Eivind S. Platou

Pentobarbital Plasma Concentrations and Cardiac Electrophysiology During Prolonged Pentobarbital Infusion Anaesthesia in the Dog

There is need for a prolonged stable level of anaesthesia, and we therefore investigated the cardiac electrophysiological effects of continuous pentobarbital infusion after initial pentobarbital injection to induce anaesthesia in dogs. Plasma concentrations of pentobarbital were measured by gas‐liquid chromatography. Heart rate, atrial, atrioventricular (AV) nodal and His‐Purkinje conduction times were measured by His bundle electrography, and atrial, AV nodal and ventricular refractoriness by programmed electrical stimulation. Over a 5‐h observation period, continuous infusion of pentobarbital 3.5 mg · kg‐1 h‐1 after an initial pentobarbital injection of 25 mg · kg‐1 intravenously gave stable mean plasma concentrations of 140‐135 μmol · l‐1. The cardiac electrophysiological variables studied did not change significantly during this period. We conclude that a stable experimental model for cardiac electrophysiological studies can be obtained for several hours by‐continuous pentobarbital infusion.

Class III antiarrhythmic action linked with positive inotropy: antiarrhythmic, electrophysiological, and hemodynamic effects of the sea-anemone polypeptide ATX II in the dog heart in situ.

Summary: Most antiarrhythmic drugs are more or less negatively inotropic. Positively inotropic properties, however, have been demonstrated for some class III antiarrhythmic drugs. To test the hypothesis that class III antiarrhythmic effect and positive inotropy may be linked, we used the sea-anemone polypeptide ATX II, which in isolated heart muscle preparations has been shown to specifically inhibit the inactivation of the sodium channel and thereby increase action potential duration and inotropy. We used 12 pentobarbital-anesthetized dogs. Atrial arrhythmias were induced by high-rate stimulation of the right atrium in 5 dogs. Cardiac electro-physiological effects were studied by His-bundle electrography, programmed electrical stimulation, and monophasic action potential (MAP) recordings in 7 autonomically blocked dogs. ATX II (1.0–5.0 μg/kg i.v.) converted the arrhythmias, and in the autonomically blocked dogs markedly increased atrial and ventricular refractoriness and ventricular MAP duration without influencing atrial or ventricular conduction velocities, heart rate, or AV-nodal refractoriness. ATX II induced a marked increase in left ventricular dP/dt max. The study indicates that ATX II has class III antiarrhythmic effect, and that the electrophysiological and positive inotropic effects of ATX II have a common mechanism.

Cardiac electrophysiological and hemodynamic effects of beta-adrenoceptor blockade and thoracic epidural analgesia in the dog.

To investigate whether thoracic epidural analgesia (TEA) has additional cardiac electrophysiological and hemodynamic effects when induced after β-adrenergic blockade, bupivacaine (0.7–1.2 mg/kg) was injected into the epidural space at T2–3 after intravenous injection of atenolol (1.0 mg/kg) in anesthetized dogs. Cardiac electrophysiology was studied by His bundle electrography, programmed electrical stimulation, and monophasic action potential recordings. Atenolol reduced heart rate, prolonged atrio-ventricular (AV) nodal impulse conduction time and refractoriness, prolonged ventricular refractoriness and action potential duration, and decreased left ventricular (LV) dP/dt max. Addition of TEA further reduced heart rate, prolonged AV nodal conduction time and refractoriness, decreased LV dP/dt max and arterial blood pressure, but had no effect on atrial and ventricular electrophysiology. Induction of TEA during β-blockade may thus have additive depressive effects on sinoatrial and AV nodal functions, as well as on left ventricular inotropy. The study indicates that the cardiac electrophysiological effects induced by TEA are mainly caused by decreased β-receptor stimulation, but increased vagal activity may also contribute.

Effects of Thoracic Epidural Analgesia on Cardiovascular Function and Plasma Concentration of Free Fatty Acids and Catecholamines in the Dog

Increased plasma levels of free fatty acids (FFA), leading to increases in the myocardial oxygen demand, are seen after, for example, surgical stress, traumas and myocardial infarction. The present study was undertaken to investigate the cardiovascular effects of thoracic epidural analgesia (TEA) and the effect of TEA on the plasma concentration of FFA and catecholamines. In 10 sodium‐pentobarbital‐anaesthetized dogs the local anaesthetic agent bupivacaine was injected into the thoracic epidural space via a surgically introduced catheter. TEA markedly reduced heart rate, mean aortic blood pressure, left ventricular systolic blood pressure and dP/dtmax. TEA reduced the plasma concentration of FFA. The FFA‐lowering effect was greatest when the FFA values were high. The effect of TEA on the plasma concentration of noradrenaline and adrenaline was inconsistent and seemed to be of minor importance for the haemodynamic and FFA effects of TEA. The study indicates that TEA, by its haemodynamic and FFA‐lowering effects, may reduce myocardial oxygen demand.

Class III antiarrhythmic action in experimental atrial fibrillation and flutter in dogs.

Summary Progress in the pharmacological treatment of atrial fibrillation and flutter has been achieved by the introduction of the class III antiarrhythmic drug amiodarone. In the present study we tested amiodarone and a new class III antiarrhythmic drug, melperone, in experimentally induced atrial fibrillation and flutter in pentobarbital-anesthetized dogs. By high-rate stimulation in the right atrium, atrial fibrillation was induced in 4, and atrial flutter in 10 out of 22 dogs. Atrial flutter rate was 496 ± 13 min 1 (median ± 95% confidence interval). Both drugs converted the arrhythmias at doses from 2.5 to 10 mg/kg 1 and reduced the atrial flutter rate before conversion. Average ventricular rate during arrhythmias (261 - 16 min 1) decreased after amiodarone. and was unchanged or, in three out of nine dogs, increased after melperone. The doses of amiodarone converting the arrhythmias increased atrial refractoriness, whereas the effects on AV nodal conduction and refractoriness were variable. The results support the concept that atrial flutter is due to circus movement where the flutter rate is dependent upon atrial refractoriness. The class III antiarrhythmic drugs amiodarone and melperone seem to be equally potent in converting atrial arrhythmias.

Vasodilator and inotropic effects of the antiarrhythmic drug melperone.

We investigated the hemodynamic and inotropic effects of the new class III antiarrhythmic drug melperone. In eight pentobarbital-anesthetized dogs, the effects of intravenous melperone 0.5, 2.5, and 12.5 mg·kg-1 were tested. During atrial pacing we measured cardiac output (CO), mean aortic blood pressure (MAP), right (RV) and left (LV) ventricular pressures, and LV dP/dt. In six RV papillary muscles isolated from cats and suspended in a muscle bath containing Krebs-Henseleit solution, we studied the direct effects of melperone 10-8 - 5 · 10-5 M. Administration of melperone decreased total peripheral resistance, MAP, RV and LV systolic and end-diastolic pressures, while CO remained unchanged. Melperone increased LV dF/dtmax. The contractile force (F) and dP/dtmax of the isolated ventricular muscle preparations increased slightly with increasing concentrations of melperone, up to 10-5 M. In conclusion, melperone has vasodilator and slight positive inotropic effects in addition to its class III antiarrhythmic effect.

Plasma levels and cardiac electrophysiological effects of meleperone in the dog

The butyrophenone neuroleptic melperone has recently been shown to possess antiarrhythmic properties in man and animals. We studied the correlation between plasma concentration of melperone and the electrophysiological and blood pressure effects of the drug in 20 pentobarbital-anaesthetized dogs. Linear correlations were found between the log melperone plasma concentration and decreases in mean aortic blood pressure and heart rate, and increases in atrial and AV nodal refractoriness. The correlations were better after pretreatment with the beta 1-blocker atenolol. There was a linear correlation between log melperone plasma concentration and increases in ventricular refractoriness only after atenolol. No correlation was found between log melperone plasma concentration and decreases in AV nodal conduction time. Apart from the effect on AV nodal conduction time, the relationship between plasma concentration of melperone and the electrophysiological and blood pressure effects after beta 1-blockade fits well into an overall log concentration-effect relationship. The poorer correlation without beta 1-blockade was probably due to a combination of direct and indirect effects of the drug.