Functional characterization of alpha-adrenoceptors mediating pupillary dilation in rats.

Previously, we reported that the alpha(1A)-adrenoceptor, but not the alpha(1D)-adrenoceptor, mediates pupillary dilation elicited by sympathetic nerve stimulation in rats. This study was undertaken to further characterize the alpha-adrenoceptor subtypes mediating pupillary dilation in response to both neural and agonist activation. Pupillary dilator response curves were generated by intravenous injection of norepinephrine in pentobarbital-anesthetized rats. Involvement of alpha(1)-adrenoceptors was established as mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenoceptor antagonists, phentolamine (0.3-3 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as by the selective alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg). The alpha(2)-adrenoceptor antagonist, rauwolscine (0.5 mg/kg), was without antagonistic effects. alpha(1A)-Adrenoceptor selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), the alpha(1B)-adrenoceptor selective antagonist, 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765314; 0.3-1 mg/kg), as well as the alpha(1D)-adrenoceptor selective antagonist, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1 mg/kg), were used to delineate the adrenoceptor subtypes involved. Mydriatic responses to norepinephrine were significantly antagonized by intravenous administration of both WB-4101 and 5-methylurapidil, but neither by L-765314 nor by BMY-7378. L-765314 (0.3-3 mg/kg, i.v.) was also ineffective in inhibiting the mydriasis evoked by cervical sympathetic nerve stimulation. These results suggest that alpha(1B)-adrenoceptors do not mediate sympathetic mydriasis in rats, and that the alpha(1A)-adrenoceptor is the exclusive subtype mediating mydriatic responses in this species.

A modern rationale for the use of phenoxybenzamine in urinary tract disorders and other conditions.

BACKGROUND: Phenoxybenzamine (PBZ) is a nonselective, irreversible alpha-adrenergic receptor antagonist that is approved for the treatment of diaphoresis and hypertension associated with pheochromocytoma. It may also be useful in several chronic conditions whose pathogenesis is mediated or affected by alpha-adrenergic stimulation, such as lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) and neurogenic bladder (eg, secondary to myelomeningocele and in sphincter dyssynergia and autonomic dysreflexia); in an adjunctive role after urogenital surgery or brachytherapy by relieving symptoms associated with increased alpha-adrenergic tone; and in the treatment of complex regional pain syndrome (CRPS) and prostatitis. However, carcinogenic concerns may have limited its potential application. OBJECTIVE: The purpose of this article is to reassess the usefulness and contemporary application of PBZ for the control of urinary tract symptoms associated with BPH and neurogenic bladder, after urogenital surgery and brachytherapy, and in certain other conditions (eg, CRPS, prostatitis). METHODS: A search of literature published from 1966 to 2002 was performed on MEDLINE using the search terms phenoxybenzamine, alpha-adrenergic blockers, benign prostatic hyperplasia, neurogenic bladder, urinary retention, and complex regional pain RESULTS: Despite concerns about possible carcinogenicity, no reports of drug-related tumors have been made since PBZ's introduction in 1953. Investigators have used PBZ in off-label trials to alleviate symptoms of a variety of conditions that cause urinary retention. In adult male patients with retention due to inguinal hernioplasty and female patients with retention caused by vaginal repair, as well as in pediatric patients with myelomeningocele, treatment with PBZ improved bladder function and, in the patients with myelomeningocele, was associated with reduced incidence of urinary tract infection. Larger tri- als of PBZ in men with BPH produced significant urinary symptom relief (P < 0.05 in 2 studies). Moreover, studies suggest that PBZ may be useful in alleviating pain due to trauma and CRPS. The most common adverse events appear to be dizziness, impotence and ejaculatory dysfunction, and nasal stuffiness. CONCLUSIONS: No drug-related tumors in humans have been reported after -50 years of clinical experience with PBZ. Clinical trials have demonstrated that it can relieve symptoms in patients with BPH and other urologic and pain-related conditions.

Phenoxybenzamine placental transfer during the third trimester.

OBJECTIVE: To report phenoxybenzamine placental transfer in the treatment of maternal hypertension secondary to pheochromocytoma. CASE SUMMARY: A 22-year-old woman diagnosed with pheochromocytoma was medically managed at 33 weeks gestation with oral phenoxybenzamine and labetalol until delivery 26 days later. To determine phenoxybenzamine placental passage, at the time of cesarean section simultaneous samples were obtained from the cord blood, maternal blood, and amniotic fluid. Additional blood samples were obtained from the newborn at 32 and 80 hours of life. Mean concentrations of phenoxybenzamine from cord and maternal plasma and in amniotic fluid were 103.3, 66, and 79.3 ng/mL, respectively; the newborn's plasma concentration at 32 hours of life was 22.3 ng/mL. At the time of delivery, the 2475-g male infant exhibited perinatal depression; mild transient hypotension was also noted for the first few days of life. DISCUSSION: The fetal-maternal plasma accumulation ratio of 1.6:1 indicates that at this gestational age after 26 days of therapy, the placental transfer of phenoxybenzamine occurs and is accompanied by accumulation in the fetal blood. CONCLUSIONS: Because of the placental transfer of phenoxybenzamine, mild perinatal depression and transient hypotension may occur in newborns of mothers receiving this medication. These newborns must be closely monitored during the first few days of life for respiratory depression and hypotension.

Tissue distribution of phenoxybenzamine in the rat. Lack of adipose tissue storage.

Rats were given the basic lipophilic drug, phenoxybenzamine, in single i.v. doses of 0.4 and 30 mg/kg. The drug was determined in plasma and 7 tissues by a new HPLC method. Adipose tissue reached peak levels after 30 minutes. At that time levels in heart, kidney, and brain were higher than in subcutaneous, epididymal, and mesenteric adipose tissues. The percentage metabolites in adipose tissue, kidney, and liver was 0, 88, and 96, respectively. Pretreatment with SKF 525-A inhibited metabolism and increased the tissue levels of unchanged drug, however, even under these conditions storage in adipose tissues did not occur, the adipose storage index being still less than unity. These results contradict findings of the 1950s which have been repeatedly reported in textbooks and reviews, but they confirm observations that basic drugs, even when highly lipophilic, are not being stored in adipose tissues.