The effect of alpha 2 adrenoceptor blockers on aggressive behavior in mice: implications for the actions of adrenoceptor agents.

The effects of three alpha 2 adrenoceptor blockers (idazoxan, yohimbine and CH-38083) on isolation-induced aggressive behavior was studied in male mice. The three drugs produced different behavioral profiles. Idazoxan reduced aggressiveness dose-dependently by decreasing the duration of offensive/aggressive interactions and increasing the duration of defensive behaviors. The other two drugs produced only parts of the dual action of idazoxan: yohimbine affected mainly defensive behaviors, while CH-38083 affected only the time spent with fighting. Saline injections per se also influenced behavior and, in contrast to alpha 2 adrenoceptor blockers, induced an increase in aggressiveness. These results are different from those previously obtained in rats, which show bell-shaped dose-response curves in response to alpha 2 adrenoceptor blockers (small doses increased, while large doses decreased aggression). It is postulated that the strong behavioral reaction of mice to the injection per se may mask the aggression-heightening effects of small doses of alpha 2 adrenoceptor blockers in this species. A theory is also presented regarding the complexity of adrenoceptor interactions when both pre-, and postsynaptic alpha 2 adrenoceptors are blocked.

Alpha 2-adrenoceptor blockade, pituitary-adrenal hormones, and agonistic interactions in rats.

The effects of adrenergic activation on aggressiveness and the aggression induced endocrine changes were tested in rats. Alpha 2 adrenoceptor blockers were used for enhancing activation of the adrenergic system, and changes in aggressiveness were tested in resident-intruder contests. Three experiments were conducted. In experiment 1, saline injected rats responded to the presence of an opponent by aggression and the increase in plasma ACTH and corticosterone. Intraperitoneal administration of 1 mg/kg CH-38083 (an alpha 2 adrenoceptor antagonist) produced a several fold increase in clinch fighting and mutual upright scores, and also further enhanced the plasma ACTH and corticosterone response. In experiment 2, the effect of three doses (0.5, 1 and 2 mg/kg) of three different alpha 2 adrenoceptor blockers CH-38083, idazoxan and yohimbine were tested. All the substances increased aggression at 0.5 and 1 mg/kg; at 2 mg/kg the effect of idazoxan and yohimbine disappeared, while with CH-38083 an additional increase was obtained. In yohimbine treated animals the enhancement of aggression was reduced already at 1 mg/kg. In experiment 3, indomethacin, a potent inhibitor of the catecholamine-induced ACTH release completely abolished the effects of the alpha 2 adrenoceptor antagonist CH-38083: the intensity of agonistic interactions, as well as ACTH and corticosterone plasma concentrations, returned to control levels. The possible role of catecholamines and the stress hormones in the activation of aggression is discussed.

Biotransformation of cibenzoline to 2-(2,2-diphenylcyclopropyl)-1H-imidazole.

A microsomal metabolite of cibenzoline, 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole butanedioate, was identified by n.m.r. as the 4,5-dehydro analogue, 2-(2,2-diphenylcyclopropyl)-1H-imidazole. Three dogs dosed orally with 13.8 mg/kg 14C-cibenzoline base excreted 1.8-3.5% of the dose as this metabolite in the urine. Mean plasma concentrations of cibenzoline reached a peak of 1.5 micrograms/ml at 2 h while mean concentrations of the metabolite of 0.4-0.5 micrograms/ml were found between 2 and 7 h. The metabolite was synthesized and found to decrease the frequency of ventricular premature depolarizations in conscious dogs having a two-stage occlusion of the left anterior descending coronary artery performed 48 h before. It did not inhibit ventricular arrhythmia in rats induced by i.v. infusion of aconitine. Thus, in contrast to cibenzoline, the metabolite does not appear to be a true antiarrhythmic agent.

Indirect blood pressure determination by Doppler technique in renal hypertensive cats.

The Doppler ultrasonic recording technique was used to measure systolic and diastolic blood pressures indirectly in renal hypertensive cats. The accuracy of the method was evaluated by comparing indirect blood pressures from one leg of a cat with direct pressure measurements from the other leg. A linear relationship existed between indirect and direct systolic and diastolic pressures. The consistency of the method was assessed by measuring blood pressure during a 5-h monitoring period in normotensive and renal hypertensive cats. No significant variation occurred over this period. The sensitivity of the method to blood pressure changes was determined also. A significant reduction in systolic and diastolic pressure induced by hydralazine, 10 mg/kg po, was recorded during a 5-h monitoring period. The development of renovascular hypertension was followed for approximately 70 days. Systolic pressure rose in a logarithmic fashion from 160 to a maximum of 240 mmHg. It was concluded that the Doppler ultrasonic technique is a simple and reliable method for recording indirect blood pressure acutely and chronically in conscious unrestrained cats.

Comparison of the antiarrhythmic activity of quinidine and quinine.

A comparison was made between the effects of quinidine and quinine on experimental arrhythmias and on cardiac electrophysiologic parameters. Both drugs raised ventricular fibrillation thresholds, reversed aconitine-induced atrial fibrillation, decreased ouabain-induced abnormal ventricular beats, and increased atrial refractory periods and His-Purkinje conduction time. In contrast, only quinidine antagonized acetylcholine-induced atrial fibrillation. In addition, quinidine increased ventricular fibrillation thresholds and atrial refractory periods for a longer time period than quinine. These observations are discussed in terms of choosing an appropriate model for testing new compounds with suspected quinidine-like activity.

Central effect of beta adrenergic blocking agents on arterial blood pressure.

dl-Sotalol, dl-pindolol, d-propranolol and dl-propranolol were evaluated for central hypotensive activity in chloralose-anesthetized vagotomized cats. Blood pressure and average evoked potentials recorded from one postganglionic renal nerve were measured during intraventricular (lateral ventricle) or intravenous (radial vein) infusion of each agent. Potentials were evoked in the sympathetic nerve by single shocks to the sciatic nerve. Three concentrations (1, 3, 5 mM) of each compound were infused consecutively for 20 minutes per concentration. The decrease in blood pressure after intraventricular infusion of 1 mM pindolol, 5 mM d-propranolol and 3 mM dl-propranolol was significantly greater than the decrease after intravenous infusion of the same concentrations of each agent. The decrease in the average evoked potential after intraventricular infusion of the 5 mM concentration was greater than the response after intravenous infusion. Consecutive (1, 3, 5 mM) intraventricular or intravenous infusions of sotalol did not significantly change either parameter. During intraventricular infusion of 3 mM dl-propranolol blood pressures was markedly decreased at a time when the average evoked potential was unchanged; however, parallel changes were observed during infusion of the drug in vagotomized cats in which the carotid sinus baroreceptors were also denervated. The results indicate a) that intraventricular administration of d-propranolol, dl-propranolol and dl-pindolol, but not of dl-sotalol, decreased blood pressure and discharge evoked in the postganglionic renal nerve by an action on central sympathetic structures, and b) that baroreceptor activity during hypotension can overcome the depressant effect of dl-propranolol on potentials evoked reflexly in the renal nerve.