Effects of bepridil and nifedipine on regional myocardial contractility during ischaemia in anaesthetized dogs.

Subtotal reduction (60%-70%) of blood flow in the circumflex artery in anaesthetized open-chest dogs caused a long-lasting increase (222%) in coronary vascular resistance and stable changes in myocardial segmental contractility (% delta L), as measured by the method of piezoelectric crystals. % delta L increased by 31.2% in the healthy zone while hypokinesia occurred in the moderately ischaemic zone (-50.8%). In the severely ischaemic zone there was a paradoxical lengthening (bulge or dyskinesia) of 7.3% during systole. Bepridil (2.5 mg.kg-1, IV) decreased heart rate (-15.6%) and systolic (-20.8%) and diastolic (-31.6%) blood pressure, and increased total coronary blood flow (+40.7%). % delta L was increased in the healthy zone (+20.4%) and in the moderately ischaemic zone (+48.2%). Bepridil completely inhibited the bulge in the severely ischaemic zone. Nifedipine (0.02 mg.kg-1, IV) greatly reduced systolic (-31.3%) and diastolic (-40.7%) blood pressure as well as coronary blood flow (-30.4%), without changing heart rate. A delayed increase in % delta L occurred in the healthy zone (+8.4%) and in the moderately ischaemic zone (+38.5%). In the severely ischaemic zone, there was no improvement of the bulge. The observed differences in contractility between the two calcium antagonists are discussed in terms of their haemodynamic differences. Improvement of myocardial segmental contractility, if it occurred, may have been due to bradycardia, slight decrease in contractility, as measured by LV dP/dt max/P, increased total coronary blood flow, decreased afterload, so long as it was not too great, and anti-ischaemic properties of the compound.

Bepridil-induced modifications of cardiac performance in the anesthetized dog: comparison with nitroglycerin and propranolol.

Bepridil, a new anti-anginal drug, increases coronary blood flow and reduces myocardial oxygen consumption. The comparative effects of bepridil (2.5 mg.kg-1), nitroglycerin (40 microgram/.kg-1) and propranolol (0.5 mg.kg-1) on myocardial performance, were studied in anesthetized dogs. All drugs were injected intravenously within 60 sec. Continuous recordings of left ventricular end-diastolic pressure, peripheral arterial pressure and external ventricular dimensions were made during a 31 min period following drug administration. Similarly, several contractility indices were calculated during the phase of isovolumic contraction. Bepridil was found to decrease left ventricular work, by 14.3 +/- 4.4% while increasing aortic blood flow by 24 +/- 6%. In addition, this compound weakly and only briefly decreased contractility, but reduced the afterload more markedly by 34.2 +/- 3.8%. The external ventricular circumference was only slightly increased. Nitroglycerin reduced aortic flow, ventricular dimensions together with the pre- and afterloads. Propranolol reduced aortic flow while considerably increasing ventricular dimensions and preload. Thus, in the anesthetized dog, the intravenous administration of bepridil decreases left ventricular work while increasing aortic blood flow. Both effects occur during mild and prolonged bradycardia.

Studies on the bradycardia induced by bepridil.

Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip).

[Bepridil, a functional antagonist of beta1-adrenergic stimulation. Dissociated effects on cardiostimulation and lipolysis. (author's transl)]. / Bépridil, un antagoniste fonctionnel de la stimulation adrénergioque-beta1. Dissociation des effets sur la cardiostimulation et sur la lipolyse.

1. Methods - In order to verify that the antagonism of isoprenaline by bepridil was not exclusive to cardiac receptors, anesthetized dogs were subjected to a double isoprenaline stimulation (two 15 minute perfusions at a rate of 1 microgram . kg-1 . min . -1 separated by a 75 minute interval). Bepridil at 5 mg . kg-1 was injected intravenously 45 minutes before the second isoprenaline stimulation, and compared to propranolol (1 mg . kg-1), practolol (5 mg . kg-1) and perhexiline (2.5 mg . kg-1). In addition, bepridil (1 mg . kg-1 . min . -1) and perhexiline (0.5 mg . kg-1 . min-1) were also perfused intravenously, simultaneously with the second isoprenaline stimulation. Classical cardiovascular parameters (heart rate, left dP/dt max., arterial pressure, coronary artery flow) together with plasma free fatty acid levels (FFA) were monitored at intervals of 5 minutes throughout the study. 2. Results - The two isoprenaline stimulations caused non-statistically different increases in the various parameters. All the cardiovascular effects of isoprenaline were inhibited by propranolol, except for the increase in coronary flow. Likewise, the increased plasma FFA level fell by 82.7 +/- 4.2% (p = 0.003). The tachycardia and elevated left dP/dt max. were antagonised by practolol, which the increased FFA levels fell by 64.3 +/- 4.8% (p less than 0.01). The other parameters were not altered. No signficant effect was observed with perhexiline. Rapid I.V. infection of bepridil only decreased the isoprenaline. induced tachycardia (from 74 +/- 15.6 syst. Min.-1 to 57.3 +/- 12.7 syst. min.-1). Perfusion of bepridil considerably limited the tachycardia, while moderately reducing the increased contractility later on. However, it had no effect on FFA levels or the other cardiovascular parameters. 3. Discussion and conclusions - The results obtained with propranolol and practolol are consistent with the competitive B-blocking activity of both compounds. The lack of effect noted in this instance with perhexiline may be explained by the recent hypothesis whereby this compound acts on the presynaptic nerve endings of the cardiac pacemaker system and depresses the release of endogenous noradrenaline while unable to antagonise exogenous adrenergic stimulation. The dissociated effects of bepridil with regard to cardiac and lipolytic stimulation by isoprenaline, strongly suggest functional antagonism by both compounds at cardiac level alone. This antagonism is explained by the depressant effects of bepridil on Ca2+/Na+ slow inward currents, as shown previously in myocardial preparations.

Activity of bepridil and other anti-anginals on cardiovascular modifications engendered by conditioned anxiety in the dog.

The action of bepridil (5 mg/kg), perhexilene (5 mg/kg) propranolol (0.5 mg/kg), dipyridamole (0.5 mg/kg), amiodarone (10 mg/kg), pentaerythritol tetranitrate (40 microgram/kg) and nitroglycerine (40 microgram/kg) on cardiovascular manifestations of auditory-inducted emotional stress has been investigated in the conscious dog. Bepridil, perhexilene and propranolol considerably reduce tachycardia provoked by the anxiogenic stimulus, with nitroglycerin exerting an attenuated effect and the others with no significant effect on this parameter. Beppridil, nitroglycerin, perhexilene, propranolol and pentaerythritol all significantly reduce the elevation of the Robinson index, the first four with the same intensity. Only amiodarone and dipyridamole are without effect on this parameter of cardiac workload. Finally, none of the products under investigation significantly reduces systolic hypertension, associated with the induction of conditioned anxiety.