Propranolol in experimentally induced stress

The beta-adrenergic receptor-blocking drug, d,l-propranolol, was compared with placebo for relief of experimentally induced anxiety. Subjects were chosen on the basis of having high levels of trait anxiety. Stress was induced experimentally by two performance tests. Single 40-mg doses of propranolol significantly slowed the heart rate, suggesting a satisfactory pharmacologic effect of the drug. The treatment was not superior to placebo, however, on any other measure. The experimental model used had clearly demonstrated an antianxiety effect of single 5-mg doses of diazepam. Propranolol at the dose used had little effect on psychic anxiety as determined by this model.     

Studies on the antihypertensive action of the optical isomers of propranolol in man

Summary The antihypertensive actions of (+/-)-propranolol and of (+)-propranolol were compared in 10 patients with essential hypertension and in 1 patient with renovascular hypertension. The study was of double-blind crossover design. Bith, racemic propranolol and the (+)-isomer were ineffective in 4 hypertensives. In 7 patients, including the one with renovascular hypertension, (+/-)-propranolol significantly decreased supine systolic and diastolic as well as standing systolic blood pressure. None of these parameters was altered by identical doses of (+)-propranolol. Propranolol plasma levels measured during treatment with racemic propranolol did not differ from the concentrations determined during the (+)-propranolol period. The data indicate that the hypotensive effect of propranolol in man is due to -receptor blockade.     

The effects of captopril (SQ 14,225) on bradykinin-induced bronchoconstriction in the anesthetized guinea pig.

The effect of captopril (SQ 14,225) a potent inhibitor of angiotensin converting enzyme (ACE: kininase II) on the bronchoconstrictor response to bradykinin was studied in the anesthetized guinea pig. The i.v. administration of captopril caused a profound long lasting hypotension without affecting pulmonary resistance or dynamic compliance. Similarly, the i.v. administration of bradykinin caused small increases in pulmonary resistance and decreases in dynamic compliance which were not altered by the administration of captopril. However, after beta-receptor blockade with propranolol, bradykinin-induced changes in resistance and compliance were enhanced; additional captopril administration further potentiated the bradykinin effects. The prostaglandin synthetase inhibitor indomethacin antagonized the bradykinin-induced bronchoconstriction in beta-blocked animals and its potentiation by captopril. In the isolated perfused guinea pig lung, bradykinin caused a dose dependent release of a prostaglandin-like substance which was significantly increased by captopril and antagonized by indomethacin. These results suggest that bradykinin causes a prostaglandin-mediated bronchoconstriction. Captopril, a potent inhibitor of ACE, prevents the degradation of bradykinin thus potentiating the bradykinin-induced bronchoconstriction, an effect observed in intact animals only in the absence of pulmonary beta-receptor activation.     

Increased noradrenaline release in rat portal vein during sympathetic nerve stimulation due to activation of presynaptic beta-adrenoceptors by noradrenaline and adrenaline.

With the aim of investigating whether exogenous noradrenaline (NA) and adrenaline (A) can modulate transmitter release via the stimulation of presynaptic beta-adrenoceptors, 3H-release from isolated portal veins was studied after pretreatment with 3H-1-NA, phenoxybenzamine, desipramine and normetanephrine. NA (10 muM) and A (0.05 muM) increased the fractional 3H-release elicited by sympathetic nerve stimulation by 30%. This effect could be blocked by d, 1-propranolol which per se reduced the release by 10%. It is concluded that NA can facilitate its own release via a presynaptic beta-adrenoceptor-mediated positive feed-back mechanism and that adrenaline can stimulate this beta-adrenoceptor-mediated mechanism.     

Pharmacological studies of behavioral influences on cardiovascular function

Squirrel monkeys, prepared with chronic arterial and venous catheters, responded (pressed a key) under fixed-ratio schedules of termination of a stimulus associated with electric shock or under fixed-ratio schedules of food presentation. Although there was no necessary correlation between schedule-controlled responding and cardiovascular changes, pronounced elevations in both heart rate and blood pressure occurred during and just after brief periods of fixed-ratio responding. These episodic increases in blood pressure and heart rate were as marked under schedules of food presentation as under schedules of stimulus-shock termination. Thus, these episodic changes appear to be more dependent upon the schedule-controlled behavior than upon the type of event maintaining the behavior. Pharmacological studies indicated that under the conditions of the behavioral experiments the squirrel monkey has a relatively high degree of cardiac sympathetic tone; however, blood pressure elevations produced by administration of l-norepinephrine were associated with an increased parasympathetic tone and decreased heart rate. The reflex bradycardia induced by l-norepinephrine was inhibited during periods of schedule-controlled responding, suggesting that environmental and behavioral factors can not only modulate the parameters of physiological variables but also modulate this basic cardiovascular control system.     

Protein and isoamylase content of rat-submaxillary gland under the influence of α- and β-sympathicolysis

Summary In order to study the function of adrenergic receptors in the submaxillary gland in vivo, rats were treated with the -sympathicolytic, phentolamine (Regitin^®) and with the -sympathicolytic, propranolol (Dociton^®) and the protein, amylase, and isoamylase content of their submaxillary glands were investigated. The protein concentration rises after 3 weeks of - as well as combined -and -sympathicolysis while the amylase concentrations remain, on the whole, unchanged. The pharmacologically induced secretory inhibitions are being discussed in connection with the generally accepted receptor functions.     

Development and evaluation of buccoadhesive propranolol hydrochloride tablet formulations: effect of fillers

The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass metabolism or are unstable within the rest of the gastrointestinal tract. Propranolol hydrochloride (propranolol HCl) is subjected to first-pass effect, therefore formulation of buccal-adhesive dosage form can circumvent this effect. The effect of lactose (a soluble excipient) and dicalcium phosphate (DCP) (an insoluble excipient) on dissolution rate, kinetic of release and adhesion force of buccal-adhesive tablets of propranolol HCl were evaluated. Each tablet composed of 80 mg propranolol HCl, 80 mg hydroxypropylmethylcellulose (HPMC) K4M, polycarbophil AA1 and lactose or DCP with different ratios. The results showed that the presence of the fillers increased dissolution rate of the drug. The release data also showed that the effect of lactose on the dissolution rate was greater than the DCP. Kinetic release of propranolol HCl from buccal-adhesive matrices was affected by the different ratios of polymers and fillers. The fillers reduced the bioadhesion force and this effect was more considerable in formulation containing DCP. In order to determine the mode of release, the data were analyzed based on the equation Q =kt(n). The results showed that an increase in the concentration of HPMC K4M resulted in a reduction in the value of n. The value of n was not significantly affected by an increase in the concentration of lactose or DCP. The values of n in this study were calculated to be between 0.461 and 0.619, indicating both diffusional release and erosional mechanism.     

On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization

Rationale Psychostimulant drugs exert their behavioral effects primarily through enhancement of monoaminergic neurotransmission. Augmented dopamine activity is thought to play a critical role in the psychomotor stimulant effects of amphetamine and cocaine, as well as in the development of long-term behavioral sensitization evoked by repeated exposure to amphetamine. However, despite the fact that brain dopamine and noradrenaline systems are closely interconnected, the extent to which noradrenergic transmission contributes to these behavioral effects of psychostimulants is a relatively unexplored issue. Objectives By inhibiting noradrenergic neurotransmission with the α₂-adrenoceptor agonist clonidine, the α₁-antagonist prazosin and the β-antagonist propranolol, we investigated the involvement of noradrenaline neurotransmission in the psychomotor stimulant and long-term sensitizing effects of d-amphetamine and cocaine in rats. Methods Clonidine (0.003–0.1 mg/kg), prazosin (0.1–3.0 mg/kg) and propranolol (1.0–3.0 mg/kg) were administered prior to d-amphetamine (1.0 mg/kg), cocaine (15 mg/kg) or apomorphine (1.0 mg/kg) and psychomotor activity was measured. In separate studies, clonidine (0.03 mg/kg), prazosin (1.0 mg/kg) or propranolol (3.0 mg/kg) were co-administered with d-amphetamine (2.5 mg/kg) or cocaine (30 mg/kg) for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results The psychomotor stimulant effect of d-amphetamine, but not that of cocaine or apomorphine, was dose-dependently inhibited by clonidine and prazosin, and enhanced by propranolol. Clonidine, prazosin, and propranolol did not influence the induction of sensitization by amphetamine or cocaine. Conclusions Enhancement of synaptic noradrenaline concentrations contributes to the psychomotor stimulant effect of d-amphetamine, but not cocaine or apomorphine. In addition, noradrenergic neurotransmission is not critically involved in the induction of psychostimulant sensitization.     

食管静脉曲张出血前药物干预的对照研究

目的探讨普奈洛尔、5-单硝酸异山梨醇酯(ISMN)和螺内酯联合预防首次食管胃底静脉曲张破裂出血的有效性。方法106例肝硬化食管静脉曲张患者,肝功能Child-Pugh分级为A级和B级,随机分成治疗组54例,接受口服普奈洛尔、ISMN和螺内酯联合治疗;对照组52例未接受以上药物,对两组患者进行前瞻性对照观察。随访时间为2年,治疗组完成随访51例、对照组51例。结果治疗组和对照组随访期间食管胃底静脉曲张出血率(27.5%和52.9%)间差别有统计学意义(P<0.01);再出血率间(13.7%和37.3%)差别有统计学意义(P<0.01);出血患者累计接受输入血量(7200 ml和28 600 ml)间差别有统计学意义(P<0.05)。治疗组和对照组患者随访终点Child-Pugh积分、凝血酶原活动度、脾脏长径、脾静脉内径、脾静脉血流量和门静脉血流量间差别均有统计学意义(P<0.05)。结论普奈洛尔、ISMN联合螺内酯可有效预防食管静脉曲张出血的发生。