Disease relevance of phenoxybenzamine

• In five dogs, prior alpha adrenergic receptor blockade with phenoxybenzamine prevented the rise in coronary vascular resistance with acetylstrophanthidin during ischemia [1].
• The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension [2].
• In contrast, both acute surgical sympathectomy (cervical trunk division) and alpha-receptor blockade (1.5 mg/kg of phenoxybenzamine) enhanced the maintenance of cerebral blood flow in the face of hemorrhagic hypotension in that cerebral blood flow did not decrease until mean arterial blood pressure was approximately 35% of the base-line value [3].
• A constant unilateral infusion of the catecholamine antagonist phenoxybenzamine (POB, 0.2 micrograms/kg per min) into the renal artery during hemorrhage was also performed [4].
• 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 [5].

Psychiatry related information on phenoxybenzamine

• However, PBZ-treated animals did not develop amnesia [6].
• Letter: Phenoxybenzamine in anorexia nervosa [7].
• The locomotor activity was completely blocked by pimozide, but not by phenoxybenzamine [8].
• Intrathecally administered phenoxybenzamine (1 and 5 micrograms per rat) inhibited the increase of the response latency induced by MA (50 ng per rat) injected into the NRPG but to a lesser extent than the beta-adrenoceptor antagonists [9].
• The insurmountable postsynaptic alpha-adrenoceptor antagonist phenoxybenzamine (0.2-0.8 mg/kg) had no effect on self-stimulation by itself, but potentiated the inhibitory effects of clonidine [10].

High impact information on phenoxybenzamine

• We found, using the phenoxybenzamine inactivation method, that there was a linear relationship between alpha 1 receptor density and the [Ca2+]c response; consequently, the blunted [Ca2+]c response to alpha 1-adrenergic stimulation could not be explained by the 34% downregulation of alpha 1 receptors seen in these rats [11].
• Motilin was infused intravenously with or without Phe-cyclo[Lys-Tyr(3-tBu)-betaAla-]. trifluoroacetate (GM-109; motilin antagonist), granisetron (5-HT3 antagonist), atropine, hexamethonium (C6), phenoxybenzamine, propranolol, or cimetidine [12].
• Noradrenaline and phenoxybenzamine (an alpha-adrenergic blocking agent) in vivo and in vitro (30 min) had no effect on the volume density of the secretory granules [13].
• Electrical stimulation caused an increase in tension, which was abolished by tetrodotoxin and phenoxybenzamine, indicating that electrical stimulation causes contraction by liberation of norepinephrine [14].
• After phenoxybenzamine, in the absence of vasoconstriction, this latter effect was reversed into a dose-dependent stimulation of hydrelatic secretion, suggesting that noradrenaline had a direct action on the secretory cell [15].

Chemical compound and disease context of phenoxybenzamine

• In the second group of dogs (n = 8), pretreated with the prostaglandin inhibitor indomethacin (IN, 10 mg/kg, iv), POB-infused and denervated kidneys had a significantly higher GFR (30 vs. 23 ml/min, P less than 0.05) and RBF (180 vs. 130 ml/min, P less than 0.0-5) than contralateral denervated kidneys during the hemorrhage period [4].
• In the control (C) dogs (n = 6), hemorrhage was not associated with significant changes in glomerular filtration rate (GFR) or renal blood flow (RBF) in either POB-infused and denervated or noninfused, denervated kidneys [4].
• One hour after ischemia, cerebral blood flow was markedly reduced to 5, 3, and almost 0% of the preischemic value in the untreated, phenoxybenzamine-treated, and propranolol-treated rats, respectively [16].
• In the present study, the effect of alpha-adrenoreceptor antagonists (phenoxybenzamine 1.5 mg kg-1 or phentolamine 8 mg kg-1) on pial vessel diameter was studied in the cat during hypotension and hypercapnia alone or in combination [17].
• Clonidine did not lower plasma catecholamines in patients with a pheochromocytoma in the presence or in the absence of phenoxybenzamine [18].

Biological context of phenoxybenzamine

• Noradrenaline induced a strong vasoconstriction (inhibited by phenoxybenzamine), followed by a moderate vasodilation (possibly mechanical) [15].
• After administration of phenoxybenzamine (15 mg/kg i.v.), DA produced significant increments in renal blood flow and reductions in renal vascular resistance when compared with experiments without phenoxybenzamine, suggesting even low dosages of DA exert alpha-adrenoceptor agonist activity [19].
• Four trials were carried out to study the mechanism for this observed platelet secretion: (1) phenoxybenzamine, (2) propranolol, (3) 650 mg aspirin, and (4) 80 mg aspirin were given several hours before the public speaking engagement [20].
• Pharmacologic blockade with phenoxybenzamine prevented in large part the rise in blood pressure in short-term stellate ganglion stimulations, whereas propranolol had very little effect on the pressor response, although it nearly abolished the increase in cardiac output [21].
• Cells that responded to 100 nM PE were able to generate a comparable response to 10 microM PE after inactivation of 90% of the total alpha 1-AR binding sites with phenoxybenzamine treatment [22].

Anatomical context of phenoxybenzamine

• A patient with a clinical and angiographic diagnosis of nonocclusive mesenteric ischemia had phenoxybenzamine directly infused into the superior mesenteric artery to counteract the existing splanchnic vasoconstriction [23].
• The alpha-receptor-blocking agent, phenoxybenzamine (0.25 mg/kg), was infused into either the anterior or circumflex coronary artery while collection of coronary sinus blood minimized recirculation [24].
• However, acute lumbar sympathectomy combined with injection of phenoxybenzamine into the femoral artery almost abolished the vasoconstriction induced by venous stasis [25].
• Incubation of membranes with the alpha blockers dihydroergocryptine (50 nM) and phenoxybenzamine (20 nM) prior to protease treatment diminished the increase in [3H]epinephrine binding induced by trypsin (1.5 microgram/mg) [26].
• The data also demonstrate that phenoxybenzamine irreversibly inactivates alpha 1-adrenergic receptors in rat vas deferens, but that the decrease in receptor density is much smaller than that predicted from receptor theory [27].

Associations of phenoxybenzamine with other chemical compounds

• Phenoxybenzamine (2 mg/kg i.v.) did not prevent the rise in systemic vascular resistance produced by disopyramide [28].
• Clozapine, a new neuroleptic agent with alpha-adrenergic blocking activity, or phenoxybenzamine blocked the effect of clonidine on renin release in both sodium-depleted and normal rats [29].
• Atropine (0.5 mg/kg, iv) blocked most of the reflex coronary vasodilation, indicating a parasympathetic component, and the addition of adrenergic alpha-receptor blockade with phenoxybenzamine (0.25 mg/kg, ic) abolished the remaining response, demonstrating sympathetic participation [30].
• On the day of study, the dog was anesthetized briefly (fentanyl and nitrous oxide) for percutaneous catheterization, and alpha-receptors in one myocardial region were blocked with phenoxybenzamine (0.25 mg/kg) infused selectively into the left circumflex coronary artery [31].
• Inhibition of renal vasoconstriction during hyperacute rejection by phenoxybenzamine or methylprednisolone combined with either the antiplatelet agent pyridinolcarbamate or heparin was evaluted in primates [32].

Gene context of phenoxybenzamine

• Phenoxybenzamine (PbA) inhibited with about equal apparent potency all three hOCTs, whereas the PbA derivative SKF550 ((9-fluorenyl)-N-methyl-beta-chloroethylamine) preferentially inhibited hOCT3 and hOCT2 [33].
• Injected intrathecally to mice, phenoxybenzamine blocked neurokinin-induced, but not bombesin- or somatostatin-induced, reciprocal hind limb scratching [34].
• LH and FSH responses to GnRH pulses were preserved suggesting that PBZ blocked the post-OVX increase in hypothalamic GnRH secretion [35].
• The suppressive effect of PBZ appeared to be specific to the hypothalamic-pituitary-ovarian axis as plasma PRL, TSH, and corticosterone were not decreased compared to controls [35].
• A PBZ regimen of 15 mg/kg ip at OVX followed by 10 mg/kg at 24 h and 5 mg/kg at 48 h prevented the increase in alpha, LH-beta, and FSH-beta mRNAs and LH and FSH secretion for 72 h post-OVX [35].

Analytical, diagnostic and therapeutic context of phenoxybenzamine

• The analogs were screened for dopamine-agonist action by intra-arterial injections into the renal vascular bed and for beta2-adrenergic activity by similar injections into the femoral vascular bed in dogs pretreated with phenoxybenzamine [36].
• However, after phenoxybenzamine administration, forearm vasoconstriction to norepinephrine was abolished while a residual response to lower-body negative pressure remained in each patient [37].
• The PRA response to ICV PGE2 was not affected by bilateral renal denervation or by phenoxybenzamine alone, but was attenuated by propranolol alone and was completely abolished by the combination of propranolol and phenoxybenzamine [38].
• In a double-blind study, the effects of a large dose (20 mg per kilogram) of phenoxybenzamine (PBZ) on cerebral infarction were evaluated in 120 Mongolian gerbils [39].
• Constriction to norepinephrine was abolished immediately after incubation in phenoxybenzamine and remained completely inhibited for at least 18 h (P<0.0001 ANOVA phenoxybenzamine pre-treated vs controls) [40].

References