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PubMed1976

[Effects of norepinephrine and phentolamine on acute intracranial hypertension].

It is accepted that cerebrovascular dilatation is a constant response during the advanced stage of intracranial hypertension. Severe intracranial hypertension ultimately associates with profound vasodilatation and reduces cerebral blood flow to zero. This irreversible state is called cerebral vasomotor paralysis by Langfitt et al (1965). The rich adrenergic nerve supply of the cerebral vessels suggests that pressor amines possibly affect the cerebral circulation and the cerebral vascular tone. This study is to investigate the reactivity of norepinephrine and phentolamine on intracranial pressure (ICP) in patients with severe intracranial hypertension. The ICP and systemic blood pressure (SBP) monitorings were carried out continuously after the evacuation of intracerebral hematomas due to ruptured intracranial aneurysms. Severe intracranial hypertension due to brain swelling was observed in these patients. Three stages were defined according to the reactivity to norepinephrine and phentolamine on the ICP. In Stage I, norepinephrine caused a transient decrease in the ICP and phentolamine caused a marked rise in the ICP. Stage II was marked by the absence of the ICP response to norepinephrine and phentolamine. During Stage III, the ICP changes synchronously with a variation of the SBP after the administration of norepinephrine and phentolamine. In Stage I patients, the mean ICP level was between 500-1000 mmH2O. Tracing of the ICP in this group showed transient rises called pressure waves and the waves were recurring increases in the ICP to value of 300-500 mmH2O superimposed on an elevated level of the ICP. On the other hand, in Stage II and III patients, the ICP level exceeded 1000 mmH2O. Tracing of the ICP in these groups showed only variations by the arterial pulses. The patients in Stage I had a well prognosis for life if proper treatments such as continuous ventricular drainage were carried out. The patients in Stage II and III had a poor prognosis for life inspite of continuous ventricular drainage. There are varying stages in cerebrovascular dilatation accompanying intracranial hypertension. We have no information on the mechanism of this cerebrovascular dilatation at present. However, we speculate that the pressor amines such as norepinephrine may partly participate in the mechanism responsible for the vasodilation. So, we attempt to grade the degree of this vasodilatation according to the reactivity of norepinephrine and phentolamine on the ICP. It is presumed that cerebrovascular dilatation is slight and reversible in Stage I patients, whereas cerebrovascular dilatation is profund and irreversible in Stage II and III patients. Continuous ICP recording and examination of the reactivity to norepinephrine and phentolamine on the ICP are valuable when considering the prognosis for life in patients with severe intracranial hypertension.

Adult↗
PubMed2000

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction.

Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high affinity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30-40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are sufficient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1-5 and 15) from screening to the end of treatment was significantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satisfied or very satisfied compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and efficacious for the treatment of erectile dysfunction.

Administration, Oral↗
PubMed1978

Hypocalcemic effect of phentolamine.

The effects of phentolamine on calcium and phosphate metabolism were studied in young female rats. The i.p. administration of phentolamine (1.3 to 35.1 mg/kg) produces hypocalcemic and hypophosphatemic responses that resemble those produced by the hormone calcitonin. The hypocalcemic response to phentolamine reaches a maximum one hour post injection and blood calcium concentrations return to normal three hours following drug administration. Bilateral nephrectomy does not negate the hypocalcemic effect of phentolamine indicating that the drug effect is not mediated by increased renal excretion of calcium. Thyroparathyroidectomy inhibits the hypocalcemic activity of phentolamine. The mechanism of action of phentolamine with respect to changes in circulating calcium does not involve alpha adrenergic receptor blockage since large doses of tolazoline do not result in alterations in the plasma concentration of calcium. Labeling experiments with 45Ca indicate that the administration of phentolamine results in an inhibition of bone resorption.

Animals↗
PubMed1981

Effects of phentolamine on serum concentrations of TSH and thyroid hormones in hemithyreoidectomized rats.

The effects of phentolamine on the concentrations of TSH and the thyroid hormones in hemithyreoidectomized (hemiTXized) rats have been examined. Phentolamine caused a decrease of TSH level in blood serum 30 min after the injection, suggesting an inhibiting effect of phentolamine on TSH secretion. Thyroxine (T4) concentration decreased after 30 min. While triiodothyronine (T3) fell 60 min after the injection, as either a consequence of the earlier TSH fall or a result of a direct inhibiting effect of phentolamine at the thyroid level. Three repeated injections of phentolamine to hemiTXized rats brought about an increase in TSH level, in comparison with the hemiTXized control. This increase of TSH level may be explained as a "rebound effect" resulting from the earlier strong inhibition of TSH release by phentolamine. Another possible explanation is a longer inhibiting effect of phentolamine at the thyroid level than at the pituitary level. This assumption is supported by T3 concentration which, at the same time, remains still low.

Animals↗
PubMed2000

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction.

Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high affinity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30-40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are sufficient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1-5 and 15) from screening to the end of treatment was significantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satisfied or very satisfied compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and efficacious for the treatment of erectile dysfunction. International Journal of Impotence Research (2000) 12, Suppl 1, S75-S80

Journal Article↗
PubMed1994

Phentolamine and hypoxia: modulation of contractility and alpha 1-adrenoceptors in isolated rat atria.

The hypoxia-induced effects on the binding sites and affinity constant of adrenoceptors, in the presence and absence of phentolamine, were determined for atrial membranes of hearts from normal and genetically hyperlipidaemic Yoshida (YOS) rats. Atrial function was also measured during normoxia and hypoxia, in the presence and absence of phentolamine. Hypoxia increased alpha 1-adrenoceptor density in atrial membranes of normal rats (Bmax 10.6 to 26.7 fmoles/mg protein). Phentolamine prevented the increase in the Bmax of alpha 1-adrenoceptors and increased the equilibrium dissociation constant of these receptors (KD 0.17 to 0.53 nmol/l). Beta-adrenoceptors did not change during hypoxia, but the Bmax was slightly increased (26%) in the presence of phentolamine. Thus, the alpha 1/beta ratio increased from 0.40 in normoxia to 1.06 in hypoxia. In normoxic atria from YOS rats, the alpha 1/beta ratio was already elevated (0.86) in comparison to control rats (mainly due to a higher density of alpha 1-adrenoceptors in atrial membranes from YOS rats). This ratio was not modified by hypoxia (0.84), but decreased when phentolamine was present (0.30). Hypoxia reduced the force of contraction and increased diastolic tension of atria of normal rats, while the sinus rate was not significantly modified. Phentolamine abolished the increase in diastolic tension and reduced the negative effect of hypoxia on contractile force. In YOS rat atria, functional parameters were modified by hypoxia in a qualitatively similar way to that of normal rat atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

[Sympathetically maintained pain (SMP): phentolamine test vs sympathetic nerve blockade. Comparison of two diagnostic methods].

The objective of our study was to clarify whether the phentolamine test is as suitable as sympathetic blockade in diagnosing cases of sympathetically maintained pain. The specificity and the sensitivity of both procedures were examined within a prospective and randomized study. Both a local sympathetic blockade and an intravenous phentolamine infusion were carried out in 29 patients with persistent pain in the area of the upper or lower extremities. A significant improvement was defined as reduction of pain of at least 50%. There were no complications in either test procedure. The phentolamine test registers sympathetically maintained pain well when it has a positive result (specificity of 83%). However, the phentolamine test shows only a low sensitivity of 69%. The phentolamine test, on the other hand, can be realized very easily and safely. Therefore, based on the results obtained, it is recommended that the phentolamine test be applied for primary diagnosis. In case of a negative result, further diagnosis should follow subsequently, for example with local sympathetic blockade.

Adrenergic alpha-Antagonists↗
PubMed1983

Antagonist properties of phentolamine at both presynaptic alpha 2-adrenoceptors and presynaptic dopamine receptors using field stimulated right cat atria.

Phentolamine, which is considered a specific alpha-adrenoceptor antagonist, was tested for antagonist properties at presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors present on sympathetic nerve terminals in isolated right cat atria. Field stimulation induced a transient tachycardia which was inhibited by stimulation of presynaptic dopamine receptors using apomorphine or by stimulation of presynaptic alpha 2-adrenoceptors using clonidine. The presynaptic inhibitory effects of apomorphine were competitively antagonized by sulpiride, which is considered a specific dopamine receptor antagonist, and by phentolamine and yohimbine which are considered alpha-adrenoceptor antagonists. The presynaptic inhibitory effects of clonidine were competitively antagonized by phentolamine and yohimbine but not by sulpiride. pA2 values for phentolamine against apomorphine and phentolamine against clonidine suggest that phentolamine may be an antagonist at both presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors.

Animals↗
PubMed2005

Flow-injection chemiluminescence determination of phentolamine based on its enhancing effect on the luminol-potassium ferricyanide system.

It was found that the light emission produced by the oxidation of luminol by potassium ferricyanide in the basic medium was enhanced by phentolamine, a drug recently used to treatment of male and female sexual dysfunction. The optimum conditions for this chemiluminescent reaction were studied in detail by a flow-injection system. A new, simple and rapid method has been developed under the optimum conditions for determination of phentolamine. This method has the advantages of high sensitivity, good reproducibility and low detection limit. On the basis of investigation of chemiluminescent, fluorescent and UV spectra of phentolamine in basic solution containing potassium ferricyanide and luminol, a possible mechanism of this reaction was proposed. In the optimum conditions, CL intensities are proportional to concentrations of the phentolamine in the 0.01-1 microg/mL range. The limit of detection is 3.0 ng/mL for phentolamine. The method has been applied to the determination of phentolamine in the commercial preparations, synthetic samples and biological fluids with satisfactory results.

Calibration↗
PubMed1988

Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenergic blocking agents, phentolamine and idazoxan.

The coadministration of phentolamine, an alpha-adrenoreceptor antagonist, was found to be effective in antagonizing the hepatotoxicity produced by bromobenzene in B6C3F1 mice. Multiple doses of phentolamine, administered in dosages of 10 mg/kg, attenuated almost completely the acute lethality resulting from a 0.5 ml/kg dosage of bromobenzene. Consistent with this decline in lethality, the coadministration of phentolamine significantly altered the magnitude of hepatocellular necrosis, the elevation of serum alanine aminotransferase activity, and the glutathione depression normally produced by this dose of bromobenzene. These protective effects were not limited to phentolamine. Idazoxan, an adrenergic antagonist more specific for alpha 2-receptors, was equally effective in antagonizing the bromobenzene-induced hepatotoxicity. Measurements of serum catecholamine levels revealed that the administration of hepatotoxic doses of bromobenzene elevates serum epinephrine levels. Furthermore, the phentolamine antagonism of the bromobenzene hepatotoxicity could be correlated to elevated serum epinephrine levels in both a temporal and dose-dependent manner. Although the mechanism of the phentolamine antagonism remains to be established, one promising hypothesis involves its prevention of an epinephrine-mediated compromise in the glutathione-dependent detoxification of bromobenzene.

Adrenergic alpha-Antagonists↗
PubMed2002

Comparison of the efficacy and safety of sildenafil citrate (Viagra) and oral phentolamine for the treatment of erectile dysfunction.

This open-label, multi-center study from Mexico compared the efficacy and safety of oral sildenafil and phentolamine in men with erectile dysfunction. Patients received sildenafil (25-100 mg; n=123) or phentolamine (40 mg; n=119) for 8 weeks, and efficacy was assessed using the International Index of Erectile Function (IIEF) as well as two global efficacy questions. Mean scores for the erectile function domain of the IIEF were significantly higher for sildenafil (27.23 +/- 0.62; P=0.0001) than for phentolamine (19.35 +/- 0.66). Approximately twice as many men receiving sildenafil had successful attempts at sexual intercourse (88% vs 42%), improved erections (95% vs 51.1%), and improved ability to have sexual intercourse (94.4% vs 46.4%) compared with phentolamine. The most common adverse events included rhinitis, headache, tachycardia, and nausea, with a higher frequency reported in patients receiving phentolamine than sildenafil (41% vs 33%), with the exception of headache, which was reported more frequently in sildenafil users. Overall, sildenafil was more effective and appeared to be better tolerated than phentolamine for the treatment of erectile dysfunction.

Administration, Oral↗
PubMed1983

Haemodynamic and metabolic effects of alpha-adrenoceptor blockade with phentolamine at rest and during forearm exercise.

The pre- and post-junctional alpha-adrenoceptor blocking agent, phentolamine, was given by intravenous infusion to eight healthy volunteers during rest, forearm exercise and post-exercise. Phentolamine produced a sustained increase in heart rate. The diastolic blood pressure decreased slightly whereas systolic and mean blood pressures remained unchanged. Phentolamine caused a marked increase in the forearm blood flow and a decrease in vascular resistance at rest and post-exercise, but did not influence the blood flow or vascular resistance in the exercising forearm. There was a small increase in arterial blood glucose concentration, and a decrease in blood alanine concentration during drug infusion. Blood lactate was not affected by phentolamine. The arterial concentrations of free fatty acids and glycerol increased, and the concentration of triglycerides decreased during phentolamine infusion. Forearm exchange of glucose, lactate, alanine, glycerol, free fatty acids, triglycerides and forearm oxygen consumption were not changed significantly. These findings corroborate the concept that alpha-adrenoceptor induced vasoconstriction plays a subordinate role in exercising skeletal muscle. All of the metabolic findings might be explained as secondary to an increased noradrenaline release during phentolamine infusion.

Adult↗
PubMed1987

Alpha-adrenoceptor blockade by phentolamine inhibits beta-adrenergically and cholinergically induced glucagon secretion in the mouse.

Glucagon secretion is known to be stimulated by activation of the alpha-adrenoceptors. In this study, we investigated whether alpha-adrenoceptor blockade by phentolamine affects basal and stimulated glucagon secretion in the mouse. Phentolamine was injected intraperitoneally to mice at dose levels varying from 2.6 to 260 mumol/kg. It was found that, while decreasing plasma glucose levels, phentolamine did not over this wide dose range affect basal glucagon concentrations indicating an inhibition of the hypoglycaemia-induced glucagon secretion. Further, phentolamine clearly inhibited the glucagon secretory response to beta-adrenergic or cholinergic stimulation. Thus, phentolamine (2.6 mumol/kg), impaired the glucagon secretory response to the beta 2-adrenoceptor agonist terbutaline by 51% (P less than 0.01), and to the cholinergic agonist carbachol by 44% (P less than 0.02). We conclude that alpha-adrenoceptor blockade by phentolamine inhibits the glucagon secretion following hypoglycaemia or stimulation by beta-adrenergic and cholinergic agonists. Thus, the alpha-adrenoceptors seem to be of great importance for glucagon secretion in the mouse.

Adrenergic alpha-Antagonists↗
PubMed1997

Phentolamine block of KATP channels is mediated by Kir6.2.

The ATP-sensitive K+-channel (KATP channel) plays a key role in insulin secretion from pancreatic beta cells. It is closed both by glucose metabolism and the sulfonylurea drugs that are used in the treatment of noninsulin-dependent diabetes mellitus, thereby initiating a membrane depolarization that activates voltage-dependent Ca2+ entry and insulin release. The beta cell KATP channel is a complex of two proteins: Kir6.2 and SUR1. The former is an ATP-sensitive K+-selective pore, whereas SUR1 is a channel regulator that endows Kir6.2 with sensitivity to sulfonylureas. A number of drugs containing an imidazoline moiety, such as phentolamine, also act as potent stimulators of insulin secretion, but their mechanism of action is unknown. We have used a truncated form of Kir6.2, which expresses independently of SUR1, to show that phentolamine does not inhibit KATP channels by interacting with SUR1. Instead, our results argue that phentolamine may interact directly with Kir6.2 to produce a voltage-independent reduction in channel activity. The single-channel conductance is unaffected. Although the ATP molecule also contains an imidazoline group, the site at which phentolamine blocks is not identical to the ATP-inhibitory site, because phentolamine block of an ATP-insensitive mutant (K185Q) is normal. KATP channels also are found in the heart where they are involved in the response to cardiac ischemia: they also are blocked by phentolamine. Our results suggest that this may be because Kir6.2, which is expressed in the heart, forms the pore of the cardiac KATP channel.

ATP-Binding Cassette Transporters↗
PubMed1978

Circulatory and alpha-adrenoceptor blocking effects of phentolamine.

1 Intravenously administered phentolamine provoked immediate decreases in diastolic blood pressure but increases in heart rate and cardiac output. 2 These immediate circulatory effects had largely disappeared twenty minutes after administration and at this time phentolamine did not inhibit increases in blood pressure which were provoked during hand immersion in ice-cold water. 3 Log dose-response curves of noradrenaline induced increases in systolic and diastolic pressure 20 min after intravenous phentolamine were shifted to the right in a parallel manner compared with the curves before phentolamine administration. 4 It was concluded that the immediate and short acting effects induced by phentolamine are due to a non-specific vasodilator effect but in addition phentolamine causes a longer acting alpha-adrenoceptor blockade at vascular adrenoceptor sites. However, by producing both pre- and post-synaptic alpha-adrenoceptor blockade this may explain why this drug exerts only a weak antihypertensive effect.

Adrenergic alpha-Antagonists↗
PubMed1994

Phentolamine test for operative complications of pheochromocytoma: its prognostic importance.

The purpose of this investigation was to assess whether the phentolamine test is able to predict blood pressure fluctuations during operations on patients with pheochromocytoma. We administered 5 mg phentolamine intravenously to 11 patients with pheochromocytoma and 6 patients with essential hypertension, pretreated with alpha-adrenoceptor antagonists. Plasma concentrations of epinephrine and norepinephrine were determined before and after phentolamine administration, and blood pressure was measured repeatedly. Subsequently, all patients with pheochromocytoma underwent adrenal operations. Evidence is presented to show that: (1) in patients with pheochromocytoma whose blood pressure remains stable during their operation, phentolamine produces no clear effects on mean blood pressure (MBP), plasma epinephrine and plasma norepinephrine except in one patient with Sipple's syndrome, (2) in patients with pheochromocytoma exhibiting unstable blood pressure changes during surgery, phentolamine lowers MBP and raises plasma norepinephrine and (3) in patients with essential hypertension, MBP and plasma catecholamines remain unchanged following phentolamine administration. Based on these findings, this pharmacological test appears to be useful for predicting hemodynamic stability in patients with pheochromocytoma pretreated with alpha-adrenoceptor antagonists.

Adrenal Gland Neoplasms↗
PubMed1972

Comparison of blockade at alpha-adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man.

1. The antagonism at alpha-adrenoceptors by thymoxamine and phentolamine of the response to noradrenaline was investigated in the limb veins and arteries of man.2. Brachial artery infusions of thymoxamine (40 mug/min) produced rises in resting arterial flow of up to 100%. When infused mixed with noradrenaline, thymoxamine (40 mug/min) attenuated the blood flow response to noradrenaline. Blockade was of a similar degree to that which occurred following a 10 min infusion of phentolamine (40 mug/min).3. Local intravenous infusion of thymoxamine (400-2,000 ng/min) mixed with noradrenaline attenuated the venoconstrictor response to noradrenaline. The degree of attenuation was similar to that seen after a 10 min infusion of phentolamine (500 ng/min). Blockade after thymoxamine did not last longer than 16 minutes. Neither thymoxamine nor phentolamine altered resting venous compliance.4. Local intravenous infusions of thymoxamine (500 ng/min) and phentolamine (500 ng/min) abolished the sympathetically mediated venoconstriction produced by overbreathing.5. Systemic injection of thymoxamine (0.1 mg/kg) did not block the reduction in forearm arterial flow produced by locally infused noradrenaline. In two out of three experiments, however, it produced some antagonism of noradrenaline induced venoconstriction. Systemic phentolamine (5 mg) blocked the effect of noradrenaline in the arterial bed, but antagonized its actions in the veins in only one out of three experiments.

Adrenergic alpha-Antagonists↗
PubMed1988

Phentolamine lacks alpha 2-adrenoceptor agonist activity in anaesthetized dogs.

1. This study was performed in order to determine whether the blockade of sympathetic vasoconstriction in anaesthetized dogs by phentolamine is due to the antagonist action of the drug at postjunctional adrenoceptors, or is due to depression of neurotransmitter release by an agonist action at prejunctional adrenoceptors. 2. In dogs made areflexic by ganglion blockade with hexamethonium, phentolamine (0.5 mg i.a. or 0.5 mg kg-1 i.v.) elevated or did not affect femoral blood flow. By contrast, clonidine (0.5-2.5 nmol, i.a.) produced femoral vasoconstriction, which was attenuated by prior administration of phentolamine. 3. Prior blockade of prejunctional alpha 2-adrenoceptors with yohimbine (30 micrograms kg-1, i.v.) did not reduce the blocking effect of phentolamine (0.5 mg kg-1, i.v.) on neurogenic vasoconstriction. 4. The results indicate that, in anaesthetized dogs, phentolamine lacks appreciable agonist activity at either prejunctional or postjunctional alpha 2-adrenoceptors. The blockade of neurogenic responses by phentolamine is therefore likely to be due to postjunctional adrenoceptor blockade.

Adrenergic alpha-Agonists↗