[Effect of hypothermia on intraventricular conduction problems caused by bupivacaine].
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Animals↗
Biomedical subjects
G Faucon
Publications and source records attributed to G Faucon.
[Effects of hypo- and hypernatremia on depression of ventricular conduction and arrhythmia induced by bupivacaine].
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Animals↗
Biphasic dose-response relationship observed with Bay k 8644 on atrioventricular nodal conduction inhibited by verapamil.
The effects of a calcium channel blocker, verapamil, on the atrioventricular (AV) node, are antagonized by calcium, intravenously infused, so long as plasma calcium concentration does not reach 5.0 or 5.5 mmol.l-1, as previously shown. Beyond this, the antagonistic effects decrease progressively, so that there is a bell-shaped relationship between dose (or concentration) and response. The purpose of the present experiments has been to investigate a possible similar dose-response curve with a calcium channel activator, Bay k 8644. The study was carried out in anaesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitary electrodes and the AV nodal effective refractory period was measured by the extrastimulus method. Verapamil impaired AV nodal conduction and additional infusion of Bay k 8644 at a rate of 1 microgram.kg-1.min-1 partly antagonized this effect. Increasing the infusion rate of Bay k 8644 to 5 micrograms.kg-1.min-1 did not further increase but reduced the antagonism. In other experiments where infusion of calcium had partly antagonized the effect of verapamil, Bay k 8644 infused after cessation of calcium infusion did not further antagonize the effect of verapamil which even became again increasingly marked. Consequently, in the AV node depressed by a calcium channel blocker, Bay k 8644 gives rise to a bell-shaped dose-response relationship of its verapamil-antagonistic action and the reversal of this action by high doses of Bay k 8644 can be observed after both administration of either calcium or Bay k 8644 in moderate doses.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Doxorubicin concentrations in plasma and myocardium and their respective roles in cardiotoxicity.
Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than in the plasma (about 4,000 ng/g, i.e., 50 times higher). After the intravenous infusion of doxorubicin (1.5 mg/kg over 15 min) to conscious dogs, the drug concentration appeared to decline very slowly in the myocardium, since it was close to 200 ng/g at the 7th day, whereas the plasma concentration had fallen to zero, and the drug was still detected in the cardiac tissue 21 days after the administration. As myocardial concentrations of doxorubicin persist long after plasma clearance is complete, the hazards of repeated administration, based on plasma kinetic patterns, must be emphasized.
Animals↗
[Systemic toxicity of local anesthetics. Pharmacokinetic and pharmacodynamic factors].
Local anaesthetics can have systemic adverse effects, mostly affecting the central nervous system and the heart. The physicochemical characteristics of the different local anaesthetics are recalled, for they determine the relationship between structure, activity and toxicity. The pharmacokinetic factors involved in the toxic effects of local anaesthetics, whether the drug is given in a single extravascular dose or, accidentally, within a blood vessel, are discussed. The toxic effects of repeated administrations of local anaesthetics depend on the metabolism of the drug as well as on pharmacokinetic factors. Possible maximal doses and drug interactions are also discussed. The mechanism of action of local anaesthetics, which block the sodium channel, explains their tissue toxicity and, more specifically, their central nervous and cardiovascular toxicities, which are more pronounced for the more potent local anaesthetic agents (bupivacaine, etidocaine). Systemic maternal effects and transplacental passage probably explain their foetal toxicity. Specific toxic effects are seen with some drugs, such as methaemoglobinaemia and allergic reactions (rarely for amide agents). Overall, local anaesthetic accidents are rare, but they must be prevented.
Anesthesia, Intravenous↗
A case of sotalol poisoning with fatal outcome.
The case of a 58 year old woman who died after ingestion of 14.4 g of sotalol and 50 mg of triazolam is described. Despite medical treatment, intracardiac pacing and hemodialysis, cardiovascular failure persisted and became irreversible. High sotalol concentrations were observed in plasma (65 micrograms/ml) and in post mortem tissues samples. Tissue to plasma ratios ranged from 2.5 to 6. The high drug concentration found in heart tissue (104.4 micrograms/g) explains the difficulties experienced in the sotalol poisoning.
Chromatography, High Pressure Liquid↗
[The calcium channel in the various elements making up the myocardium].
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Animals↗
Haemodynamic effects of high plasma concentrations of bupivacaine in the dog.
The threshold concentrations responsible for circulatory collapse were experimentally investigated by intravenously infusing the drug at high rates (0.2 and 0.3 mg kg-1 min-1 over 20 min, and 0.4 mg kg-1 over 10 min) to 11 anaesthetized and ventilated dogs. Bupivacaine plasma concentrations at the time of haemodynamic measurements were, respectively, 4303 +/- 46, 5829 +/- 615, and 8930 +/- 689 ng ml-1 (means +/- SEM). Cardiac output appeared to be the first and the most affected of the haemodynamic variables studied. Its reduction was already significant with the 0.2 mg kg-1 min-1 bupivacaine infusion, whereas mean systolic blood pressure remained unchanged because of the compensatory increase in vascular resistance. The fall of cardiac output was enhanced by the rise in bupivacaine infusion rate, with simultaneous substantial decreases in left ventricular pressure and LV dP/dt max. At this stage, the increase in systemic vascular resistance was less marked than at low infusion rates, and was not sufficient to prevent hypotension. The variations of mean pulmonary blood pressure and pulmonary capillary wedge pressure did not reach statistical significance, and the absence of significant change in mean pulmonary blood pressure at the time cardiac output was reduced reflected the increase in pulmonary vascular resistance. These results suggest that high plasma concentrations of bupivacaine exert a depressant effect on cardiac contractions earlier than on arteriolar tone.
Animals↗
Potentiation by acetylcholine of the effects of a calcium channel activator, Bay k 8644, on dog atria in situ.
The effects of Bay k 8644 were studied in the canine in situ heart under vagal influence and out of this influence on sinus rate and sinus recovery time, conduction time and effective refractory period (ERP) in the atrioventricular (AV) node and ERP of the atrial muscle. Bay k 8644, intravenously infused at the 2 micrograms X kg-1 X min-1 rate for 30 min, enhanced the inhibition of the atrial specialized tissue as well as the shortening of the atrial muscle ERP during vagal activity, elicited by the injection of dextromoramide into the cisterna magna. It did not develop any atrial action in the absence of vagal activity, suppressed by atropine. The reflex increase of vagal tone, in response to a small increase in blood pressure produced by Bay k 8644, is not the only cause of the phenomena observed in the former case. The observations can be explained primarily in terms of an interaction between Bay k 8644 and acetylcholine (ACh):ACh intraaortically injected near the coronary ostia, in a dose just sufficient to slow down sinus rate before Bay k 8644, reduced the rate by 50% at the end of a 60 min infusion of Bay k 8644 and the ACh threshold dose necessary to elicit a short third degree AV block before Bay k 8644 was reduced by 50% at the end of a 30 min infusion of Bay k 8644. Therefore, ACh appeared to be capable of enhancing the effects of a calcium channel activator as well as the effects of hypercalcaemia, as earlier reported.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Doxorubicin concentration time course in the myocardium after single administration to the dog. Possible role in the cardiac effects.
Three hours after i.v. administration of doxorubicin, concentrations of the drug in the myocardium are much higher (about 50 times) and decrease much more slowly (drug still detected 21 days later) than those in the plasma, so that storage results from too early readministration, with possible toxic signs.
Animals↗
Role of calcium in the rate-dependent depression of atrioventricular nodal conduction in the dog heart under vagal influence.
Increase in heart rate may be detrimental to atrioventricular conduction. The effects of such an increase were investigated in the paced intact dog heart, by measuring the conduction time in the atrioventricular node (obtained from the His bundle potential recording) and the effective refractory period in this node as determined by the extrastimulus method. Investigations on atrioventricular nodal conduction were performed with and without vagal influence. After central restoration of vagal tone by dextromoramide in anesthetized animals, both parameters appeared to lengthen as the heart rate rose. This lengthening became considerable at the highest rates. After blockade of cholinergic receptors by atropine, no significant change occurred when the heart rate was raised. The prolongation observed under vagal tone was enhanced by the rise in the plasma calcium concentration to 3.10 mmol X l-1 and reduced by a calcium influx inhibitor, verapamil, in 0.2 mg X kg-1 dose. These effects are related to the calcium intracellular concentration, since the rise in this concentration beyond an optimum has been demonstrated to inhibit the calcium and potassium channel.
Animals↗
Effect of isoproterenol on the metabolism of myocardial fatty acids.
The effect of beta-adrenergic stimulation on myocardial fatty acid metabolism was studied in the anesthetized open-chest dog. Isoproterenol (1 microgram/kg/min) was infused; and samples of arterial blood and of left ventricular wall were taken at the 5th min for the determination of the following variables: in arterial blood: lactate and serial free fatty acids (FFA); in myocardial tissue: creatine phosphate (CP), ATP, lactate, carnitine, acylcarnitine, glycerol, and the fatty acid content of each of phospholipids (PL), cholesterol esters (CE), triglycerides (TG), diglycerides (DG), monoglycerides (MG), and FFA. A capillary gas chromatography was used for fatty acid assay. Isoproterenol decreased the content of creatine phosphate but not of ATP. Lactate increased in both arterial blood and myocardial tissue. The five-fold increase in arterial FFA (P less than 0.001) was accompanied with a significant increase in FFA serum/tissue ratio. Free carnitine decreased and acylcarnitine increased. Triglycerides content (which is expressed in terms of its total fatty acid content) was considerably reduced by beta-stimulation in comparison with control group (2694 +/- 689 vs. 7518 +/- 833 nmol/g wet wt, P less than 0.001), and tissue glycerol increased (P less than 0.01). The decrease in total MG content was significant, but not that of DG, nor that of CE. Total PL content did not change. The most marked individual changes (except in PL) were observed on monounsaturated fatty acids, 18: 1 omega 9, 18: 1 omega 7, and 16: 1 cis. The significant changes of monounsaturated/saturated and of 16:1 cis/16:1 trans ratios, in arterial FFA and tissue TG, suggested modifications in the distribution of fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Electrophysiological study in the dog of the risk of cardiac toxicity of bupivacaine.
The risk of toxic effects on the heart of bupivacaine following several kinds of locoregional anaesthesia has been investigated in the dog in situ heart by determining conduction time and effective refractory period in the various parts of the conduction system and the ventricular muscle, as well as the discharge rate of the sinus node. Bupivacaine, i.v. infused at 3 rates, 0.2, 0.3 and 0.4 mg X kg-1 X min-1, proved to have depressant effects on conduction, automatism and excitability. It slows down conduction in all the parts of the myocardium, considerably at high stimulation frequencies, but always much more in the His-Purkinje system and the ventricular contractile fibres than in the atrioventricular node, because it tends to block the sodium rather than the calcium or potassium channel. Its effect remain more moderate, indeed, on sinus automatism and atrial and mainly ventricular refractoriness. Its danger lies, therefore, in the inhibition of conduction, with atrioventricular or His bundle branch block, but more frequently reentrant arrhythmias, likely to result in ventricular fibrillation. However: these alterations are observed with very high plasma levels (about 4 to 9 micrograms X ml-1), much higher than usual peak concentrations following spinal anaesthesia (0.10 micrograms X ml-1) or even epidural anaesthesia or brachial plexus block (1.20 micrograms X ml-1); reversal of these alterations occurs rapidly (reduction by 50% within 30 min for instance), when they have not led to ventricular fibrillation or they have not been associated with circulatory collapse.
Action Potentials↗
Protection against ventricular and atrial fibrillation by sotalol.
Sotalol is not only a beta blocker but a class III antiarrhythmic drug. Its possible antifibrillatory activity was therefore investigated in both the ventricles and atria of dog heart in situ, since vulnerability to fibrillation is not the same in both these parts of the myocardium. Fibrillation threshold was measured concurrently with the duration and amplitude of monophasic action potential, the effective refractory period, the conduction time in the contractile fibres, and after fibrillation had been triggered the fibrillation rate. Variables were measured at 5 and 10 min after sotalol had been given intravenously in closed chest dogs in three doses (1, 1, and 2 mg X kg-1) at 15 min interval. Sotalol produced a rise in fibrillation threshold that occurred simultaneously with a prolongation in monophasic action potential duration and effective refractory period of the contractile fibres and a slowing in fibrillation rate, whereas conduction time was not affected. The changes appeared, however, to be less pronounced in the ventricles than in the atria, in which vulnerability to fibrillation, normally increased by vagal tone, had been previously enhanced by acetylcholine. Sotalol antagonised the changes due to acetylcholine. In both the atria and the ventricles the first dose (1 mg X kg-1), which produced plasma concentrations of approximately 2 micrograms X ml-1 10 min after injection, produced a submaximal effect. Nevertheless, subsequent administrations increased the beneficial effects but not in proportion to the dose and plasma concentrations.
Action Potentials↗
Centrally mediated cardiovascular effects of nicergoline in the dog compared to those of clonidine.
The intracisternal administration of nicergoline (5 micrograms/kg) or clonidine (4 micrograms/kg) in chloralose-anesthetized dogs induced significant decreases in blood pressure and heart rate. The same dose of nicergoline induced similar effects on atropine-pretreated dogs. Guanethidine pretreatment (30 mg/kg i.v. the day before) prevented the hypotension but not the bradycardia induced by clonidine. Guanethidine prevented both the hypotension and the bradycardia induced by nicergoline. Thus, nicergoline, unlike clonidine, does not increase cardiac parasympathetic activity. When administered by the same route at the same doses, nicergoline did not change the slope and reduced the amplitude whereas clonidine increased both the slope and the amplitude of the heart period vs. blood pressure curve obtained by intravenous administration of phenylephrine. Taken together, these results suggest that nicergoline and clonidine probably act on different structures within the central nervous system.
Animals↗
[Concentration and pharmacokinetics of daunorubicin in leukemic cells in vivo].
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Daunorubicin↗
Assay of lipids in dog myocardium using capillary gas chromatography and derivatization with boron trifluoride and methanol.
The fatty acids of three lipid classes (free fatty acids, triglycerides, and cholesteryl esters) from dog heart were analysed by gas chromatography. Samples of the left ventricle were homogenized and total lipids were extracted. After separation by thin-layer chromatography, the bands of the lipid classes studied were scraped off, transmethylated according to the boron trifluoride-methanol procedure, and the fatty acid methyl esters were extracted and analysed. The problems related to the quantitation of fatty acids were investigated, namely transmethylation procedure, thin-layer chromatography, and gas chromatographic conditions. Fatty acid methyl esters were separated on capillary columns coated in the laboratory with SP 2340 stationary phase. The high performance of the separation ensured the reliability and the precision of the analysis.
Animals↗
Biphasic effect of a gradual rise in plasma calcium concentration on vulnerability to fibrillation.
The possible potentiation by a rise in plasma calcium concentration of the effects of acetylcholine (ACh) on the atrial myocardium was investigated, mainly with a view to define the increase in vulnerability to fibrillation by hypercalcaemia. The effective refractory period (ERP) of the atrial myocardium, the atrial fibrillation threshold (AFT) and the atrial fibrillation rate (AFR) were measured repeatedly before and during the intravenous infusion of calcium at the rates of 0.025, 0.050 and 0.100 mmol . kg-1 . min-1 in dogs whose heart was, in addition, submitted to a cholinergic influence. 1. As long as the rise in plasma calcium concentration did not reach 100% approximately, this influence was enhanced considerably: in particular, ACh shortened ERP and raised AFR to a much larger extent, so that it resulted in fibrillation with a minor electrical stimulation. 2. When the rise in plasma calcium concentration exceeded 100%, hypercalcaemia became inhibitory of the effects of ACh, with a reversal in the modification of all the parameters, AFT especially, and, finally, prevention or even conversion to sinus rhythm of fibrillation.
Acetylcholine↗