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Experimental canine coronary artery stenosis associated with endothelial injury results in a typical pattern of coronary flow characterized by gradual decreases in blood flow to almost zero values followed by abrupt restorations to original levels. Cyclic flow variations (CFVs) are the consequence of recurrent platelet aggregation at the site of the stenosis and subsequent dislodgement of the thrombus. The present study was designed to test the efficacy of diltiazem, nifedipine, and verapamil in inhibiting in vivo platelet aggregation as compared with that of aspirin and ketanserin, two potent reference compounds effective in this model. Except for aspirin, compounds were given as a slow intravenous infusion (i.v.) for 60 min to avoid hemodynamic changes. Diltiazem (0.01 mg/kg/min), nifedipine (3 micrograms/kg/min), and verapamil (0.01 mg/kg/min) were totally inactive against CFVs. A higher dose of verapamil (0.02 mg/kg/min) abolished CFVs in 3 of 4 dogs, but serious side effects were observed [atrioventricular (AV) block and death of 2 animals]. Aspirin (10 mg/kg bolus) caused complete inhibition of CFVs in 4 of 4 dogs, and ketanserin (0.01 mg/kg/min) abolished CFVs in 4 of 5 dogs. These data suggest that calcium channel blockade alone in contrast to cyclooxygenase inhibition or 5-HT2 antagonism cannot inhibit thrombus formation in this model.

The effects of the 5-hydroxytryptamine1A agonists, 8-OH-DPAT, buspirone and flesinoxan, on the delayed hyperactivity and on the ensuing neuronal degeneration induced by transient global cerebral ischaemia, were studied. In normothermic, male Mongolian gerbils, subjected to 3 min bilateral carotid artery ligation, the locomotor activity was measured 1 day after ischaemia. The neuronal damage was quantified 7 days later using an image analysis system. Buspirone (3 and 10 mg/kg, i.p.) and flesinoxan (1 and 3 mg/kg, i.p.), administered twice a day for 3 days both in pre- and post-ischaemic conditions, failed to significantly protect the CA1 zone of the hippocampus against neuronal damage. In contrast, 8-OH-DPat (1 and 3 mg/kg, i.p.) significantly reduced the neuronal degeneration. All compounds abolished the hyperactivity but there was no correlation between this parameter and the extent of the reduction in neuronal damage. The ineffectiveness of buspirone and flesinoxan was not the result of too low a dose - as evidenced by the complete inhibition of hyperactivity with both compounds and by the appearance of a serotonin behavior syndrome with flesinoxan - but is possibly related to a partial agonist activity at the 5-hydroxytryptamine1A receptor, as reported for buspirone. Further studies are necessary to explain the differences between these agonists.

Stimulation of the 5-HT2A receptors by serotonin has been reported to exert an excitatory effect on neocortical neurons in rats and mice, to facilitate ischaemia-induced release of excitatory amino acids and to mediate the vasomotor constrictor component of the response of blood vessels to 5-HT. 5-HT2A receptor antagonists have, therefore, been proposed as potential protectants against the effects of cerebral ischaemia. The aim of this study was to evaluate the effects of two relatively selective 5-HT2A receptor antagonists, ketanserin and ritanserin, on delayed hyperactivity and the ensuing neuronal degeneration induced by 3 minutes of bilateral carotid artery ligation in Mongolian gerbils. Effects were compared to that of flunarizine, which blocks calcium overload and served as a positive control in this paradigm. Temporal and/or rectal temperatures were measured and strictly controlled during the ischaemia and the early reperfusion phase. Locomotor activity was measured one day after the ischaemia and neuronal degeneration quantified 7 days later using an image analysis system (Quantimet 570, Leica). Global ischaemia in gerbils elicits hyperactivity associated with a delayed neuronal degeneration predominantly in the CA1 zone of the hippocampus. Ketanserin and ritanserin (3 and 10 mg/kg ip, twice daily for 3 days, pre- and postischaemia) did not protect the CA1 neurons against ischaemic damage. The postischaemic hyperactivity was inhibited only with the higher dose of ketanserin. As previously reported, flunarizine (30 mg/kg po) markedly reduced neuronal degeneration (-44.2%, p < 0.01) and totally abolished the ischaemia-induced hyperactivity. These data demonstrate that ketanserin and ritanserin are not effective protectants of the gerbil hippocampus against ischaemic damage when the body temperature of the animals is controlled, thus suggesting that 5-HT2A receptors are not directly implicated in the pathogenesis of global cerebral ischaemia in this model.

Various 2-benzodioxinylaminoethanol derivatives were synthetized and investigated for beta-adrenergic blocking activity. Most compounds demonstrated a beta-blocking activity of a competitive type when evaluated in guinea pig atrial and tracheal preparations. Three compounds were more potent than practolol and propranolol. All compounds demonstrated antihypertensive properties in spontaneously hypertensive rats. The most active compound was 1-(1,4-benzodioxin-2-yl)-2-[N4-(2-methoxyphenyl)piperazino]ethanol (11), which at 2.5 mg/kg iv lowered blood pressure by 41%.

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.

The haemodynamic effects of 4 calcium antagonists, bepridil (1.25 to 5 mg/kg i.v.), diltiazem (0.1 to 0.3 mg/kg i.v.), nifedipine (0.01 to 0.03 mg/kg i.v.) and verapamil (0.1 to 0.3 mg/kg i.v.) were compared in anaesthetized open-chest dogs. The following parameters were measured: sinusal coronary blood flow (SCBF), total coronary vascular resistance (TCVR), aortic blood pressure, heart rate, left dP/dt max, amplitude of right ventricular contraction, double product, myocardial oxygen consumption (MVO2) and arterial and coronary venous blood gases (pO2 and pCO2) and pH. All 4 substances increased SCBF and decreased TCVR. The greatest effects, taking into account relative dose size, were obtained with nifedipine and verapamil. These 2 substances also had the greatest effect on systemic vasodilatation, as reflected by hypotension. The 4 substances had a direct negative chronotropic effect on the myocardium, an effect which was masked by reflex sympathetic stimulation and decreased vagal tone secondary to a drop in blood pressure. The most marked negative chronotropic effects were seen with diltiazem, verapamil and bepridil in that order. Nifedipine and verapamil produced the greatest negative inotropic effects, whereas diltiazem had very little effect on this parameter. The direct consequence of these haemodynamic effects of the 4 substances was to improve oxygenation of the myocardium. The most durable effect on PvO2 was seen with nifedipine and verapamil. The findings demonstrate not only the heterogeneous action of the 4 calcium antagonists, but also the influence of the experimental conditions on the effects obtained with these substances.

The effects of amiodarone (10 mg/kg i.v.), bepridil (2.5 mg/kg i.v.) and perhexiline (2.5 mg/kg i.v.) were compared in the anesthetized dog at doses inducing a decrease in heart rate of same intensity. This bradycardial effect existed for amiodarone and bepridil whether the heart was denervated or not. Perhexiline did not modify the rate of the denervated heart. Amiodarone decreased dp/dt max whether the heart was denervated, innervated or paced at constant rate. PO2 in coronary venous blood was transiently increased with no significant variations in coronary flow. Bepridil reduced dp/dt max only after cardiac denervation; coronary PVO2 was increased in a durable way although the rise in coronary flow did not exceed a few minutes. Perhexiline decreased dp/dt max in a durable way only when cardiac innervation was respected. It had no effect on coronary flow. The increase in coronary PVO2 was transient and depended upon bradycardia.

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.

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.

Reaction of various amines on 6-(2-bromoethyl)benzoxazolinone or its N-methylated derivative provided eleven new 6-substituted aminoalkyl analogues. In a pharmacological evaluation, several compounds bearing an arylpiperazinic moiety were found to possess significant effects on arterial blood pressure and on the central nervous system; two of them showed interesting analgesic activity.

Benzoxazolinone can be considered as a bioisosteric analogue of pyrocatechol. This concept has led to the synthesis of benzoxazolinonic phenylethanolamines. The pharmacological study shows that these compounds possess an affinity for adrenergic receptors. Compound (XXXIV), the most interesting, is a competitive alpha and beta adrenergic antagonist which has been studied for antihypertensive activity.

The antiarrhythmic effects of a novel antianginal agent, bepridil, were compared with four reference products. Bepridil increased the effective refractory period in isolated guinea-pig atria slightly more than hydroquinidine, and much more than disopyramide and lidocaine. Amiodarone was without effect. The doses of bepridil necessary for correcting atrial fibrillation induced by local application of aconitine, were similar for hydroquinidine, higher than for lidocaine and disopyramide but lower than for amiodarone. Bepridil depressed the tachycardia and ventricular fibrillation induced by perfusing aconitine in anesthetized guinea-pigs at doses of the same order of magnitude as for disopyramide and hydroquinidine. Lidocaine only exerted weak activity in this system, while amiodarone was without effect. Bepridil was less active than the four reference products, particularly disopyramide, on rhythm disorders induced by coronary artery ligation.

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.