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PubMed1980

In vivo labelling of alpha-adrenoceptor-binding sites and membrane-bound extraneuronal transport sites in the urinary bladder of the rat by 3H-ST-1059 and 3H-phentolamine. An autoradiography study.

An attempt was made to trace alpha-adrenoceptor-binding sites in the lower urinary tract tissue of the rat by means of analyzing the distribution of radioactivity in autoradiograms of freeze-dried or glutaraldehyde-fixed tissue following intravenous injection of an alpha-agonist, 3H-ST-1059, or an alpha-antagonist, 3H-phentolamine. Both drugs were rapidly excreted into the urine and reabsorbed by the bladder mucosa. This is evidenced by the presence of high amounts of silver grains superimposed onto the epithelium and bordering the lamina propria structures 10-30 min after intravenous injection of 3H-ST-1059 or 3H-phentolamine in rats not subjected to ligation of their ureters. In rats that underwent ligation of their abdominal ureters prior to intravenous injection of 3H-ST-1059 or 3H-phentolamine, silver grains were preferentially localized over the plasmalemmata of smooth muscle cells and fibroblasts of the detrusor and trigonum of the urinary bladder. Phentolamine and phenoxybenzamine but not propranolol counteracted the labelling of the plasma membranes of smooth muscle cells, fibroblasts and striated muscle fibres of the pelvic floor by low doses of 3H-ST-1059 and 3H-phentolamine, suggesting that both drugs have affinity to alpha-adrenoceptor-agonist and alpha-adrenoceptor-antagonist binding sites. Since phentolamine and phenoxybenzamine as well as hydrocortisone pretreatment also attenuated the accumulation of radiolabel in the perikarya of the three types of cells mentioned, both drugs--at the concentration used--are also substrates for membrane-bound carriers, such as uptake two according to Iversen. A more selective in vivo demonstrationof alpha-agonist-binding and alpha-antagonist-binding sites requires drugs of higher specific activity than available at present.

Adrenergic alpha-Agonists↗
PubMed1975

The influence of phentolamine on the fluorescence of catecholaminergic structures in selected areas of rat brain.

Wistar rats were given phentolamine into the ventriculus lateralis. The D1 group of rats received a larger dose than the D2 group. The animals were decapitated within 2 hours after phentolamine injection. The FALCK fluorescence technique was applied to demonstrate the fluorescence of catecholaminergic structures. The results in rat brain areas selected according to KONIG and KLIPPEL are shown in figs 10-46. Whereas earlier biochemical experiments did not show any phentolamine-induced changes in the NA level of the whole brain, the present histochemical experiments carried out with the fluorescence technique revealed the influence of phentolamine on individual structures and areas of the NA system. In comparison with the control material in 5 out of 11 areas the fluorescence was much weaker, in 3 it was similar to the control group, and in 3 (1 with a larger dose and 2 with a smaller dose of phentolamine) it was slightly stronger. The simultaneous increase of fluorescence in 6 out of 7 areas of the DA system may indicate a compensatory interaction of these areas as a response to the neuromediator decrease in the NA system. The paper discusses the increase in the intensity of fluorescence induced by a small dose of phentolamine in some brain areas, or by a large dose in others, both these alternatives depending on the neuromediator turnover.

Animals↗
PubMed1987

Stability of papaverine hydrochloride and phentolamine mesylate in injectable mixtures.

The stability of papaverine hydrochloride and phentolamine mesylate combined in a single vial was studied. Injectable mixtures (10 mL) of papaverine hydrochloride 300 mg and phentolamine mesylate 5 mg (from two sources) were prepared by adding the contents of one vial of lyophilized phentolamine mesylate to the contents of one vial of papaverine hydrochloride injection. The vials were stored at 5 degrees C and 25 degrees C. Duplicate aliquots of the mixtures were obtained, and the concentrations of papaverine hydrochloride and phentolamine mesylate remaining at time 0 and after 1, 2, 5, 10, 20, and 30 days were determined in triplicate by a stability-indicating high-performance liquid chromatographic assay. The concentration of papaverine hydrochloride stored in the vials remained constant (less than 1% loss) over the 30-day period at both 5 degrees C and 25 degrees C. Phentolamine mesylate was less stable than papaverine but still retained more than 97% of its original concentration after 30 days at 5 degrees C and more than 95% of its original concentration at 25 degrees C. Papaverine hydrochloride and phentolamine mesylate are stable in injectable mixtures when stored for up to 30 days at 5 degrees C or 25 degrees C.

Chromatography, High Pressure Liquid↗
PubMed1984

The effects of phentolamine and isoproterenol in experimental hemorrhagic shock in the dog.

The effects of phentolamine and isoproterenol were investigated in eight dogs versus eight control dogs. The dogs were placed into simulated hemorrhagic shock using a reservoir to maintain arterial pressure at 40 mmHg until the level of the reservoir decreased to 20% of the maximum shed volume, or for 2 hr in the isoproterenol groups. After 30 min, during which phentolamine, isoproterenol, or saline was infused, the remaining blood was reinfused. Phentolamine was given as a 5-mg intravenous bolus. Isoproterenol was infused at 2.0 micrograms/kg/min. The dogs were monitored until their arterial pressure declined to 70 mmHg (50 mm for isoproterenol) or death ensued. Phentolamine lowered peripheral resistance and the size of the vascular space increased as shown by the rapid uptake of blood, 214.0 +/- 12.5 ml, during the 30 min after injection. The control group took back only 72.5 +/- 7.5 ml. Although reinfusion of the shed blood restored blood pressure to near normal for a short period, all groups showed a progressive decline in arterial pressure. There was no evidence that phentolamine or isoproterenol significantly decreased capillary permeability or that renal or pulmonary function were significantly altered by treatment. A large increase in venous oxygen content occurred following phentolamine, and a mild inotropic and vasodilator action lasted for about 30 min. Isoproterenol also decreased postinfusion arterial pressure. Neither drug influenced the hypoglycemia seen after reinfusion.

Animals↗
PubMed1982

Dissimilarities between droperidol and phentolamine on vascular tone and dopamine and norepinephrine vasoconstriction.

Droperidol has been found to have an alpha-adrenoceptor blocking potency comparable to phentolamine in in vitro studies where norepinephrine was used as the alpha agonist. Because dopamine also stimulates alpha receptors, its vasoconstrictor effects should be similarly inhibited by droperidol and phentolamine. Because the aforementioned comparisons have not been examined in vivo, we continuously infused either droperidol or phentolamine into a denervated canine hindlimb, perfused at a constant rate of blood flow, and measured changes in the basal perfusion pressure and its response to intra-arterial injections of dopamine and norepinephrine. It was found that 1) droperidol was much less potent than phentolamine in blocking the vasoconstrictor response to dopamine and norepinephrine. 2) Phentolamine's inhibition of dopamine was similar to its effect on norepinephrine whereas droperidol had the opposite effect, producing a greater inhibitory effect on norepinephrine than on dopamine. 3) The initial decrease in vascular resistance at the onset of steady state plasma levels of droperidol was quite transient while with phentolamine a corresponding decrease in vascular tone was more prolonged.

Animals↗
PubMed1994

Experience with buccal phentolamine mesylate for impotence.

Satisfactory erection with penetration can be obtained in impotent men by the oral or buccal administration of the alpha-adrenergic antagonist, phentolamine. This agent is also used in conjunction with papaverine HCl for intracavernous injection. The previous observation by Gwinup, that 50 mg of phentolamine HCl po, 1.5 hours before coitus resulted in erection in 11/16 patients, is confirmed. This study, using phenoxybenzamine as the placebo, was repeated with success in 36/85 (42.3%) patients. Because of cost and to decrease the waiting time, a buccal form of phentolamine mesylate was administered (20 mg) with erection and penetration in 21/69 (31.8%). There was no correlation between the degree of penile vascular insufficiency or age and the effectiveness of phentolamine. Buccal phentolamine is shown to increase flow velocity in the dorsal penile artery. Phentolamine produces minimal side effects, including hypertension in the subjects.

Administration, Buccal↗
PubMed1998

Oral phentolamine as treatment for erectile dysfunction.

PURPOSE: For most patients with erectile dysfunction oral agents are a preferred treatment option. Oral or buccal phentolamine has been shown to produce full erections in impotent subsets of study populations. We evaluate the efficacy of oral phentolamine. MATERIALS AND METHODS: After a comprehensive evaluation 44 patients with recent onset (less than 3 years) of erectile dysfunction and a high likelihood of organogenic etiology underwent a prospective, double-blind and placebo controlled trial with oral phentolamine after placebo. RESULTS: After placebo 4 of the 44 patients who reported full erections were excluded from study. Of the 40 patients in the double-blind phase full erections were achieved by 2 of 10 with placebo, and 3 of 10 with 20 mg., 5 of 10 with 40 mg. and 4 of 10 with 60 mg. phentolamine. There were no serious complications observed during the study, and only a single minor side effect occurred in 1 patient after 60 mg. phentolamine. CONCLUSIONS: Our results indicate that oral phentolamine may be of benefit for the treatment of erectile dysfunction. Further studies are required to corroborate our findings.

Administration, Oral↗
PubMed1994

'Sympathetically maintained pain.' I. Phentolamine block questions the concept.

Patients with "reflex sympathetic dystrophy" or "causalgia" underwent sympathetic blocks. In protocol A (77 patients), we infused placebo (saline) for 30 minutes followed by phentolamine (35 mg). In protocol B (23 patients), the saline phase was followed by double-blind infusion of phentolamine or phenylephrine (500 micrograms), a second phase of saline, and then the other active drug. We assessed magnitudes of pain and mechanical hyperalgesias on a 0-to-10 pain scale and monitored sensory and sympathetic effects. With protocol A, pain diminished significantly (> or = 50%) during placebo in 22 patients (28.9%) and during phentolamine in seven (9.2%). With protocol B, four patients (17.3%) had relief of pain during placebo, four (17.3%) during phenylephrine, and two (8.7%) during phentolamine. All "phentolamine responders" had progressive pain relief from placebo. Two patients expressed relief during phenylephrine and worsening during phentolamine. Most patients did not respond significantly to saline or drugs. Thus, pharmacologic manipulation of the alpha-1 adrenergic receptor by either agonist or antagonist drug does not influence neuropathic pains. These results raise questions about the existence of "sympathetically maintained pain," as diagnosed by sympathetic blocks improperly controlled for placebo.

Adult↗
PubMedDate not supplied

Oral phentolamine (Vasomax).

Vasomax is an oral preparation of phentolamine mesilate (Zonagen Pharmaceuticals) currently undergoing worldwide regulatory approval for distribution. Phentolamine is primarily an alpha-adrenergic antagonist with mild sympatholytic action and a beta-adrenergic stimulating action. Over 30 years of clinical experience has shown it to be a strong direct vasodilator on muscular walled vessels, likely based on its inhibitory action on adenosine 5-triphosphate-sensitive potassium channels. This medication is not new, having been marketed in the United States in an oral formulation between 1952 and 1984. Phentolamine initially achieved FDA approval for preoperative use in patients with pheochromocytoma for control of blood pressure and paroxysmal hypertensive episodes. In the past it had been evaluated for hypertension, pulmonary disease, cardiac arrhythmias, angina pectoris and peripheral vascular disease. Unfortunately for most of these indications the clinical responses to oral phentolamine have been variable. The most clinically significant adverse events associated with oral phentolamine in the past were systemic hypotension and vasomotor collapse, severe gastrointestinal side effects especially diarrhea and some complaints of nasal congestion. In this review we will concentrate on phentolamine in a new preparation for on demand treatment of erectile dysfunction of mild to moderate degrees.

Journal Article↗
PubMed1988

Degradation kinetics of phentolamine hydrochloride in solution.

The degradation kinetics of phentolamine hydrochloride in aqueous solution over a pH range of 1.2 to 7.2 and its stability in propylene glycol- or polyethylene glycol 400-based solutions were investigated. The observed rate constants were shown to follow apparent first-order kinetics in all cases. The pKa determination for phentolamine hydrochloride was found to be 9.55 +/- 0.10 (n = 5) at 25 +/- 0.2 degrees C. This indicated the protonated form of phentolamine occurs in the pH range of this study. The pH-rate profile indicated a pH-independent region (pH 3.1-4.9) exists with a minimum rate around pH 2.1. The catalytic effect of acetate and phosphate buffer species is ordinary. The catalytic rate constants imposed by acetic acid, acetate ion, dihydrogen phosphate ion, and monohydrogen phosphate ion were determined to be 0.018, 0.362, 0.036, and 1.470 L mol-1 h-1, respectively. The salt effect in acetate and phosphate buffers followed the modified Debye-Huckel equation quite well. The ZAZB value obtained from the experiment closely predicts the charges of the reacting species. The apparent energy of activation was determined to be 19.72 kcal/mol for degradation of phentolamine hydrochloride in pH 3.1, 0.1 M acetate buffer solution at constant ionic strength (mu = 0.5). Irradiation with 254 nm UV light at 25 +/- 0.2 degrees C showed a ninefold increase in the degradation rate compared with the light-protected control. Propylene glycol had little or no effect on the degradation of phentolamine hydrochloride at 90 +/- 0.2 degrees C; however, polyethylene glycol 400 had a definite effect.

Buffers↗
PubMed1990

Phentolamine selectively affects the fast sodium component of sensory adaptation in an insect mechanoreceptor.

Phentolamine and related compounds have several different actions on nervous tissues in vertebrates and invertebrates, including a local anesthetic effect. However, recent work suggests that phentolamine can interfere with sensory transduction in insect mechanoreceptors at significantly lower concentrations than are required for conduction block. We tested the actions of phentolamine on sensory transduction and encoding in an insect mechanoreceptor, the cockroach tactile spine neuron and found that 500 microM phentolamine increased the action potential threshold by 50%. The passive membrane properties of the neuron were not affected, but one component of dynamic threshold change was strongly and selectively reduced. This component has previously been attributed to slowly inactivating sodium channels in the action potential initiating region, suggesting that these channels are the most phentolamine-sensitive sites.

Action Potentials↗
PubMed1988

Phentolamine, a deceptive tool to investigate sympathetic nervous control of insulin release.

We investigated the effects of phentolamine and another more selective alpha 2-adrenoceptor antagonist, rauwolscine, on insulin release in vivo (in female Wistar-rats) and in vitro (in perfused rat pancreas and in isolated perifused mouse islets). Phentolamine was found to significantly increase glucose-induced insulin release. On the other hand, rauwolscine failed to do so, when applied in a concentration that effectively antagonized the inhibitory effect of clonidine. These results demonstrate that phentolamine is capable of directly stimulating insulin release. This effect is thus not mediated by alpha-adrenoceptors. For this reason phentolamine is not an appropriate tool to study possible inhibitory effects of the sympathetic nervous system on insulin release. An enhanced insulin response as may be observed in animals and in man in the presence of phentolamine does not furnish evidence for a tonic inhibitory control of the islet cells by the sympathetic nervous system.

Animals↗
PubMed1990

Influence of ambient temperature on sleep and body temperature after phentolamine in rats.

Phentolamine, an alpha-adrenoceptor antagonist, both decreases rapid-eye-movement sleep (REMS) and causes a dose- and ambient temperature (Ta)-dependent drop in body temperature (Tb). The purpose of this paper was to examine the correlation between changes in sleep and changes in Tb after phentolamine at various Ta's. Tb and sleep were recorded in male rats for 4 h after i.p. injection of either saline or phentolamine (1 mg/kg at Ta 20 degrees C; 5 mg/kg at 20, 30 and 32 degrees C; 10 mg/kg at 20, 30, 32, and 34 degrees C). Changes in sleep were highly correlated with changes in Tb: when Tb dropped, amounts of sleep, especially REMS, also were decreased. The largest effects were seen at Ta 20 degrees C. After 5 mg/kg, Tb was below normal for 2 h and latency to REMS increased 82 +/- 27 min (P less than 0.025). After 10 mg/kg Tb was decreased for 3 h, and latency to REMS increased 91 +/- 19 min (P less than 0.001). While Tb was lower amounts of REMS were also decreased. Smaller effects were observed on slow wave sleep. At those conditions where phentolamine had no effect on Tb (i.e. Ta 20 degrees C, 1 mg/kg, and Ta 32 degrees C, 5 and 10 mg/kg) no differences were found in any measure of sleep. These results demonstrate that the effects of phentolamine on sleep are not caused by direct action on sleep mechanisms, but rather by its actions on thermoregulatory and possibly other mechanisms that modulate sleep.

Animals↗
PubMed2005

Effect of phentolamine on the hyperemic response to adenosine in patients with microvascular disease.

For accurate measurement of the fractional flow reserve (FFR) of the myocardium, the presence of maximum hyperemia is of paramount importance. It has been suggested that the hyperemic effect of the conventionally used hyperemic stimulus, adenosine, could be submaximal in patients who have microvascular dysfunction and that adding alpha-blocking agents could augment the hyperemic response in these patients. We studied the effect of the nonselective alpha-blocking agent phentolamine, which was administered in addition to adenosine after achieving hyperemia, in patients who had microvascular disease and those who did not. Thirty patients who were referred for percutaneous coronary intervention were selected. Of these 30 patients, 15 had strong indications for microvascular disease and 15 did not. FFR was measured using intracoronary adenosine, intravenous adenosine, and intracoronary papaverine before and after intracoronary administration of the nonselective alpha blocker phentolamine. In patients who did not have microvascular disease, no differences in hyperemic response to adenosine were noted, whether or not alpha blockade was given before adenosine administration; FFR levels before and after phentolamine were 0.76 and 0.75, respectively, using intracoronary adenosine (p = 0.10) and 0.75 and 0.74, respectively, using intravenous adenosine (p = 0.20). In contrast, in patients who had microvascular disease, some increase in hyperemic response was observed after administration of phentolamine; FFR levels decreased from 0.74 to 0.70 using intracoronary adenosine (p = 0.003) and from 0.75 to 0.72 using intravenous adenosine (p = 0.04). Although statistically significant, the observed further decrease in microvascular resistance after addition of phentolamine was small and did not affect clinical decision making in any patient. In conclusion, when measuring FFR, routinely adding an alpha-blocking agent to adenosine does not affect clinical decision making.

Adenosine↗
PubMed2005

Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed1998

Vasoactive cocktails for erectile dysfunction: chemical stability of PGE1, papaverine and phentolamine.

PURPOSE: Vasoactive cocktails are widely used in diagnosing and treating erectile dysfunction, especially in poor responders to prostaglandin E1 (PGE1). However, very little information as to their chemical interactions and stability is available, despite the huge amount of published work regarding their clinical efficacy. Obviously, medical and legal problems are involved. MATERIALS AND METHODS: We analyzed four kinds of vasoactive cocktails, composed of papaverine, phentolamine and PGE1 in different combinations, using High Performance Liquid Chromatography analysis after 5 to 60 days of storage at temperatures between 2 and 8C. SPSS MANOVA analysis and a t-test for paired samples were used for statistical purposes. RESULTS: Papaverine and phentolamine concentrations showed no significant variations during the 2 month study, ranging from a minimum of 96.75+/-1.20 to a maximum of 103.00+/-0.20% of the starting values. In the same period, PGE1 showed an accelerated degradation profile, reaching concentration values, after 60 days, of 76.00+/-2.28% and 70.20+/-2.02% when added to phentolamine or papaverine respectively and 70.00+/-2.40% with both. CONCLUSIONS: Papaverine and phentolamine are characterized by chemical stability when blended together or with PGE1. Papaverine and/or phentolamine increase the naturally occurring degradation of PGE1 in physiological solution. This effect is most evident in the first 10 days. Papaverine has the greatest deteriorating effect on PGE1. A safe and proper use of these cocktails should take into account the variations of PGE1 concentration.

Adrenergic alpha-Antagonists↗
PubMed1988

Is phentolamine stable in solution with papaverine.

Although the intracorporeal injection of mixtures of phentolamine and papaverine is used commonly in the diagnosis and treatment of erectile dysfunction, pharmacological data relating to the stability of such drug mixtures are lacking. The stability of phentolamine mesylate in aqueous solution and in solution with papaverine (0.83 mg. per cc phentolamine and 25 mg. per cc papaverine) was ascertained by high performance liquid chromatography and gas chromatography with mass spectrometry. No degradation of phentolamine occurred during 40 days whether the drug or drug combination was refrigerated or stored at room temperature. Phentolamine is stable for at least 40 days when mixed with papaverine.

Chromatography, High Pressure Liquid↗
PubMed2002

Long-term safety and efficacy of oral phentolamine mesylate (Vasomax) in men with mild to moderate erectile dysfunction.

The objectives of this study were to evaluate long-term safety and efficacy of phentolamine mesylate, an orally active, rapid-acting alpha-adrenergic receptor antagonist, for the treatment of men suffering from erectile dysfunction (ED). It was an open-label study involving more than 2000 patients. Men received phentolamine mesylate 40 mg or 80 mg (10 tablets/month) as needed for up to 13 months and self-assessed erectile performance using two validated questionnaires. Treatment with phentolamine mesylate was associated with increases in Erectile Function Domain score of the IIEF, successful vaginal penetrations, and in overall satisfaction. Most adverse events were mild or moderate in severity and consistent with the known pharmacodynamic properties of phentolamine. In conclusion, phentolamine mesylate is safe and effective in the long-term treatment of men with mild to moderate ED.

Administration, Oral↗