Combination Of Phenoxybenzamine Research Articles

The activities of alpha- and beta-adrenoceptive blocking agents in reducing intestinal relaxation due to sympathetic stimulation in the pithed rat.

Abstract A pithed rat preparation, stimulated electrically via the pithing rod left in position, was employed to examine the effects of drugs, administered intravenously, on relaxation of a loop of ileum. Relaxation due to injected isoprenaline could be largely blocked by propranolol but that due to nervous stimulation or injected noradrenaline was blocked to only a lesser extent by either propranolol or phenoxybenzamine alone. The combination of phenoxy-benzamine and propranolol was more effective against relaxation from nervous stimulation than either drug alone but was still not as effective against this as against noradrenaline, or as propranolol alone against isoprenaline. It is concluded that intestinal relaxation after nervous stimulation involves both α- and β-adrenergic activity, in variable proportions. Adrenoceptive antagonists are not as effective in blocking these receptors as they are for those concerned in relaxation after injected catecholamines.

Neurotransmitter release in an arterial preparation and the action of alpha-adrenoceptor antagonists.

1 This study examined the potentiating effects of competitive antagonists of the adrenergic alpha2 receptors and of phenoxybenzamine (POB) an irreversible antagonist, on the stimulation-induced efflux of [3H]-noradrenaline in arterial tissue of rabbit. This was done to determine if the lack of concordance of efflux potentiation by antagonists with the expectations of presynaptic negative feedback theory can be attributed to increasingly successful competition from rising perineuronal transmitter concentrations, when stimulation parameters are increased, in the presence of a fixed concentration of competitive antagonist. 2 Tissues were stimulated with a fixed pulse number and frequency, to rule out confounding factors, and major alterations in the concentration of released transmitter were achieved through variations in the pulse duration. 3 Rauwolscine potentiated transmitter release less at the longest, rather than at the shortest pulse duration, and showed a potentiation of release that was indifferent to the quantities of released transmitter. This was also seen with POB although it binds covalently to the presynaptic receptor. 4 Noradrenaline inhibited stimulation-induced transmitter release confirming the presence of presynaptic alpha inhibitory sites. 5 Yohimbine potentiated transmitter release the same as did rauwolscine and POB, and protected the relevant sites against POB potentiation, confirming site identity. The combination of POB and rauwolscine had no greater effect than did either alone certifying that they acted similarly and that maximally effective concentrations of each were used. 6 Consequently, noradrenaline breakthrough of presynaptic receptor blockade does not explain the non-conforming observations made with competitive antagonists in tests of presynaptic theory.

Prejunctional actions of N-ethyl-maleimide and phenoxybenzamine in rat vas deferens

In studies of electrically evoked isometric contractions of rat vas deferens, N-ethyl-maleimide (30 μM) pretreatment significantly reduced the prejunctional inhibitory potencies of xylazine and 5-hydroxytryptamine but failed to affect the potency of the α 1-adrenoceptor agonist amidephrine. Phenoxybenzamine (1 μM) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (10 μM) produced significant shifts in the potency of xylazine and significantly reduced the maximum inhibition, but the combination of phenoxybenzamine or EEDQ and N-ethyl-maleimide (30 μM) produced no further alteration in the effects of xylazine. In displacement studies, N-ethyl-maleimide displaced the binding of [ 3 H] MK 912 ((2S,12bS)1',3'- dimethylspiro- (1,3,4,5',6,6',7,12b- octahydro-2H- benzo[b] furo[2,3-a] quinazoline)-2,4'- pyrimidin-2' one) to rat renal cortex memebranes with a K i of 466 ± 133 μM ( n = 5), and so does not bind to α 2-adrenoceptors in the concentration range in which it affects prejunctional receptor mediated responses. This may suggest that N-ethyl-maleimide has actions other than inactivation of G-proteins or that the irreversible α 2-adrenoceptor antagonists phenoxybenzamine and EEDQ inactivate G-proteins sensitive to N-ethyl-maleimide in concentrations at which they bind to α 2-adrenoceptors.

Peripheral and central adrenoceptor modulation of the behavioural effects of clozapine in the paw test.

1. In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side-effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test. 2. The alpha 1-adrenoceptor agonist, ST 587 but not the peripherally working alpha 1-agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The alpha 1-antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time. 3. The alpha 2-adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the alpha 2-antagonist rauwolscine nor by the alpha 1-antagonist phenoxybenzamine. Rauwolscine or the peripherally working alpha 2-antagonist L-659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations. 4. In contrast to the beta 2-adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting beta-agonist, (-)-isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The beta-antagonist, (-)-propranolol as well as the peripherally acting beta-antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting beta 1-antagonist, atenolol, as well as low doses of the beta2-antagonist, ICI-118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (-)-isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.5. It is concluded that blockade of central alpha l-adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral beta 1- and/or beta 2-adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the alpha 1-adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side-effects.

Pressor responses to the α 1-adrenoceptor agonist cirazoline: effects of captopril, phenoxybenzamine and nifedipine

We have examined the effects of captopril on pressor responses to the selective α 1-adrenoceptor agonist cirazoline in the pithed rat preparation following treatment with phenoxybenzamine and/or nifedipine. Pretreatment with captopril reduced the pressor responses to cirazoline and displaced the dose-response curve for this agonist to the right, significantly increasing the ED 50 without altering the maximum response. Pretreatment with phenoxybenzamine accentuated the inhibitory actions of captopril and a combination of phenoxybenzamine and captopril significantly increased the ED 50 without altering the maximum response. Administration of nifedipine in animals, which had already received phenoxybenzamine and captopril, led to a further displacement to the right of the cirazoline dose-response curve. The ED 50 was found to be significantly increased and the maximum response was now significantly depressed. Captopril produced further additive inhibition with nifedipine and phenoxybenzamine of the vasoconstrictor effects of cirazoline. These data indicate, perhaps not surprisingly, that the cellular basis for the inhibitory effects of captopril is different from that of nifedine and phenoxybenzamine, however, more importantly, that captopril may directly, or indirectly, inhibit receptor-operated cation channel mediated pressor responses.

Role of angiotensin and adrenoceptors in hemodynamic response to aortic cross-clamping.

An earlier study has shown that angiotensin and catecholamines were responsible for the vasoconstriction observed in the isolated hindlimb preparation during aortic cross-clamping. That study also demonstrated that when vasoconstriction was blocked with an alpha-adrenergic antagonist, phenoxybenzamine, vasodilation was elicited by aortic cross-clamping. The present study tested the hypothesis that this vasodilation was mediated via beta-adrenergic receptors. Eighteen dogs had their hindlimb denervated, vascularly isolated, and pump perfused with blood drained from the inferior vena cava, after passing through a gas-exchanging membrane where oxygen and carbon dioxide tensions were normalized. Left and right thoracotomies were performed, and the aorta and inferior vena cava were cross-clamped. The cross-clamping was associated with 29-37% increase in limb vascular resistance in control dogs (n = 6), in animals pretreated with propranolol (2 mg/kg, n = 6), and in dogs pretreated with a combination of phenoxybenzamine (3 mg/kg) and propranolol (2 mg/kg, n = 6). In animals pretreated with a combination of phenoxybenzamine, propranolol, and enalaprilat (2 mg/kg, n = 6), an angiotensin-converting enzyme inhibitor, limb vascular resistance did not change. This study has confirmed that aortic cross-clamping is associated with vasoconstriction induced by angiotensin and activation of alpha-adrenoceptors and has further demonstrated that vasodilation is attributable to beta-adrenoceptor activation.

Surgical Management of Pheochromocytoma with the Use of Metyrosine

Despite recommended preoperative preparation with alpha-adrenergic blockers, severe hemodynamic instability may occur during operations to resect pheochromocytoma. We combined the alpha-blocker phenoxybenzamine with the tyrosine hydroxylase inhibitor metyrosine in an attempt to better manage the hypertension of patients with pheochromocytoma undergoing surgical resection. This report reviews the cases of 25 consecutive patients undergoing surgery for known intra-abdominal pheochromocytoma. Each patient had elevated serum or urine levels of catecholamines or their metabolites. Nineteen patients were prepared before operation with phenoxybenzamine and metyrosine and six patients were given phenoxybenzamine alone. There were no significant differences in maximum, minimum, or mean blood pressure before or after tumor resection between patients who received metyrosine and those who did not. However careful review suggested that those who received metyrosine had more severe disease as judged by biochemical criteria. Study of selected patients matched for age and severity of disease suggested that the intraoperative blood pressure management of patients prepared with phenoxybenzamine and metyrosine was facilitated. In addition metyrosine-prepared patients lost less blood and required less volume replacement during surgery than did non-metyrosine-prepared patients. There were no apparent differences in postoperative fluid requirements. Although the study is not a prospective randomized trial, a retrospective review of patients managed with the combination of phenoxybenzamine and metyrosine suggests that surgery to resect pheochromocytoma can be better performed with both drugs than with phenoxybenzamine alone. The combination regimen appears to result in better blood pressure control, less blood loss, and the need for less intraoperative fluid replacement than does the traditional method of single-agent alpha-adrenergic blockade.

An examination of the sources of calcium for contractions mediated by postjunctional α1‐ and α2‐adrenoceptors in several blood vessels isolated from the rabbit

1. The roles of intracellular and extracellular-derived Ca2+ in alpha-adrenoceptor-mediated contractions to noradrenaline (NA) have been investigated in several isolated blood vessels from the rabbit by examining responses in the presence of a modified Krebs-Henseleit saline with 2.5 mM Ca2+ and a Ca2(+)-buffered saline with 0.1 microM free Ca2+. 2. NA was tested in preparations of the abdominal aorta, distal saphenous artery, renal vein, lateral saphenous vein, plantaris vein and ear vein exposed to a Ca2(+)-buffered saline with 0.1 microM [Ca2+]. A concentration of NA which was maximally effective in modified Krebs-Henseleit saline, produced an initial transient contraction (ITC) followed by a relaxation towards baseline. This is evidence that alpha-adrenoceptor-mediated responses in all these blood vessels depend upon calcium from both sources. 3. The ITC was particularly pronounced in the arteries and was associated more closely with the alpha 1-receptor subtype. In the abdominal aorta, distal saphenous artery and renal vein the ITC can almost exclusively be attributed to an alpha 1-adrenoceptor (prazosin-sensitive, rauwolscine-resistant). In the ear vein, and to a lesser extent the plantaris vein, the ITC was mediated in part by an alpha 2-adrenoceptor (prazosin-resistant, rauwolscine-sensitive). 4. alpha 2-Adrenoceptors in the lateral saphenous vein largely account for the response to NA in modified Krebs-Henseleit saline, but alpha 1-adrenoceptors mediate the ITC in Ca2(+)-buffered saline. After selective inactivation of alpha 1-adrenoceptors with a combination of phenoxybenzamine and rauwolscine, responses to NA in modified Krebs-Henseleit saline are slow in onset and there is no ITC in Ca2(+)-buffered saline. 5. The possible significance of the coupling of postjunctional alpha 2-adrenoceptors to dual sources of Ca2 + is discussed in relation to the interaction between alpha-adrenoceptor subtypes and the ease of demonstrating functional alpha 2-adrenoceptors in isolated blood vessels.

Pharmacological alteration of antigen-induced contraction of lung parenchymal strips isolated from the actively sensitized guinea pig

Several drugs, known to influence the action or formation of histamine and SRS-A, were examined for their abilities to alter antigen (ovalbumin)-induced contractions of guinea-pig isolated lung parenchymal strips. Cumulative dose-response effects of ovalbumin were obtained on paired parenchymal strips, one used as control and the other drug treated. When used alone, mepyramine, 10 −6 M, phenoxybenzamine, 3 × 10 −5 M and FPL55712, 10 −5 M, did not alter ovalbumin-induced contractions. 5,8,11,14-eicosatetraynoic acid (ETYA), 10 −4 M, produced a small (2.5-fold) rightward shift of the dose-response curves to ovalbumin and histamine. Indomethacin, 5 × 10 −6 M, produced a small increase in the maximum response to ovalbumin and a small (2-fold) rightward shift of the histamine dose-response curve. The effect of indomethacin on ovalbumin-induced contraction was not seen in the presence of phenoxybenzamine and may therefore be due to an increase in histamine release. Combination of indomethacin with FPL55712 or ETYA did not alter antigen-induced contractions. The effect of ETYA on the histamine dose-response curve was not seen in the presence of indomethacin. Combination of phenoxybenzamine with FPL55712 or ETYA caused a marked reduction of the maximum contractile response to ovalbumin. The effect of phenoxybenzamine and ETYA was not observed in the presence of indomethacin. The results suggest that the ability of ETYA to reduce antigen responses in the absence or presence of phenoxybenzamine as well as histamine-induced contraction is related to inhibition of contractile product(s) of cyclooxygenase metabolism of arachidonic acid. Even though substantial antagonism of antigen-induced contractions of guinea-pig parenchymal strips could only be achieved with a combination of drugs, the magnitude of the antagonism was not as large as observed in other pulmonary smooth muscle preparations. This may reflect the existence of other contractile mediators, different interactions between known mediators of immediate hypersensitivity reactions or relative insensitivity of parenchymal strips to effects of the drugs.

The effect of dopamine on human gastric smooth muscle.

Dopamine had inhibitory effects on contractions of human gastric smooth muscle strips. Inhibition of spontaneous contractions occurred at high concentrations only, the mean maximum inhibition being 17% at a concentration of 4.7 X 10(-4) M. It was unaffected by haloperidol (10(-5) M) or tetrodotoxin (10(-6) M) but was abolished by a combination of phenoxybenzamine (10(-5) M) and propranolol (10(-5) M). Isoprenaline caused a dose-dependent inhibition of spontaneous contractions with mean maximal inhibition at a concentration of 4.6 X 10(-6) M. These results suggest that there are no specific dopamine receptors in human gastric smooth muscle and that dopamine-induced inhibitory effects are due to stimulation of adrenergic receptors.

Differential effects of typical and atypical neuroleptics on alpha-noradrenergic and dopaminergic postsynaptic receptors

Mezilamine (2-methylamino-4- N-methylpiperazino-5-methylthio-6-chloropyrimidine), a new antidopaminergic agent, is more effective, in vitro and in vivo, in competing for the binding of [ 3H]-haloperidol in rat tuberculum olfactorium than in rat striatum. Such effects, similar to atypical neuroleptics (clozapine, sulpiride), are opposite to classical neuroleptics like chlorpromazine or UK 177 (2-benzilamino-4- N-methylpiperazino-5-methylthio-6-chloropyrimidine). Mezilamine displaces 10 times more [ 3H]-clonidine binding than [ 3H]-WB 4101 binding in rat cerebral cortex and such a preference for α-agonist rather than antagonist sites is also opposite to most neuroleptics, including UK 177. A combination of phenoxybenzamine and mezilamine causes catalepsy and produces a preferential acceleration of striatal dopamine turnover whereas mezilamine alone is more effective on the mesolimbic system. Such results suggest that α-agonist activity in combination with antidopaminergic properties may limit the extrapyramidal effects and induce a selective neuroleptic action in the mesolimbic system.

Effects of phenoxybenzamine hydrochloride on canine lower urinary tract Clinical implications

The results of our study show that phenoxybenzamine hydrochloride, a potent long-acting alpha-adrenergic blocker, has clearly demonstrable effects on urethral function. In a dose of 0.5 mg. per kilogram of body weight it caused a significant lowering of the resting urethral pressure, a decrease in the arterial pressure, and no change in the intravesical pressure. Higher doses caused similar but more pronounced and prolonged effects. The combined use of phenoxybenzamine and bethanechol increased the intravesical pressure and decreased the urethral pressure. It appears that the predominant mechanism of urethral resistance is alpha-adrenergic activity in smooth muscle. A review of the medical literature, our experimental studies, and limited clinical application lead us to conclude that phenoxybenzamine could be useful in treating neurogenic vesical dysfunction of various types, urethral syndrome, urgency incontinence, functional outlet obstruction with or without vesicoureteral reflux, drug-related obstructive urinary symptoms, partial prostatic obstruction, and ureteral colic. The combination of phenoxybenzamine and bethanechol could be used in managing patients with atony of the bladder of neuropathic or myopathic origin.

The action of para-methoxyphenylethylamine (PMPEA) on monosynaptic reflex transmission in the cat.

1. The intravenous injection of para-methoxyphenylethylamine (PMPEA) into cats produces an increase in the size of the spinal cord monosynaptic reflex. The reflex elevation occurs within 30 s of drug administration, reaches a peak within 2 min, and lasts about 20 min.2. The action of PMPEA is similar for extensor (gastrocnemius-soleus) and flexor (posterior biceps-semitendinosus) monosynaptic reflexes.3. Repeated doses of PMPEA give comparable effects. The degree of monosynaptic reflex elevation is dose related.4. The action of PMPEA is antagonized by phenoxybenzamine and by methysergide or cyproheptadine. The combination of phenoxybenzamine with either of the latter is particularly effective in preventing the reflex facilitation by PMPEA.5. It is concluded that PMPEA has a central action on the spinal cord. It seems likely that monoaminergic synapses are involved.