcium. 4 Contractions (measured with an optical technique) accompanying either action potentials or second inward currents (in response to depolarizations to 0 mV) were reduced by both anaesthetics. The mechanisms for calcium entry during contractions accompanying pulses to positive potentials such as + 60 mV are thought to differ from those accompanying second inward currents which are evoked by pulses from -40 to 0 mV. Enflurane enhanced the amplitudes of contractions accompanying pulses to positive potentials; in contrast these contractions were depressed by propofol. 5 In experiments where recovery processes were investigated by use of pairs of voltage-clamp pulses with a variable interval between them, enflurane but not propofol slowed the recovery of contractions and calcium-activated 'tail' currents. These observations are consistent with the hypothesis that enflurane may impair calcium handling by the sarcoplasmic reticulum whereas propofol has little, if any, effect at this site. 6 In conclusion, the actions of propofol and enflurane on second inward currents contribute to their effects on action potentials and contraction. The negative inotropic effect of both anaesthetics may result partly from reduced calcium influx to trigger contraction, and for enflurane, partly from an impairment of calcium handling by the sarcoplasmic reticulum.

The effects of propofol and enflurane on single calcium channel currents of guinea‐pig isolated ventricular myocytes

“…This depression of contractility may arise, at least in part, from a reduction of the inward calcium current into cardiac cells (Ikemoto et al, 1985;Terrar & Victory, 1988a,b;Puttick & Terrar, 1989;1992;Hirota et al, 1989;Niggli et al, 1989;Bosnjak et al, 1991). This would be expected to reduce the cytosolic calcium transient (both directly because calcium entering would be reduced and indirectly since calciuminduced calcium release from the sarcoplasmic reticulum would be expected to be less); this in turn would reduce contraction.…”

“…Two different anaesthetics were chosen: the intravenous agent, propofol (2,4-diisopropylphenol) and the inhalational halogenated anaesthetic, enflurane. Preliminary observations have been presented to the British Pharmacological Society (Puttick & Terrar, 1991).…”

“…Conditions for these experiments were broadly similar to those described above except that the concentration of Bay K 8644 was 1 AM and analysis of channel opening and closing was carried Drugs Propofol (ICI) was used as the clinically available preparation at a final concentration of 100 ILM. In experiments with enflurane (Abbott), the solution was pre-equilibrated for at least 45 min with an Enfluratec vaporiser (see Terrar & Victory, 1988a,b;Puttick & Terrar, 1992). The enflurane concentration in the bath was assayed by infrared spectrophotometry (Speden, 1963); 3% enflurane corresponded to a bath concentration of 1.46 ± 0.09 mM.…”

“…The enflurane concentration in the bath was assayed by infrared spectrophotometry (Speden, 1963); 3% enflurane corresponded to a bath concentration of 1.46 ± 0.09 mM. The concentrations of propofol and enflurane was chosen on the basis of the doseresponse curves for these drugs on whole-cell calcium currents recorded from a previous series of experiments in guinea-pig ventricular cells (Puttick & Terrar, 1992). Bay K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate) was obtained from Calbiochem.…”

Propofol-associated QTc prolongation

“…Several pharmacologic mechanisms have been identified that may support the cogency of propofol's association with these adverse cardiovascular effects. For example, propofol has been shown to block L-type calcium channels [Fassl et al 2011], a mechanism for QTc abbreviation unless IKr and L-type calcium channel blockade are present resulting in IKs inhibition and QTc prolongation [Puttick andTerrar, 1992, Heath andTerrar, 1996]. Other mechanisms include inhibition of volume-sensitive chloride channels in coronary artery smooth muscle cells [Masuda et al 2003], a property which may cause depolarization and block adenosine triphosphate channels in rat cardiomyocytes [Kawano et al 2004] or polymorphic ventricular tachycardia in rabbits with long QT syndrome type 2 [Odening et al 2008].…”