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Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

The aim of this study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochondria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were measured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindoprilate. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial permeability transition pores. This opening is mainly due to oxidative stress and calcium overload and seems to be the pivotal event in cell death after I/R. No drug treatment changed haemodynamic and electrophysiological parameters, but amlodipine and perindoprilate, either alone or combined, prevented mitochondrial alterations but only partially. The preservation of mitochondrial structure and functions reported in our study probably plays an important role in preventing calcium overload and mPTP opening during myocardial I/R by a specially increased CRC, which can explain their cardioprotective effects., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. The heart rate (HR), duration of monophasic action potentials (dMAP), and peak of the time derivative of left ventricular pressure (LV dP/dt max) were measured during ischemia and after 1 min of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from the left ventricle ischemic area at the end of the experiment. I/R induced expected effects, namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species (ROS) production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores (mPTP). Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences. The protective effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria., (© 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Société Française de Pharmacologie et de Thérapeutique.)

Class Ic antiarrhythmic drugs, which are known to slow down conduction in the ventricular muscle, are likely to impair synchrony in activity of the ventricular fibres. Asynchronous activation was first investigated between an ischaemic and a normal area by the simultaneous recording in anaesthetized, open-chest pigs of two left ventricular monophasic action potentials (MAPs) under ventricular pacing at a high rate of 180 beats.min-1. Asynchronous activation was then investigated in the intact myocardium according to the distance separating the recording from the pacing electrode. Furthermore, mechanical effects of left ventricular systole were observed by recording dP/dt(max) and mean arterial blood pressure during the pacing periods. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery near its origin; as a result, activation time reached 85 ms in the ischaemic area under flecainide administered iv in a 2.5 mg.kg-1 dose instead of approximately 60 ms in the normal area for fibres equi-distant from the pacing electrode. Similar delays in activation were observed in the intact myocardium, depending on whether the explored region was close to or far from the pacing electrode. In the latter case, the difference in activation time may become markedly greater if the distance or the dose of flecainide are increased. This difference, which possibly exceeds one-third of the MAP duration (practically unchanged by flecainide), may account for the occurrence of fibrillation or the sudden loss of systole mechanical efficacy.

The cardiac adrenergic system is known to have practically no influence on conduction velocity in the ventricles under normal conditions. The effects of isoproterenol and propranolol were investigated on depression of intraventricular conduction induced by a class IC antiarrhythmic drug, cibenzoline, in anaesthetized, closed-chest dogs. In addition to electrocardiogram for measurement of QRS duration in sinus rhythm, conduction time was measured in the ventricular contractile tissue between an electrode advanced to the apex and a pacing electrode near the base, at 400- and 200-ms pacing periods. Effective refractory period (ERP) was measured concurrently according to the extrastimulus method. After intraventricular conduction had been slowed down by cibenzoline IV administered (loading dose of 3 mg/kg plus infusion of 0.2 mg/kg/min over 15 min), isoproterenol was infused or propranolol injected by the intravenous route also (0.5 mn/micrograms/kg/min over 5 min and 0.4 mg/kg, respectively). When conduction time has been raised by 75/150% (depending on the pacing rate), isoproterenol appears to attenuate and propranolol to aggravate substantially the impairment of conduction, whereas the reduction undergone by ERP does not differ from usual. Thus, reentrant arrhythmias might be prevented by isoproterenol and triggered by propranolol. Intraventricular conduction, when depressed, therefore, is sensitive to adrenergic drugs, probably because of the enhanced influence of polarization of the fibres in the presence of a sodium conductance impairment.