R. Xhonneux

An improved method to correct the QT interval of the electrocardiogram for changes in heart rate

The adequacy of the Bazett formula to correct for heart rate-induced changes in the QT interval of the electrocardiogram has been frequently questioned. In the present study, a simple linear equation was derived, which in anesthetized dogs corrects more adequately for changes in heart rate than the Bazett formula. Regression analysis of experimental data yielded the following equation: QTc = QT - 0.087 (RR - 1000) = QT - 87 (60/HR - 1). The reliability of this equation was investigated in experiments on anesthetized dogs with different cardioactive drugs with a known mechanism of action.

pharmacological and Hemodynamic Profile of Nebivolol, * a Chemically Novel, Potent, and Selective β1-adrenergic Antagonist

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.

Cardioprotective effects of lidoflazine during 1-hour normothermic global ischemia.

The cardioprotective effects of lidofiazine, a drug with calcium homeostatic properties, were investigated in dogs subjected to 1 hour of normothermic global ischemia, followed by reperfusion. None of the eight control dogs could be weaned from the extracorporeal bypass, confirming the severity of the ischemic model. All eight acutely pretreated dogs showed rapid recovery from the prolonged ischemic arrest and could support their own circulation. Recovery of preischemic values was 95% for systolic aortic pressure, 71% for diastolic aortic pressure, 99% for left ventricular dP/dt max and 80% for cardiac output. Light and electron microscopy and calcium cytochemistry were performed on left ventricular biopsies taken before, during and after ischemic arrest. In the control dogs, loss of structural integrity of the sarcolemma and mitochondria was prominent at the end of the ischemic period. Intracellular edema, hypercontraction of sarcomeres and great accumulation of calcium in severely damaged mitochondria occurred after 5 and 30 minutes of reperfusion. In the lidofiazine‐treated dogs, such lesions were largely prevented during the ischemic period and completely reversed after reperfusion. These observations suggest that the tolerance to ischemia is markedly augmented by lidoflazine.

Nebivolol is devoid of intrinsic sympathomimetic activity.

Nebivolol is a chemically novel, potent and selective beta 1-adrenoceptor-blocking agent that acutely lowers arterial blood pressure in hypertensive patients and rats without depressing, or even enhancing, left ventricular function. These properties could be compatible with a partial agonistic effect of beta-adrenoceptor-blocking agents. It was the aim of the present study to investigate whether nebivolol has intrinsic sympathomimetic properties. The study was performed on reserpinized dogs and spontaneously hypertensive rats, and on various isolated tissues from various species. Unlike pindolol and practolol, nebivolol did not exert a stimulating effect on the heart rate and left ventricular function in reserpinized animals and/or in isolated atria of reserpinized rats at doses that are clinically active. Nebivolol did not induce relaxation of isolated coronary arteries and saphenous veins at concentrations that block beta-adrenoceptors. These findings indicate that nebivolol is devoid of intrinsic sympathomimetic activity at clinically relevant doses.

Cardiovascular effects of dl-nebivolol and its enantiomers — a comparison with those of atenolol

In the present study, we investigated the cardiovascular effects of dl-nebivolol, a newly synthetized, chemically novel, beta 1-adrenoceptor antagonist and its enantiomers, d-nebivolol (SRRR) and l-nebivolol (RSSS), in closed-chest anesthetized dogs, using atenolol as a reference substance. Results from preliminary studies in vitro indicate that d-nebivolol is the beta 1-adrenoceptor antagonist and that l-nebivolol is practically devoid of beta-adrenoceptor-blocking properties. Unlike atenolol, dl-nebivolol does not depress left ventricular function and slightly, but significantly, reduces peripheral vascular resistance over the dose range from 0.0025 to 0.04 mg.kg-1 i.v. These observations are likely to be clinically relevant because one daily oral dose of 5 mg dl-nebivolol effectively lowers arterial blood pressure in patients with hypertension. The favorable hemodynamic profile of dl-nebivolol can be ascribed to the l-enantiomer because the cardiovascular effects of this enantiomer are similar to those of the racemate. The cardiovascular profile of the d-enantiomer is similar to that of atenolol, albeit that its depressant effect on left ventricular function occurs at higher doses.

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

Electrophysiological effects of droperidol in different cardiac tissues

SummaryThe effect of droperidol in concentrations between 0.05 and 5 mg/l was evaluated on different electrophysiological variables in auricular preparations of the guinea-pig, papillary muscles of dog and cat, Purkinje fibres of the dog, cow and sheep. At low concentrations (0.25 to 0.5 mg/l) droperidol decreased pacemaker activity and prolonged the effective refractory period. The inhibition of pacemaker activity was not accompanied by a reduction in the rate of early diastolic depolarization, but was related to an inhibition of the depolarization process during late diastole. At high concentrations (5 mg/l) resting potential, action potential amplitude, (dV/dt)max and conduction velocity were reduced. Reduction of dV/dt during the upstroke was more pronounced at lower membrane potentials, the inactivation curve was shifted to more negative membrane potentials. The action potential was lengthened or shortened, the effect being dependent on the frequency, dose, exposure time and animal species. Droperidol had no deleterious effect on Ca-mediated action potentials. The antiarrhythmic activity of droperidol in therapeutic concentrations (0.25 and 0.5 mg/l) can be explained by the reduction of pacemaker activity and the lengthening of the effective refractory period. In terms of changes in ion conductance most effects can be explained by a reduction in Na conductance. No simple explanation can be offered for the complex changes in action potential duration.

Animal Pharmacology of Nebivolol

SummaryNebivolol is a mixture of equal amounts of 2 enantiomers: SR3-nebivolol (d-nebivolol) and RS3-nebivolol (l-nebivolol). SR3-nebivolol is a potent and selective β1-adrenergic antagonist both in vitro and in vivo. Nebivolol acutely lowers blood pressure in spontaneously hypertensive rats and induces a slight decrease in total peripheral vascular resistance and a slight increase in cardiac output in anaesthetised dogs. These haemodynamic effects cannot be explained by β1-adrenergic antagonism and are largely attributable to RS3-nebivolol.

Stimulation of the coronary collateral circulation by lidoflazine (R 7904)

SummaryLidoflazine, a new and very longacting coronary vasodilator was given to 18 dogs with a chronically developing stenosis and occlusion of the circumflex coronary artery for 4 and 6 weeks respectively. 18 other dogs with chronically developing stenoses leading to occlusion of the circumflex artery were used as controls. Lidoflazine in a dosis of 20 mg/kg/day increased the speed of development of the collateral circulation and prohibited symptoms of permanent cardiac hypoxia. Permanent myocardial hypoxia, caused by a higher degree of physical activity in a group of “freely exercising” dogs produced the same favorable effects on the canine coronary collateral circulation.

Interaction between S2-serotonergic and alpha 1-adrenergic receptor activities at vascular sites.

Serotonin enhances (amplifies) the vasoconstrictor effect of norepinephrine not only on isolated large blood vessels and isolated perfused vascular beds but also in vivo. This amplification can be observed with endogenous serotonin released from aggregating platelets and with endogenous norepinephrine released from the adrenergic nerves in the blood vessel wall. It is due to an interaction between S2-serotonergic and alpha 1-adrenergic mechanisms. Combined S2-serotonergic and alpha 1-adrenergic antagonism is more effective than either one alone against contractions evoked with the combination of serotonin and an alpha 1-adrenergic agonist. In spontaneously hypertensive rats, S2-serotonergic antagonism alone does not reduce blood pressure but combined S2-serotonergic and alpha 1-adrenergic blockade lowers blood pressure more than alpha 1-adrenergic blockade alone. This suggests that the interaction between S2-serotonergic and alpha 1-adrenergic vasoconstrictor responses may play a role in the maintenance of high blood pressure.