The effect of nifedipine on the monophasic action potential and refractoriness of the right ventricle of the dog heart in situ after beta-adrenergic receptor blockade.

The effect of nifedipine, a calcium-antagonistic drug, was studied on the electrophysiology of the right ventricle in the dog heart in situ. Monophasic action potential recordings were obtained by the suction electrode technique and refractoriness was measured by means of programmed electrical stimulation. Pentobarbital anaesthesia was used. As the basic cardiac effects of nifedipine can be altered by the release of catecholamines from sympathetic nerves of the heart and vessels, the dogs were pretreated with the beta-adrenergic receptor blocking agent acebutolol which increased the action potential duration and the refractoriness. Intravenous injection of nifedipine 30 microgram/kg body weight decreased the times for 50 and 90 per cent repolarization of the monophasic action potential and to a smaller extent the effective and functional refractory period. It is suggested that nifedipine decreases the action potential duration and the refractoriness of the right ventricle of the dog heart in situ due to a direct effect of the drug on the myocardium.     

The Effect of Nifedipine on the Monophasic Action Potential and Refractoriness of the Right Ventricle of the Dog Heart in Situ after β-Adrenergic Receptor Blockade

Abstract The effect of nifedipine, a calcium-antagonistic drug, was studied on the electrophysiology of the right ventricle in the dog heart in situ. Monophasic action potential recordings were obtained by the suction electrode technique and refractoriness was measured by means of programmed electrical stimulation. Pentobarbitdl anaesthesia was used. As the basic cardiac effects of nifedipine can be altered by the release of catecholamines from sympathetic nerves of the heart and vessels, the dogs were pretreated with the β-adrenergic receptor blocking agent acebutolol which increased the action potential duration and the refractoriness. Intravenous injection of nifedipine 30 μg/kg body weight decreased the times for 50 and 90 per cent repolarization of the monophasic action potential and to a smaller extent the effective and functional refractory period. It is suggested that nifedipine decreases the action potential duration and the refractoriness of the right ventricle of the dog heart in situ due to a direct effect of the drug on the myocardium.     

Effects of artilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction

The electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti-arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley-Liss, Inc.     

Antifibrillatory properties of mivacurium in a canine model of atrial fibrillation

The electrophysiologic actions of the competitive neuromuscular blocker mivacurium (0.05-0.8 mg/kg IV; N = 10) and atropine sulfate [0.01-0.16 mg/Kg intravenously (IV), N = 6] were determined under control conditions, during right vagus nerve stimulation, and during anterior right ganglionated plexus stimulation. Both drugs suppressed shortening of right atrial monophasic action potential (MAP) duration, right atrial refractoriness, and right superior pulmonary vein sleeve refractoriness produced by vagus nerve or ganglionated plexus stimulation and suppressed the induction of atrial fibrillation. Suppression of atrial fibrillation by atropine was accompanied by improved sinus and atrioventricular (AV) nodal function, increasing the ventricular heart rate observed during sinus rhythm and atrial fibrillation and eliminating the depressant actions of vagus nerve stimulation on sinoatrial (SA) and AV nodal function. Unlike atropine, mivacurium selectively antagonized the effects of vagus nerve and ganglionated plexus stimulation on atrial and pulmonary vein sleeve myocardium (shortening of action potential duration/refractoriness and increased atrial vulnerability) without altering sinus or AV nodal function under control conditions or during vagus nerve stimulation. The selective inhibition of parasympathetic nervous system effects in atrium versus sinus and AV nodes by mivacurium may represent a selective mechanism for the suppression of atrial fibrillation without altering SA and AV nodal function.     

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

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 electrophysiological 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 micrograms/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.     

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiarrhythmic and electrophysiologic effects of MDL 11,939, a novel class III antiarrhythmic agent in anesthetized dogs.

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.     

Modification by glibenclamide of the electrophysiological consequences of myocardial ischaemia in dogs and rabbits

Summary Glibenclamide has been shown to block ATP-dependent K⁺ channels in the heart and prevent the shortening of cardiac action potentials caused by hypoxia in vitro. The present study examines the ability of glibenclamide to modify the effect of acute ischaemia on monophasic action potential duration in pentobarbital-anaesthetized rabbits, and on monophasic action potential duration and ventricular fibrillation threshold in pentobarbital-anaesthetized dogs. Left ventricular endocardial monophasic action potential duration was measured using a contact electrode catheter, and ventricular fibrillation threshold was measured by the single pulse method. Ischaemia was produced in rabbits by occluding the circumflex coronary for 5 min and in dogs by occluding the left anterior descending coronary artery for 40 min. In rabbits, glibenclamide (0.3 – 3 mg/kg, i. v.) had no effect on baseline monophasic action potential duration, but attenuated action potential shortening during ischaemia in a dose-related manner. In dogs, monophasic action potential duration did not shorten during ischaemia in the vehicle group, but tended to increase in the glibenclamide group (0.5 mg/kg, i. v.) both before and during ischaemia (7 ± 5% and 14 ± 8%, respectively, NS). Likewise, ventricular effective refractory period was significantly increased by glibenclamide prior to ischaemia (5 ± 1%). Ventricular fibrillation threshold tended to increase during 40 min of ischaemia in vehicle-treated dogs (40 ± 29%, NS), but was unchanged during ischaemia in the glibenclamide-treated dogs. Consistent with the increase in ventricular effective refractive period and monophasic action potential duration in dogs, glibenclamide (10^–7 – 10^–5 mol/l) significantly increased action potential duration in normoxic canine Purkinje fibres to a maximum of 19 – 2% at 95% repolarization. These data suggest that the opening of ATP-dependent K⁺ channels contributes to action potential shortening duration ischaemia in rabbits, but do not provide evidence that glibenclamide, at the dose studied, reduces the susceptibility to electrically-induced ventricular fibrillation in dogs subjected to acute ischaemia.Send offprint requests to Jeffrey Smallwood at the above address     

β-Adrenoceptor antagonists: studies on behaviour (delayed differentiation) in the monkey (Macaca mulatta)

1 Activity of six β-adrenoceptor antagonists was studied on behavioural activity (delayed differentiation) in the monkey (Macaca mulatta). The drugs, three relatively lipophilic antagonists (propranolol, oxprenolol and metoprolol), and three relatively hydrophilic antagonists (acebutolol, atenolol and sotalol), were given by intraperitoneal injection (5 to 30 mg/kg).

2 With atenolol (25 to 30 mg/kg), total response time was increased, but there was no effect on the number of correct responses. With acebutolol (25 to 30 mg/kg), the number of correct responses was reduced, but there was no effect on total response time. With metoprolol (25 to 30 mg/kg), there was an increase in total response time and a decrease in the number of correct responses, and correct responses were decreased 4 h after injection over the whole dose range (5 to 30 mg/kg).

3 Some animals failed to respond or complete the task with 30 mg/kg oxprenolol, 25 mg/kg sotalol and 20 mg/kg propranolol. With 25 mg/kg oxprenolol, the total response time was increased and the number of correct responses was decreased. With 5-20 mg/kg sotalol, total response time was increased, but there was no effect on the number of correct responses. With 15 mg/kg of (±)-propranolol and its isomers, there were increases in total response time and decreases in correct responses.

4 The studies suggest that lipophilic antagonists, such as propranolol, oxprenolol and metoprolol, are likely to have, at least, effects on the central nervous system, while hydrophilic antagonists may modify the peripheral nervous system. In the dose-ranges studied, propranolol had the greatest, and atenolol and acebutolol had the least effects. Atenolol and acebutolol may prove to be particularly useful in man when disturbances of the nervous system are to be avoided.

     

Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiarrhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased susceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr channel blocker, dofetilide (Tikosyn, 0.025 mg/kg/5 min), and the less specific ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on anti-arrhythmic dosages reported in the literature. Monophasic action potential catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (dofetilide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was comparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmias.     

Effects of disopyramide on repolarisation and intraventricular conduction in man

Summary Right ventricular repolarisation and refractoriness after therapeutic doses of disopyramide have been studied in 10 patients with coronary artery disease by recording monophasic action potentials (MAP) during programmed stimulation. Using 2 catheters, with the tip of one in the apex and the other in the outflow tract of right ventricle, conduction intervals for propagation of stimuli in the ventricle were also measured. Disopyramide increased the duration of MAP signals at 90% repolarisation (MAP₉₀), the QT-interval and the right ventricular effective refractory period (V-ERP). The ratio refractoriness/action potential duration was slightly increased. Early premature action potentials were more markedly prolonged in relation to steady-state action potentials. The differences between the shortest and longest premature action potentials, however, were not changed significantly. The conduction intervals of the normal and premature paced beats were significantly prolonged.The observed effects of disopyramide on conduction and action potential duration may be of major importance for its effect on termination and slowing ventricular tachycardias. Its influence on the duration of premature action potentials in man is consistent with the results of in vitro studies.     

A comparison of the cardioselectivity of five beta-adrenoceptor blocking drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.     

The effect of atenolol on the cardiovascular system (author's transl)

Effects of atenolol on the cardiovascular system were studied in rats and dogs. Atenolol (10 microgram/kg - 3 mg/kg) did not increase heart rate significantly in rats pretreated with reserpine (5 mg/kg), while a significant increase occurred with practolol (30 microgram/kg - 3 mg/kg). Atenolol (100 microgram/kg) inhibited the response of canine heart (heart rate and myocardial contractile force) to isoproterenol to a similar degree as seen with propranolol (100 microgram/kg) did. The ability of atenolol to inhibit vasodilating action of isoproterenol, however, was about 1/12 of that of propranolol. Atenolol (0.5 mg/kg) did not inhibit hemodynamic responses to ouabain and CaCl2 in dogs, while this drug inhibited these responses to isoproterenol. Atenolol decreased heart rate, myocardial contractile force, left ventricular pressure, and rate of rise of the left ventricular pressure (dp/dt LV max) dose-dependently. Atenolol (1 mg/kg) decreased coronary venous outflow and myocardial oxygen consumption in dogs, but did not alter the myocardium to a more reduced state, as determined by coronary arterial and venous lactate and pyruvate levels. These results confirmed that atenolol is a potent cardioselective beta-blocker devoid of intrinsic sympathomimetic action. The results also suggest that atenolol inhibits cardiac function without disturbing the intracellular redox state of the myocardium.     

Comparative beta-adrenoceptor blocking effects of propranolol, bisoprolol, atenolol, acebutolol and diacetolol on the human isolated bronchus.

Five beta-adrenoceptor blockers, propranolol, acebutolol, diacebutolol, atenolol and bisoprolol, were tested for their antagonistic effect against isoprenaline on human isolated bronchi. The results showed (1) that only propranolol exerted a competitive antagonistic effect against isoprenaline (pA2 = 9.40 +/- 0.22, n = 7) whereas the other drugs did not, and (2) that, in the presence of beta-adrenoceptor blockers in the plasma concentrations reported after a single usual therapeutic dose, the doses of isoprenaline giving the same bronchodilator effect must be multiplied by 32.6, 5.51, 4.63, 2.82 and 1.95 respectively with propranolol, diacetolol, acebutolol, atenolol, and bisoprolol. It was concluded that (1) atenolol and bisoprolol were the least potent drugs at bronchial level in therapeutic plasma concentrations and (2) that tests performed on the human isolated bronchus might be a useful screening procedure for new drugs with potential activity on the airways.     

Stability of atenolol, acebutolol and propranolol in acidic environment depending on its diversified polarity

The main objective of this research was to investigate the relationship between the polarity of atenolol, acebutolol, and propranolol described by logP and kinetic and thermodynamic parameters characterizing their degradation process in acidic solution. Hydrolysis was carried out in hydrochloric acid at molal concentrations of 0.1 mol/L, 0.5 mol/L, and 1 mol/L for 2 hr at 40 degrees C, 60 degrees C, and 90 degrees C. Chromatographic-densitometric method was used for the determination of drugs under investigation. The identification of degradation products was carried out by using 1H NMR. The degradation processes that occurred in drugs under investigation are described with kinetic parameters (k, t0.1, and t0.5) and energy of activation (Ea). It has been found that the stability of drugs increases toward lipophilic propranolol in the assumed experimental model. The rate constants k decrease, contrary to t0.1, t0.5, and Ea, which vary comparably to logP, thus increasing from the most hydrophilic atenolol, through acebutolol, of lower polarity, to the most lipophilic propranolol. This study demonstrated that the stability of chosen beta-adrenergic blocking agents increases with their lipophilicity.     

Sotalol exhibits reverse use-dependent action on monophasic action potentials in normal but not in infarcted canine ventricular myocardium.

In 12 anesthetized mongrel dogs (30 mg/kg pentobarbital), a thoracotomy was performed, and the left anterior descending coronary artery was ligated proximally. Eight to 12 days later, monophasic action potentials were recorded endocardially from the apex of the noninfarcted right ventricle and infarcted areas of the left ventricle, and the effects of 1.5 mg/kg intravenous sotalol were evaluated. Monophasic action potentials from the infarcted zone of the left ventricle were obtained from areas where fractionated bipolar electrograms could be recorded; this was histologically confirmed. After sotalol, in sinus rhythm, the monophasic action potential duration at 90% repolarization of the infarcted zone increased from 186 +/- 31 to 226 +/- 45 ms (+ 22%, p less than 0.05), and monophasic action potential duration of the noninfarcted zone increased from 184 +/- 31 to 225 +/- 47 ms (+ 22%, p less than 0.05). Programmed ventricular stimulation was performed with single extrastimuli at a basic drive cycle length of 300 ms. With long coupling intervals (290 ms), monophasic action potential duration of the infarcted zone increased from 165 +/- 23 to 183 +/- 25 ms (+ 11%, p less than 0.05) after sotalol; and monophasic action potential duration of the noninfarcted zone increased from 159 +/- 20 to 180 +/- 25 ms (+ 13%, p less than 0.05). With short coupling intervals (200 ms), the monophasic action potential duration of the noninfarcted zone increased from 157 +/- 19 to 173 +/- 18 ms (+ 10%, p less than 0.05), and monophasic action potential duration of the noninfarcted zone increased from 150 +/- 18 to 157 +/- 18 ms (+ 5%, NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of propranolol and acebutolol on left ventricular function and coronary haemodynamics in the conscious dog with myocardial ischaemia.

1 The cardiovascular effects of the beta-adrenoceptor blocking drugs, propranolol and acebutolol, on regional coronary blood flow and left ventricular function have been investigated in the conscious dog with developing myocardial infarction. 2 Propranolol (1 to 1.5 mg/kg) or acebutolol (4 to 5 mg/kg) were administered intravenously 2 to 3 h after occlusion of the left anterior descending coronary artery. 3 Propranolol or acebutolol administration resulted in a relative increase in flow to the ischaemic area of the myocardium, particularly to the subendocardium. 4 Propranolol produced a greater reduction in heart rate and myocardial contractility than acebutolol. 5 These results demonstrate that beta-adrenoceptor blocking drugs reduce myocardial oxygen consumption and increase coronary flow to the ischaemic area of the myocardium after coronary artery occlusion in the conscious dog.     

Electropharmacologic synergism with mexiletine and quinidine

We have previously shown that combination therapy with mexiletine and quinidine is more effective and causes fewer side effects than either agent alone in the treatment of patients with serious ventricular arrhythmias. To further assess this enhanced antiarrhythmic effect, the electrophysiologic actions of mexiletine and quinidine alone and in combination were evaluated in isolated perfused rabbit hearts. Dose-response curves were constructed for right ventricular effective refractory period, epicardial monophasic action potential duration, and conduction time (the time from pacing stimulus to the upstroke of the monophasic action potential signals) during constant rate pacing. No significant changes in these parameters were seen in 15 preparations treated with saline over a duration of 1 h (a time equal to the longest experiments). With gradually increasing concentrations of mexiletine (2.3-36 microM) prolongation of conduction time (12 +/- 5 msec, mean +/- SE, p less than 0.05) paralleled change in ventricular refractoriness (20 +/- 5 msec, mean +/- SE, p less than 0.05) but occurred in the absence of any significant change in monophasic action potential duration. With gradually increasing concentrations of quinidine (0.55-34 microM/L) prolongation of ventricular refractoriness (65 +/- 7 msec, mean +/- SE, p less than 0.01) and monophasic action potential duration (65 +/- 7 msec, mean +/- SE, p less than 0.01) occurred in parallel and at concentrations less than those required to prolong conduction time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the blood pressure in rats (author's transl)]

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.     

Analysis of proarrhythmic potential of antipsychotics risperidone and olanzapine in anesthetized dogs

In vitro electrophysiological studies have shown that second-generation antipsychotic drugs risperidone and olanzapine inhibit rapidly activating delayed rectifier K(+) currents and prolong action potential duration of the isolated ventricular myocardium. In this study, we analyzed in vivo cardiohemodynamic and electrophysiological profiles of risperidone and olanzapine using the halothane-anesthetized canine model to clarify their proarrhythmic potential. A clinically relevant dose of risperidone (0.03 mg/kg, i.v.) did not affect the ventricular repolarization process, whereas the supra-therapeutic doses (0.3 and 3 mg/kg, i.v.) prolonged the duration of monophasic action potential of the ventricle. Furthermore, the terminal repolarization period, an index of extent of electrical vulnerability, was prolonged after the supra-therapeutic doses. In contrast, therapeutic to supra-therapeutic doses of olanzapine (0.03-3 mg/kg, i.v.) hardly affected the ventricular repolarization process. Therefore, more caution has to be paid on the use of risperidone than olanzapine for patients with risks of the elevated plasma concentration.