Biomedical subjects

J Pitha

Publications and source records attributed to J Pitha.

At least 37 records · Page 2Linked to original sources

PubMed1989

Tubulointerstitial nephritis due to vancomycin.

Vancomycin was used to treat a patient with Staphylococcus aureus endocarditis. After 3 weeks of therapy, the patient developed a diffuse maculopapular rash, which resolved upon stopping the drug. Rechallenge with vancomycin several days later resulted in reappearance of the rash and rapid onset of acute anuric renal failure. Renal biopsy revealed acute granulomatous interstitial nephritis. This is the first report of biopsy-proven vancomycin-induced acute interstitial nephritis. Renal function should be monitored closely in patients receiving vancomycin therapy.

Aged↗

PubMed1989

Alkylating prazosin analogue: irreversible label for alpha 1-adrenoceptors.

A series of prazosin analogues comprised of N-acyl derivatives of N'-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazine was prepared and the nature of their binding to alpha 1-adrenoceptors was investigated. Derivatives with alpha, beta-unsaturated acyclic acyls had some affinity but no irreversible action at the receptor. Other potent compounds, also without irreversible activity, contained cinnamoyl or (phenylamino)thiocarbonyl residues. High affinity and irreversible binding were obtained with a bicyclo[2.2.2]octa-2,5-dien-2-ylcarbonyl derivative. The conjugated double bond in this compound was in about the same position and distance from the pharmacophore as in some of the above compounds of high affinity but with no irreversible action. Two consecutive recognition steps were thought to be involved in irreversible blockade: reversible binding of the pharmacophore part of the molecule to the binding site of the receptor, followed by reaction of the chemoreactive part with an adjacent nucleophile of the receptor. The present results suggest that for the second step to occur efficiently, some affinity for the receptor must be present even in the chemoreactive part of the molecule; simple spanning of the binding and nucleophile sites of the receptor was insufficient.

Acylation↗

PubMed1989

Testosterone in a cyclodextrin-containing formulation: behavioral and physiological effects of episode-like pulses in rats.

Testosterone, administered in the form of an inclusion complex with 2-hydroxypropyl-beta-cyclodextrin by subcutaneous injection, enters the circulation in a manner markedly similar to the natural episodic release by the testes. The effects of a regimen of once-a-day administration of complexed testosterone to adult (castrated or intact) rats and to senescent (intact) rats were investigated. Although this procedure left the castrated animals with concentrations of circulatory hormone far below physiological levels for much of the day, a significant improvement in androgen-sensitive behavior and physiology was obtained. Furthermore, the testosterone effects were more pronounced when high doses were used periodically rather than when the same total amount of testosterone was equally divided among doses. The same supplementation to intact rats intensified androgen-sensitive behavior and physiology over normal levels. In senescent rats uniform pulses of the testosterone complex also improved behavior and physiology. Specifically, spermatogenesis was stimulated and, notably, the treatment increased muscle weight without substantial enlargement of the prostate. Since the testosterone-cyclodextrin complex also can be effectively administered as a sublingual tablet, the data suggest that similar regimens may be recommended for elderly men suffering from decreases in muscle mass.

Aggression↗

PubMed1989

Interaction of a chemically reactive prazosin analog with alpha-1 adrenoceptors of rat tissues.

An alkylating analog of prazosin, SZL49 [1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2.2.2]octa-2,5- diene-2-carbonyl)-piperazine], was synthesized and its pharmacological properties examined. SZL49 competed with nanomolar potency at [3H]prazosin binding sites of rat tissues. Pretreatment of membranes with SZL49 (10 nM) followed by washing led to a reduction in [3H]prazosin binding without a change in the Kd of the remaining sites. However, preincubation even at a concentration of 1 microM, led to only a 50% reduction in binding. Higher concentrations of SZL49 in the preincubation mixtures increased the Kd of the remaining sites. Pretreatment of membranes with phenoxybenzamine led to greater than 80% reduction in these sites. Preincubating membranes with SZL49 together with prazosin prevented the loss of binding caused by SZL49 alone. Utilizing different buffers or altering the ratio of absolute amounts of SZL49 and receptors in the preincubations failed to increase the blockade of [3H]prazosin binding sites. SZL49 was injected i.p. into rats and 16 hr later membranes were prepared from tissues and [3H]prazosin saturation experiments were performed. Whereas Kd values in brain and heart were no different from controls, the Kd value of the remaining kidney binding sites was increased approximately 5-fold in test animals in contrast to in vitro experiments. Maximum binding values of heart were reduced significantly by approximately 42%. Maximum binding values of kidney and brain were reduced about 21 and 36%, respectively. In functional studies with isolated rat aorta, pretreatment with SZL49, followed by a 1.5 hr washout, shifted to the right in a dose-dependent manner the dose-response curves for phenylephrine and norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1989

Effect of an alkylating analog of prazosin on alpha-1 adrenoceptor subtypes and arterial blood pressure.

Previous studies have shown that a chemically reactive analog of prazosin, SZL-49, reduces the alpha-1 adrenoceptor population by a maximum of 60% (Kusiak et al., 1989). These data support the idea that alpha-1 receptor subtypes exist and only one is sensitive to alkylation by SZL-49. In the present study male rats were injected (i.p.) with SZL-49 (0.5-30 mg/kg) and the effects on [3H]prazosin binding, systemic arterial blood pressure and the pressor response to phenylephrine were assessed 24 hr later. SZL-49 treatment decreased the number of [3H]prazosin sites without affecting receptor affinity. The maximal reduction in binding sites was 60% (32 fmol/mg). At doses of 0.5-, 1-, 5- and 10-mg/kg SZL-49 reduced the receptor number to the same level (83 fmol/mg control; 47-60 fmol/mg treated). Injection of SZL-49 had no effect on resting blood pressure. However, drug treatment (0.5 mg/kg and greater) shifted the phenylephrine dose-response curve to the right. The maximal 1-, 5- and 10-mg/kg SZL-49, the ED50 for phenylephrine was approximately the same. Therefore, over a 20-fold range of SZL-49 concentrations no further reduction in receptor number or phenylephrine ED50 was observed. These data support the idea that S2L-49-sensitive and resistant alpha-1 receptors exist in vivo. The alkylation resistant receptor is capable of maintaining resting blood pressure. Furthermore, both receptors appear to be involved in mediating the increase in blood pressure observed with phenylephrine.

Adrenergic alpha-Antagonists↗

PubMed1988

Persistent beta-adrenoceptor blockade with alkylating pindolol (BIM) in guinea-pig left atria and trachea.

The actions of alkylating pindolol (N8-bromoacetyl-N1-3'-(4-indolyloxy)-2'-hydroxypropyl[z]-1,8- diamino-p-menthane; BIM) have been examined on beta-adrenoceptors in guinea-pig left atria and trachea. In organ bath experiments, addition of BIM (greater than or equal to 0.1 microM), followed by washout, produced concentration-dependent rightward shifts of the dose-response curve to cumulative additions of (-)-isoprenaline and oxymethylene-isoprenaline and reductions in the maximal response. The "apparent" pA2 value for BIM was 9.23 +/- 0.20 (slope = 0.98 +/- 0.20). Changes in the maximal density of beta-adrenoceptor binding sites were determined in guinea-pig left atrial membranes using [125I]-cyanopindolol. BIM (0.1, 1.0 and 10 microM) produced 14, 23 and 41% reductions in Bmax with no change in KD. The binding of [125I]-BIM to guinea-pig left atrial membranes had a high non-specific binding component and a pseudo-Hill coefficient less than unity. The "apparent" KD value of [125I]-BIM at beta-adrenoceptor binding sites was 85.7 +/- 57.9 pM.

Adrenergic beta-Antagonists↗

PubMed1988

2-Hydroxypropyldigitonin: synthesis and properties of preparations differing in degree of substitution.

Reaction of propylene oxide with digitonin in strong aqueous alkali yielded water soluble, nontoxic solubilizers of drugs and hormones, the molecular composition of which could be fully deduced from plasma desorption mass spectrometry data. Preparations with average degrees of substitution ranging from 0.7 to 4.5 were investigated, and all the distributions of degrees of substitution observed were relatively narrow and symmetrical; thus, the reactivity of primary and secondary hydroxyls of saponin and of its conversion products had to be quite similar. The effects of the average degree of substitution of 2-hydroxypropyldigitonins on the formation of micelles and on the solubilization of four drugs into aqueous solutions were found to be minor. On the other hand, the ability to hemolyze erythrocytes decreased sharply with an increasing average degree of substitution.

Animals↗

PubMed1988

Epididymal sperm profiles in young adult, middle-aged, and testosterone-supplemented old rats.

Both ejaculated semen and epididymal contents from an individual male contain sperm that differ in various physicochemical characteristics. An experiment is reported in which epididymides from rats 5-24 months old were subjected to density gradient centrifugation to separate gametes of different stages of maturity. The research was designed to examine typical changes in "profiles" of sperm maturity during the reproductive lifetime of rats. Also, testosterone complexed with cyclodextrin that mimics the episodic release of the endogenous hormone was used to supplement the decreased circulating titers of some of the old males. Results revealed clear ontogenetic patterns of gradually decreasing reproductive competence as measured by absolute numbers of sperm, circulating levels of testosterone, and various other physiological markers of fertility. Sperm profiles also revealed age-specific changes with a shift toward progressively more mature, perhaps senile, gametes that begins at middle age. Testosterone supplementation (400 micrograms/kg b.w./day for 30 days) failed to restore sperm numbers or other measures of physiology in the old males, but the steroid modified sperm profiles to approximate more closely the profiles characteristic of young adult males than either untreated middle-aged or old males. The data were interpreted as suggesting that epididymal sperm profiles clearly identify males of different ages, and that the aging epididymis retains its capacity to respond to manipulations that modify the endocrine milieu.

Aging↗

PubMed1988

Drug solubilizers to aid pharmacologists: amorphous cyclodextrin derivatives.

Conversion of crystalline alpha-, beta-, or gamma-cyclodextrins into amorphous mixtures of water soluble derivatives yields non-toxic solubilizers which dissolve drugs through the formation of inclusion complexes. From these types of compounds 2-hydroxypropyl ethers of cyclodextrins have presently been investigated and the ranges for the safe use in working with (a) receptor binding assays on membrane preparations, (b) cells in vitro, and (c) parenteral use in mice were established for these compounds. The drugs which were investigated were dissolved in amounts linearly proportionate to the concentration of the solubilizers used and did not precipitate upon dilution by aqueous media. These solubilizers may considerably facilitate pharmacological evaluation of new, water insoluble potential drugs.

Adenylyl Cyclases↗

PubMed1988

Amorphous water-soluble cyclodextrin derivatives: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisobutyl, and carboxamidomethyl derivatives of beta-cyclodextrin.

The pharmaceutical usefulness of natural, crystalline cyclodextrins can be improved by chemical conversions into water-soluble, amorphous mixtures of their derivatives. Reaction of beta-cyclodextrin with 2-chloroethanol, 3-chloropropanol, isobutylene oxide, or iodoacetamide yielded the title compounds. Distributions of the substitution degree were close to symmetrical and relatively narrow. The average substitution degrees increased with the amount of alkylating reagent used in the preparation. The number of components (half-width of distribution) increased with increasing average substitution degree. Further, distributions of the substitution degree were measured in glucose derivatives after hydrolysis of 2-hydroxyethyl, 2-hydroxypropyl, and 2-hydroxyisobutyl-beta-cyclodextrin. The results show an uneven distribution of substituents around the cyclodextrins, suggesting that growth of oligoglycol side chains and/or clustering of substituents on one glucose residue occurs.

Chemical Phenomena↗

PubMed1988

Irreversible binding and recovery of the norepinephrine uptake system using an alkylating derivative of norepinephrine.

The effects of bromoacetylaminomenthylnorepinephrine (BAAN) on the sodium-dependent, high-affinity norepinephrine (NE) uptake system in rat brain synaptosomes and CNS neuronal cultures were investigated. BAAN inhibited [3H]NE uptake into synaptosomes in a dose- and time-dependent manner (IC50, 6.5 microM). Pretreatment of cortical synaptosomes or neuronal cells with BAAN alone, followed by washing to remove free drug, reduced the Vmax but did not alter the Km value for [3H]NE uptake. The BAAN-induced reduction in Vmax was attenuated by concurrent pretreatment with desipramine and blocked by the reaction of BAAN with dithiothreitol or cysteine. In contrast, BAAN was 19-fold less potent at inhibiting [3H]dopamine uptake in striatal synaptosomes, and no change in the Vmax or Km value for [3H]dopamine uptake was observed after a pretreatment with BAAN followed by washing. Furthermore, the irreversible beta-antagonist, bromoacetylalprenololmentane, was equipotent to BAAN for inhibiting [3H]NE uptake into cortical synaptosomes, but did not alter the Vmax or Km for [3H]NE after pretreatment. In neuronal cultures, BAAN inhibited sodium-dependent uptake of [3H]NE (IC50, 5.6 microM) with no effect on sodium-independent uptake. After pretreatment of cultures with 30 microM BAAN followed by washing, there was a 74% decrease in the Vmax for [3H]NE uptake. Following a 24-h lag period, uptake recovered to the control level within 48 h; however, recovery was completely blocked by cycloheximide. The data indicate that BAAN irreversibly binds to the [3H]NE uptake system in both CNS synaptosomes and neuronal cultures and may be a useful probe for studying the turnover of the [3H]NE uptake system.

Adrenergic beta-Antagonists↗

PubMed1988

Percutaneous catheter ablation at the mitral annulus in canines using a bipolar epicardial-endocardial electrode configuration.

For potential application in ablating left free-wall accessory AV pathways with direct current shocks, a new epicardial-endocardial electrode configuration, designed to focus the current field across the mitral annulus, was tested in dogs. A catheter electrode in the coronary sinus (epicardial electrode) was used as the cathode, and a catheter electrode in the left ventricle (endocardial electrode) placed beneath the mitral valve, high against the mitral annulus and directly across from the epicardial electrode formed the anode. Two shocks, each of 30, 40, or 50 joules (J) were delivered in nine, three, and four dogs, respectively. The first shock was applied to the anterior or lateral wall and the second shock to the posterior wall, except in one dog which received one anterior and one lateral shock. Two dogs receiving 50 J shocks died acutely, one due to rupture of the coronary sinus and cardiac tamponade and the other had unexplained electromechanical dissociation. The remaining 14 dogs tolerated the two shocks well and were sacrificed 3-5 days later for pathological examination of the heart. Shocks in the anterior and lateral regions produced atrial necrosis (height 1.5-11 mm, width 1.5-12 mm and depth 1-3 mm) in 10 of 14 dogs and ventricular necrosis (height 4-27 mm, width 4-33 mm, and depth 5-14 mm) in all 14 dogs. Ideal lesions with atrial necrosis extending down to the annulus and ventricular necrosis extending to the epicardial aspect of the ventricular crest occurred in five dogs in which the endocardial electrode was positioned high against the annulus. In the other nine dogs, the endocardial electrode was located 6-18 mm below the annulus, as estimated by the center of ventricular necrosis. In these dogs, the ventricular lesions did not extend to the epicardial aspect of the crest and, in four dogs, no atrial necrosis was found. Shocks delivered to the posterior wall produced no atrial or ventricular necrosis except in one dog receiving a 50 J shock. It is concluded that, using the epicardial-endocardial electrode configuration with the LV catheter positioned high against the annulus, shocks of less than 50 J in dogs safely produce atrial and ventricular necrosis adjacent to the mitral annulus in the anterior and lateral regions but not in the posterior regions. Similar lesions in man may be capable of interrupting left anterior and lateral accessory AV pathways.

Animals↗

PubMed1988

Radiofrequency current directed across the mitral anulus with a bipolar epicardial-endocardial catheter electrode configuration in dogs.

This study tested the capability of low-power radiofrequency current delivered through a bipolar "epicardial-endocardial" catheter electrode configuration to produce discrete epicardial left atrial (LA) and left ventricular (LV) necrosis adjacent to the mitral anulus for potential application in ablating left free-wall accessory atrioventricular pathways. In 15 anesthetized, closed-chest dogs, a 6F electrode catheter was inserted via the jugular vein into the coronary sinus (CS). A second catheter was inserted via the femoral artery into the left ventricle and positioned beneath the mitral valve, high against the anulus, and directly opposite the CS electrode. The LV tip electrode was positioned to record the largest LA potential to ensure proximity to the anulus. Thirty-four sites were tested (five anterior, 14 lateral, and 15 posterior). Radiofrequency current (continuous wave, 625 kHz) was delivered between the CS and LV electrodes at 37-55 V (median, 41 V) for 4-60 seconds (median, 20 seconds). Current ranged from 0.10 to 0.35 A (median, 0.18 A), resulting in power ranging from 4.3 to 19.2 W (median, 7.3 W) and total energy of 51-446 J (median, 152 J). Dogs were sacrificed 2-9 days later. The CS was grossly intact in all dogs and thrombosed in one dog. The circumflex artery was grossly normal in all dogs. Necrosis of a small segment of the arterial wall was found microscopically in one dog. Lesions were identified at 30 of the 34 sites. Twenty-two (73%) of the 30 lesions consisted of a cylindrical-shaped area of necrosis extending between the anulus and CS with diameter ranging from 2.1 to 15.0 mm (median, 4.0 mm). Atrial and ventricular epicardial necrosis extended 0-7.0 mm (median, 2.5 mm) and 0-6.8 mm (median, 2.6 mm) beyond the anulus, respectively. At the remaining eight (27%) sites, little or no epicardial injury occurred, possibly because of downward displacement of LV electrode (four sites) or positioning of LV electrode within a trabecular recess (four sites). We conclude that 1) radiofrequency current delivered between CS and LV produced, at 22 (65%) of 34 sites, LA and LV necrosis adjacent to the anulus without rupture of the CS and that 2) large, sharp LA potentials help identify an optimal anular location of LV electrode. This technique may have clinical usefulness for ablating left free-wall accessory atrioventricular connections.

Animals↗

PubMed1988

Alkylation of alpha-1 receptors with a chemically reactive analog of prazosin reveals low affinity sites for norepinephrine in rabbit aorta.

The effect of a newly synthesized irreversible blocker of the alpha-1 receptor [1-(4-amino-6,7-dimethoxy-2-quinazolnyl)-4-(2-bicyclo[2,2,2] octa-2,5-dienylcarbonyl)-piperazine; SZL-49] has been evaluated in contractile studies in rabbit aorta and binding studies in aorta and brain. SZL-49 produced long lasting inhibition of norepinephrine-induced contractions which was apparent 21 hr after drug washout. The inhibition, which was dose and time dependent, was characterized by progressive shift to the right in the norepinephrine dose-response curve. The ED50 for norepinephrine was shifted from 10(-7) M to 8 X 10(-7), 3 X 10(-6), 1 X 10(-5) and 5 X 10(-4) M after incubation (30 min) and washout of increasing concentrations of SZL-49. Surprisingly, SZL-49, irrespective of the dose or incubation time, did not decrease the maximal response of aortic rings to norepinephrine. This resulted in a norepinephrine dose-response curve after SZL-treatment that is parallel to the control. SZL-49 had no effect on the spasmogenic actions of histamine, serotonin, KCl or CaCl2. In contrast to the inhibitory pattern seen with SZL-49, incubation with 10(-7) M phenoxybenzamine shifted the norepinephrine dose-response curve to the right in a nonparallel manner and significantly depressed the maximal response obtainable with norepinephrine. Incubation with 10(-6) M phenoxybenzamine for 30 min virtually abolished the response to norepinephrine. Phenoxybenzamine (10(-7) M) was without effect on aortic rings treated with a maximally effective dose of SZL-49. Prazosin weakly antagonized the contractile actions of norepinephrine observed after SZL-49 treatment, whereas yohimbine was without effect on these norepinephrine-induced contractions. In control binding studies [3H]prazosin bound to two classes of sites in both aorta and brain preparations. Affinities and densities for these sites were K1 = 67.5 pM, K2 = 309 pM; R1 = 38.2 fmol/mg, R2 = 46.47 fmol/mg in aorta and K1 = 29.6 pM, K2 = 182 pM; R1 = 6.6 fmol/mg and R2 = 30.4 fmol/mg in brain. Treatment with increasing amounts of SZL-49 (10(-10) to 10(-8) M) progressively reduced the number of [3H]prazosin sites without altering the affinity of the sites remaining. At 10(-7) M, SZL-49 eliminated completely all specific [3H]prazosin binding. Our results indicate that the site mediating norepinephrine contraction after treatment with SZL-49 does not possess the characteristics of an alpha-1 receptor and supports the hypothesis that a low affinity site for norepinephrine and prazosin exists in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗

PubMed1988

Bilateral elastofibroma dorsi.

Elastofibroma, a rare, noncapsulated, benign entity (pseudotumor), is characterized by the proliferation of fibrous tissue with elastin and scattered islands of adipose tissue that occurs most often in the infrascapular area of elderly women. We report on a 44-year-old man with bilateral infrascapular elastofibromas.

Fibroma↗

PubMed1987

Reaction of cyclodextrins with propylene oxide or with glycidol: analysis of product distribution.

Reaction of cyclomalto-hexaose, -heptaose, or -octaose with propylene oxide in strong aqueous alkali gave products in which distribution of the degrees of substitution was relatively narrow and nearly symmetrical, and increased with the average degree of substitution. When an equimolar mixture of cyclomalto-hexaose, heptaose, or -octaose was used, the average degrees of substitution of all three carbohydrates were close to each other. These findings indicate that the reactivities of the hydroxyl groups of cyclomalto-hexaose, -heptaose, or -octaose, and of all their (2-hydroxypropyl) ethers formed in the reactions, are quite similar. Reaction of cyclomaltoheptaose with glycidol also yielded a product having a narrow distribution of degree of substitution, but which was slightly skewed towards the higher degrees. Thus, as it proceeds, this etherification leads to products having higher reactivity towards the epoxide.

Cyclodextrins↗

PubMed1987

A bromoacetylated analogue of cyanopindolol: an irreversible antagonist at rat beta-adrenoceptors.

A high affinity, chemically reactive cyanopindolol derivative. N8-bromoacetyl-N1-3'-(2-cyano-4-indolyloxy)-2'-hydroxypropyl-[Z]-1 ,8-diamino-p-menthane (Br-CYP) was synthesized and its interaction with beta-adrenoceptors characterized. Studies with rat heart, lung, brain, and red blood cell membranes indicated that the compound displaced 3H-dihydroalprenolol (3H-DHA) from beta-adrenoceptors with IC50 values in the nanomolar range. The concentration of functional beta-adrenoceptors in membranes was markedly reduced when membranes were preincubated with Br-CYP and then extensively washed prior to assay. (+/-)Alprenolol and (-)isoproterenol, but not (+)isoproterenol, when included in the preincubation prevented this reduction in binding sites by Br-CYP. Br-CYP was active in vivo when injected intraperitoneally into rats. A dose of 10 micrograms/kg reduced the concentration of binding sites in membranes from heart by 30%, lung by 36%, and RBC by 70%, but did not affect sites on brain membranes 16 hours after injection. Higher doses blocked virtually all the 3H-DHA binding sites in the peripheral organs studied. Br-CYP reduced the concentration of beta-adrenoceptors in membranes from these same tissues (but not brain tissue) as long as two weeks after injection with recovery of binding occurring more rapidly in heart tissue than lung and red blood cells. These results suggest that Br-CYP may be a useful compound for in vivo studies of the biochemistry and pharmacology of beta-adrenergic systems.

Adrenergic beta-Antagonists↗

PubMed1987

Inhibition of alpha 1-adrenergic responsiveness in intact cells by a new, irreversible receptor antagonist.

A novel alpha 1-adrenoreceptor antagonist, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo [2.2.2] octa-2,5-dienylcarbonyl) piperazine, was synthesized and shown to potently block alpha 1-adrenoceptor-induced Ca2+ mobilization in intact rat parotid acinar cells. Irreversible inhibition was complete in less than 5 min. This alkylating prazosin derivative blocked Ca2+ release (IC50 approximately 5 X 10(-10)M) and [3H]-prazosin membrane binding (IC50 approximately 3 X 10(-10)M) in a concentration dependent fashion and increased the EC50 of epinephrine for Ca2+ efflux by approximately 35 fold. The agent however had no effect on muscarinic receptor-induced Ca2+ mobilization, or beta-adrenoreceptor-induced protein secretion, from cells. These findings suggest that this irreversible alpha 1-adrenoreceptor antagonist will be a valuable tool in probing alpha 1-adrenoreceptor function and metabolism in intact cells.

Adrenergic alpha-Antagonists↗