Α-adrenergic Receptor Blocker Research Articles

CLINICAL PHARMACOLOGICAL STUDIES OF INDORAMIN IN MAN

1 The effects of indoramin, a hypotensive drug with competitive α-adrenergic receptor blocking properties, were studied in a double-blind investigation in healthy human subjects. 2 Indoramin (20 mg) orally produced a significant fall in blood pressure at high exercise loads when compared with placebo. 3 Indoramin (20 and 40 mg) reduced erect blood pressures during a period of 6 h when compared with placebo in another double-blind study. 4 Histamine skin wheals were also reduced in a dose-related manner but no effect on critical flicker frequency was demonstrated. 5 The pressor response to intravenous noradrenaline showed a parallel time-related shift to the right after the intravenous administration of 20 mg of indoramin. 6 The effect of intravenous indoramin (10 mg) on myocardial function was studied with noninvasive techniques. No effect was demonstrated on systolic time intervals, cardiac output or ejection fraction. 7 Indoramin (20 mg) given orally twice daily for 2 weeks reduced erect and supine blood pressures without evidence of drug accumulation. 8 No drug-related effects on biochemical or haematologic values were detected.

Synthesis of rat hepatic zinc thionein in response to the stress of sham operation

Following sham operation for adrenalectomy, a dramatic 30-fold increase in rat hepatic zinc thionein occurs, peaking at 18 hours after surgery. Hepatic cytosolic and serum zinc levels rise concomitantly with zinc thionein. Copper in hepatic thionein and cytosol rises only slightly and serum copper not at all during the period of observation. In the period 18 to 48 hours after surgery the content of hepatic zinc thionein decreases with a t 1 2 of 16.4 hours. Pretreatment with cycloheximide (1 mg/kg b.w.) two hours before surgery inhibits the rise in zinc thionein by 52%, the rise in cytosolic zinc by 56%, and actually causes a decrease in serum zinc by 33%. Pretreatment with the α-adrenergic receptor blocker, phetolamine (10 mg/kg b.w.), or the β-adrenergic receptor blocker, propranolol (10 mg/kg b.w.), 30 minutes before surgery also inhibited the rise in zinc thionein (82% and 60%, respectively) and cytosolic zinc (75% and 47%, respectively), and decreased serum zinc (38% and 44%, respectively) 19 hours after surgery. Treatment with corticosterone (40 mg/kg b.w.) alone or epinephrine (1–20 μg/kg b.w.) alone did not alter hepatic zinc thionein levels 18 hours late, although they each caused hypozincemia and epinephrine raised cytosolic zinc levels. Treatment with corticosterone and epinephrine together did, however, raise zinc thionein levels 3.2-fold (P<0.02). These experiments are consistent with the hypothesis that adrenal hormones are involved in the regulation of zinc metabolism, and, hence, zinc thionein in levels in rat liver following the stress of sham operation.

Noradrenergic and serotonergic mediation of spinal analgesia mechanisms

The effects of α-adrenergic and serotonergic receptor agonist administration on spinal analgesia mechanisms (D'Amour-Smith analgesia assay) were examined in the spinal rat from 6 h to 3 weeks following transection. Analgesia (increased response latency)_was observed following administration of the α-adrenergic agonists, clonidine or xylazine at all times after transection. This dose-response-related analgesia was blocked by pretreatment with the α-adrenergic receptor blocker phenoxybenzamine but not by the serotonergic receptor blocker metergoline. Biochemical asay of spinal cord noradrenaline (NA) caudal to the level of transection indicated that the above drugs were effective agonists even when NA levels were not detectable suggesting a mechanism of action via direct Receptor stimulation. Administration of the serotonergic receptor stimulants quipazine or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was analgesic only during the first few postoperative days. Specificity of these drugs for the serotonergic receptor is supported by the observations that the drug induced analgesia was blocked by pretreatment with metergoline but not by phenoxybenzamine and that while quipazine or 5-MeODMT administration was only analgesic immediately following transection, α-adrenergic agonists were effective at all times. The implications of the present data for the involvement of descending NA and serotonergic fiber systems in the mediation of narcotic analgesia is discussed. The present data suggest that C.N.S. active α-adrenergic agonists may represent a class of non-narcotic analgesics of future clinical importance.

Beta adrenergic-mediated myofibrillar disruption and enzyme efflux in an experimental myopathy related to isometric muscle activity

Adrenal demedullation significantly inhibits the enormous increase in plasma creatine phosphokinase (CPK) activity and myofibrillar disruption which follow treatment with phencyclidine (PCP) and restraint in the rat. To determine if the effects of adrenal demedullation were due to the lack of epinephrine, we studied the effects of the β-adrenergic receptor blockers, propranolol and 3-morpholino-4-[3- t-butyl-amino-2-hydroxypropoxy]-1,2,5-thiadiazole hydrogen maleate (MK-950) on these myopathic parameters in intact rats subjected to PCP plus restraint. Both drugs significantly inhibited the myopathy. Pretreatment with either phenoxybenzamine, at effective α-adrenergic receptor blocking doses, or atropine, at effective antimuscarinic anticholinergic doses, had no effect on these parameters. Plasma CPK activity and the percentage of muscle fibers with extensive myofibrillar disruptions following PCP and restraint were significantly correlated for all treatments, except phenoxybenzamine ( r = +0.71, N = 17, P < 0.001). These findings indicate the importance of adrenal epinephrine to the etiology of this myopathy. It is proposed that epinephrine stimulates a β-adrenergic process which ultimately leads to a hypoxic state and muscle injury.

The role of prostaglandins in the control of gonadotropin and prolactin secretion

Experimental evidence has recently accumulated indicating that administration of some prostaglandins (PGs), particularly those of the E and F series can evoke release of gonadotropic hormones (LH and FSH) and prolactin (PRL) by the anterior pituitary gland. Rather than acting on the pituitary directly, PGs are thought to exert their effects on the hypothalamus. In the case of LH and FSH they stimulate the release of lutenizing hormone-releasing hormone (LHRH). In the case of PRL, PGEs may act by inhibiting the release of PIF (prolactin-inhibiting factor) and/or by enhancing the release of PRF (prolactin-releasing factor). Pharmacologic inhibition of PG synthesis depresses the PRL release induced by estrogen without reducing pituitary PRL release from TRH. Blockade of PG synthesis also decreases LH release in a variety of circumstances, but does not inhibit the pituitary response to LHRH, thus supporting the concept that PGs may play a physiological role in the neural control of the release of this hormone. At the hypothalamus, PGE 2 appears to stimulate LHRH release by acting directly on LHRH-secreting elements located in the medial basal hypothalamic-median eminence region (MBH-ME) and the preoptic-anterior hypothalamic (POA-AHA) areas. Radioimmunoassayable PGE and bicassayable PGF content of the ME of the rat is much greater than that of the MBH. Similarly, in vitro release of PGEs by the ME is several times greater than that of the MBH. In vitro incubation of MEs with norepinephrine (NE) results in PGE ands TI-release by the tissue. Inhibition of PG synthesis with indomethacin prevents not only the elevation in PGE levels induced by NE but also the increase in LHRH release induced by both dopamine (DA) and NE suggesting that PGs are physiologically involved in the process of neurotransmitter induced release of LHRH. Moreover, release of PGEs from the ME is reduced by incubation of the tissue with α-adrenergic or dopaminergic receptor blockers and the in vitro response of the ME LHRH terminals to PGEs is enhanced by in vivo pretreatment with ovarian steroids. In conclusion, these recent observations coupled to the aforementioned findings provide strong evidence in support of a physiological role for PGs in the hypothalamic control of gonadotropin release.

Prazosin in the Diagnosis and Treatment of Pheochromocytoma

In a patient with paraganglioma, severe hypertension due to high levels of plasma norepinephrine was easily controlled with prazosin hydrochloride, 6 to 8 mg/day for 19 days before surgery. A prolonged antihypertensive response to the first two 1-mg doses suggested the presence of pheochromocytoma. This experience dramatizes the remarkable effectiveness of prazosin as a postsynaptic alpha-adrenergic receptor blocker and invites further trials of the drug for both the diagnosis and treatment of pheochromocytoma.

Effects of cholinergic drugs on growth hormone release

Acetylcholine and the cholinergic agonists, pilocarpine and physostigmine, increased GH release in vivo . The increase in GH release by pilocarpine was reversed by concurrent administration of the cholinergic receptor blocker, atropine, whereas atropine alone did not alter serum GH concentrations. Cholinergic stimulation of GH release appears to be partially mediated through a catecholaminergic system since the response was partially inhibited by pimozide, a dopamine receptor blocker, or phentolamine, an α-adrenergic receptor blocker. The cholinergic system may function physiologically to help regulate GH release.

Effects of systemic and intracerebral administration of adrenergic receptor blocking drugs on the conditioned avoidance behavior and maze learning in rats

(1) Effects of α- and β-adrenergic receptor blocking drugs, given systemically or intracerebrally into the brainstem, were studied on the acquisition, retention and extinction of conditioned avoidance behavior. (2) The systemic administration of β-adrenergic receptor blockers, Trasicor and GYKI 41099, led to a marked suppression of the acquisition of a two-way avoidance response but did not modify the retention or the extinction of the avoidance response. (3) Injection of GYKI 41099 into the brainstem reticular formation resulted in a decrease in the acquisition of the conditioned avoidance response. (4) The same treatment with an α-adrenergic receptor blocker, phenoxybenzamine, failed to influence the acquisition of the conditioned avoidance response. (5) These observations led to the conclusion that β-adrenergic receptors are involved in modulating the acquisition of a conditioned response although they do not play a significant role in the retention or the extinction processes.

Potentiation of eating associated with tricyclic antidepressant drug activation of α-adrenergic neurons in the paraventricular hypothalamus

1. 1. Tricyclic antidepressants (desipramine, protriptyline, and amitriptyline), which block presynaptic norepinephrine (NE) uptake and perhaps enhance its release, elicited eating behavior after injection into the hypothalamic paraventricular nucleus of satiated rats. 2. 2. This eating effect of the antidepressant drugs was positively correlated in magnitude with the same effect observed with exogenous NE in the same animals. 3. 3. The eating response elicited by desipramine was selectively antagonized by central injection of α-adrenergic receptor blockers. 4. 4. Local pretreatment with NE synthesis inhibitors similarly blocked the desipramine eating response but had no effect on NE-elicited eating. 5. 5. It is suggested that the antidepressant drugs are stimulating eating through endogenous NE synthesized and stored within adrenergic neurons of the paraventricular hypothalamic region.

Behavioral effects of intraseptal injections of adrenergic drugs in rats

Injections of 5-10 µg of crystalline norepinephrine into the ventromedial septum of Sprague-Dawley rats decreased the rate of responding and increased the number of shocks received on a free-operant avoidance schedule and increased the rate of anticipatory errors and decreased the number of reinforcements received on a DRL schedule. Ventromedial septal injections of the α-adrenergic receptor blocker, Dibenzyline, had opposite effects and improved performance on both schedules, whereas intraseptal injections of the β-adrenergic receptor blockers, dichloroisoproterenol and LB-46, did not modify behavior on these schedules. A different pattern of results was obtained when these drugs were injected into the dorsolateral septum. These results suggest that the septum, especially the ventromedial portion, contains α-adrenoceptive neurons that may function to modulate arousal or the effectiveness of both positive and negative reinforcement.

Angiotensin-norepinephrine interaction on sodium intake

Sodium intake in sodium depleted rats was prevented by blocking catecholamine synthesis with DL-α-methyl-p-tyrosine (α-MT). The effect was specific for sodium intake since water deprived rats after α-MT drank the same amount of water as the control group. The injection of Angiotensin II (A II) or norepinephrine (NE) in the third ventricle did not induce any response. However, the same dose of A II and NE injected together into the third ventricle of sodium-depleted α-MT treated rats, restored the sodium intake to normal levels. The same response was observed after injection of NE mixed with cocaine. The α-adrenergic receptor blocker dibenamine reduced sodium intake in sodium depleted rats. When both blockers α-MT and dibenamine were injected, the intraventricular administration of A II plus NE did not reverse the inhibition of sodium intake produced by the blockers. The findings reported suggest that A II might influence sodium appetite by interacting with NE, an effect possibly mediated through α-adrenergic receptors.

Catecholamines and self-stimulation: Evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine

Investigation of the role of noradrenaline (NA) and dopamine (DA) in self-stimulation showed that d-amphetamine (which releases more DA than does l-amphetamine, but not more NA) was much more effective than l-amphetamine in enhancing self-stimulation of NA sites in the locus coerulus and near-lateral hypothalamus. In DA sites in the substantia nigra and far-lateral hypothalamus the effects of the 2 isomers were confirmed to be more nearly equal. Thymoxamine HCl (10 mg/kg IP), a specific α-adrenergic receptor blocker, depressed self-stimulation at all sites, but significantly more severely at DA sites. Thus the drugs most effective in influencing self-stimulation at a particular site were those acting predominantly on the unstimulated system. These findings were interpreted in terms of a hypothesis that DA and NA play complementary roles in self-stimulation and that both are essential; or, more specifically, that DA pathways, implicated in other motivational activities, contribute to a state of drive or arousal necessary for self-stimulation; while response-contingent noradrenergic activity (elicited by the electrodes directly, or indirectly via a transsynaptic route) mediates reinforcement. Further predictions from this hypothesis were tested as follows: (1) Direct pharmacological stimulants of adrenergic α-receptors should disrupt self-stimulation by acting randomly on the reinforcement system and disrupting response-reward contingencies; this was confirmed by the finding that the α-receptor stimulant clonidine HCl (0.05 mg/kg) depressed self-stimulation at all sites tested. (2) Direct stimulants of DA receptors should enhance self-stimulation of NA sites by augmenting dopaminergic motivational activity; but in rats with DA electrodes, noncontingent stimulation of DA receptors would also impose similar noncontingent activity on the transsynaptic noradrenergic reinforcement pathways and thus depress self-stimulation; this was confirmed by the finding that apomorphine (0.3–1.0 mg/kg) was strongly stimulant for NA electrodes but strongly depressant for DA electrodes, and that the degree and direction of these effects was highly correlated with the differential effects of d- and l-amphetamine (rho = .65, p<0.01). Neither effect of apomorphine depended on the occurrence of motor stereotypy. These results can be interpreted in terms of 2-component models for self-stimulation, with the predominant transmitter of the drive component being identified as DA and that g the reinforcing component as NA.

Influence of acute pretreatment with Δ 9-tetrahydrocannabinol on the LD50 of various substances that alter neurohumoral transmission

Δ 9-THC significantly influenced the acute lethal effects (24 hr after a single dose) in mice of several drugs which alter cholinergic, adrenergic and serotoninergic neurotransmission. The LD50 values of carbachol chloride, arecoline HCl, physostigmine salicylate and neostigmine methylsalicylate were all significantly potentiated after pretreatment with 20.0 mg/kg of Δ 9-THC. Paradoxically, lethality produced by methacholine and exogenously administered acetylcholine were attenuated. Evidence for an α-adrenergic receptor blocking effect of Δ 9-THC was noted by the significantly larger LD50 values for 1-norepinephrine bitartrate and phenylephrine HCl when each was given in combination with Δ 9-THC. Moreover, bretylium tosylate and dl-α-methyl- p-tyrosine toxicities were also attenuated by pretreatment with Δ 9-THC. Finally, the combination of Δ 9-THC and cyproheptadine HCl was more toxic than the latter compound alone, suggesting an additive antiserotonin effect.

Pharmacological suppression of eating behavior in relation to diencephalic noradrenergic receptors

The effect of the anorexigenic agents fenfluramine and dexamphetamine was studied on the eating behavior elicited by unilateral injections of noradrenaline in the perifornical area of the rat brain. Both agents were able to inhibit the eating response. Bilateral injections of the α-adrenergic receptor blocker phentolamine were performed into the perifornical area and the effect on eating behavior of rats under three different deprivation conditions was studied. Depression of eating behavior by phentolamine was most pronounced in the group of undeprived rats that were given mealworms as highly appetizing food and absent in the group of rats who were deprived of food for 24 hours. These results are discussed in relation to the role of the noradrenergic system in the regulation of food intake.

Central effects of alpha-adrenergic blocking agents on thermoregulation against venous blood-stream cooling in unanesthetized rabbits.

The production or conservation of heat in the rabbit may be mediated in part by adrenergic neurones within thermoregulatory regions of the hypothalamus. The effect of intracerebroventricular injections of α-adrenergic receptor blocking drugs was therefore tested in unanesthetized rabbits subjected to body cooling. Cold water was passed through a metal water-jacketed cuff which was chronically implanted to enclose a section of the abdominal vena cava. The cold water cooled the venous blood returning to the heart and produced a gradual reduction in body temperature. Rectal temperature, shivering, heat loss from the ears, and the rate of body heat extraction were measured.Injection of 50 μg phenoxybenzamine or 350 μg phentolamine into a lateral cerebral ventricle during venous-blood cooling increased the rate of fall in body temperature. Shivering was reduced or abolished, but there was no increase in heat loss from the ears which remained vasoconstricted. After the drug injection, the rabbit lost less heat to the cold water flowing through the cooling cuff. When rabbits were not subjected to blood-stream cooling, the same amount of phentolamine or phenoxybenzamine injected into the lateral ventricle caused vasodilatation and increased heat loss from the ears, and a fall in rectal temperature of 0.23–1.66 °C. These effects on shivering and ear heat loss were not observed following intravenous drug injections at the same dosage, or following intraventricular injections of the drug vehicle.It is concluded that in rabbits undergoing blood-stream cooling, the augmented rate of fall of rectal temperature following intraventricular injection of alpha-receptor blocking agents is caused by reduced heat production. This effect may be due to the blockade of adrenergic synapses in the central nervous system pathways mediating shivering. The vasodilatation in the ears and the fall in body temperature produced in rabbits not undergoing venous cooling indicates that central adrenergic synapses may also mediate the control of blood flow to the skin.

Alpha and beta adrenergic receptors in amygdala: Reciprocal inhibitors and facilitators of punished operant behavior

The decrease in the suppressant effects of punishment on operant behavior, caused by direct bilateral placement of 1-norepinephrine hydrochloride in the amygdala of male rats, was reduced significantly by direct bilateral pretreatment of the amygdala with phentolamine HCl (7–14 μg), an α-adrenergic receptor blocker. Such pretreatment with a β-adrenergic receptor blocker, LB-46, [dl-4-(2-hydroxy-3-isopropylaminopropoxy)-indole] failed to have this effect. This suggests that norepinephrine decreases the suppressant effects of punishment by occupation of α-adrenergic receptors in amygdala. At these sites, direct bilateral application of 10 μg of dl-isoproterenol HCl increased the suppressant effect of punishment on operant behavior. This treatment also suppressed total non-punished responses, however, only punished responses were affected during the early stages of isoproterenol's action. This selective punishment-enhancing effect suggests that occupation of β-adrenergic receptors in the amygdala may intensify the suppressant effects of punishment. Thus, α- and β-adrenergic receptors in the amygdala appear to have antagonistic effects on punished operant behavior.

Effects on haemodynamics and plasma noradrenaline levels in man of long term treatment with imipramine, haloperidol and chlorpromazine

Haemodynamic effects in patients treated with imipramine and haloperidol were studied at rest and during exercise and were related to the arterial plasma levels of noradrenaline. The results were compared with earlier observations on untreated and chlorpromazine-treated patients studied by the same techniques. After imipramine in a daily dose of 150–350 mg, there was a tendency for the heart rate to increase but no other particular haemodynamic effects were observed. During imipramine treatment noradrenaline levels were not increased compared to the controls, at a work load of less than 900 kpm/min, after which there appeared to be some increase. After haloperidol in a dose of 12–22 mg per day no changes were observed in the circulation or plasma noradrenaline levels. More marked effects on the circulation and plasma noradrenaline levels were found in patients treated with very large doses of chlorpromazine (1800–3600 mg daily). They showed a lower cardiac output, stroke volume and systolic and mean arterial blood pressure during exercise than the other groups. In the chlorpromazine-treated group the heart rate was higher both at rest and during mild exercise. The plasma noradrenaline levels were higher at rest and at all work loads than in the other patients. It may be concluded that the haemodynamic effects of chlorpromazine and its effects on the plasma noradrenaline levels are primarily due to its peripheral α-adrenergic receptor blocking effect, which induces a compensatory increase in sympathetic nerve impulse flow. However, an increased overflow of noradrenaline from the nerve terminals per nerve impulse due to drug effects at the nerve terminal-effector cell level might also contribute to the high plasma levels of noradrenaline found after chlorpromazine treatment.

Pharmacological studies on the hypotensive effects of clonidine

The arterial pressure and heart rate of cats anaesthetized with urethane and chloralose were measured following treatment with clonidine (5 μg/kg). Blood pressure and heart rate were consistently decreased, effects which were blocked by haloperidol and phenoxybenzamine in doses which block central noradrenaline (NA) receptor sites; antagonism did not seem to be related to their peripheral adrenolytic properties. Pimozide and spiroperidol, in doses which block central dopamine but not NA receptor sites, did not block the hypotensive effects of clonidine. Pimocide and spiroperidol alone caused slight hypotension and bradycardia which, at least with regard to pimozide were not related to peripheral α-adrenergic receptor blocking activity. Clonidine potentiated these effects of pimocide and spiroperidol. The present findings indicate that the hypotensive effect of clonidine is due to stimulation of central NA receptor sites. Furthermore, dopaminergic mechanism may also be involved in vasomotor regulation.

The effect of chronic adrenergic blockade on the inhibition by epinephrine of growth hormone and insulin release in sheep.

Infusion of epinephrine inhibited growth hormone (GH) and insulin responses of intact sheep to arginine (0.5 gm/kg). Chronic exposure to the α-adrenergic receptor blocker phentolamine prevented the epinephrine inhibition of insulin release but a similar treatment with propranolol, a β-adrenergic blocking drug was ineffective. Neither phentolamine nor propranolol could counteract the inhibitory effect of epinephrine on GH secretion. It is suggested that the mechanisms mediating the effects of catecholamines on GH release and insulin secretion are different.

Adrenergic changes due to pertussis: Insulin, glucose and free fatty acids

Pertussis sensitization increases plasma insulin (IRI) levels and also facilitates insulin release by isoproterenol, norepinephrine, phenylephrine, and theophylline. Further, pertussis reverses epinephrine-induced insulin suppression. The elevated IRI levels are attenuated generally by a β-adrenergic receptor blocker, MJ-1999, and in some instances an α-adrenergic receptor blocker, phenoxybenzamine. Thus, pertussis appears to enhance the β-agonist responsiveness insofar as insulin is concerned. Pertussis Glucose Adrenergic Insulin Free fatty acids