α-adrenergic receptor

In vitro activity: Phentolamine mesylate breaks the binding of the alpha 2 receptor antagonists [3H]rauwolscine and [3H]RX 821002 with a comparatively high affinity in corpus cavernosum membranes, as well as the selective alpha 1 receptor antagonists [125I]HEAT and [3H]prazosin. When phentolamine mesylate is combined with non-adrenergic contractile agents like endothelin and KCl, as well as adrenergic agonists like phenylephrine, norepinephrine, oxymetazoline, and UK 14,304, it results in concentration-dependent relaxation in erectile tissue strips. The erectile tissue in the corpus cavernosum relaxes when phenolamine mesylate is present because it directly binds to alpha 1 and 2 adrenergic receptors and indirectly through an endothelium-mediated, non-adrenergic mechanism that may activate nitric oxide synthase.[1] Phentolamine is an alpha-adrenergic antagonist that improves the systemic absorption of the local anesthetic from the injection site by blocking the vasoconstriction linked to the epinephrine used in dental anesthetic formulations.

In mice, phentolamine (5–20 mg/kg; i.p.) attenuates DOPS (4 mg/kg, i.p.)-induced seizures and successfully prevents strychnine (2 mg/kg, i.p.)-induced seizures[2]. Intraperitoneal injection of phentolamine (1 mg/kg) enhances insulin production by blocking a2A adrenergic receptors in mouse B cells [3].

---

1. The effects of some noradrenergic agents on seizures induced by strychnine were investigated in mice. 2. Strychnine (0.5-4 mg/kg, i.p.) dose-dependently produced tonic seizures. 3. DOPS (4-8 mg/kg, i.p.) significantly shortened the latency of seizures elicited by strychnine (2 mg/kg, i.p.). Similarly, DOPS (4 mg/kg, i.p.) effectively increased the incidence and significantly shortened the latency of seizures induced by strychnine (1 mg/kg, i.p.). 4. Imipramine (20-40 mg/kg, i.p.) and pargyline (200 mg/kg, i.p.) significantly shortened the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 5. Phentolamine (5-20 mg/kg, i.p.) effectively antagonised the seizures elicited by strychnine (2 mg/kg, i.p.). Furthermore, phentolamine (10 mg/kg, i.p.) attenuated the seizure-potentiating effect of DOPS (4 mg/kg, i.p.). 6. Propranolol (0.5-2 mg/kg, i.p.) and prazosin (1-2 mg/kg, i.p.) reduced the incidence and significantly delayed the latency of seizures induced by strychnine (2 mg/kg, i.p.). 7. Reserpine (5-10 mg/kg, i.p.) significantly prolonged the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 8. Clonidine (0.25-1 mg/kg, i.p.) dose-dependently and significantly antagonised strychnine (2 mg/kg, i.p.)-induced seizures. 9. Idazoxan (1-4 mg/kg, i.p.) in a dose related manner significantly shortened the latency of seizures induced by strychnine (2 mg/kg, i.p.). Similarly, idazoxan (2 mg/kg, i.p.) profoundly potentiated seizures elicited by strychnine (1 mg/kg, i.p.). Idazoxan (4 mg/kg, i.p.) significantly antagonised the protective effect of clonidine (1 mg/kg, i.p.) against strychnine (2 mg/kg, i.p.)-induced seizures. 10. Disulfiram (3 x 25 - 3 x 100 mg/kg, i.p.) significantly attenuated strychnine (2 mg/kg, i.p.)-induced seizures. DOPS (4 mg/kg, i.p.) significantly potentiated strychnine seizures in disulfiram (3 x 100 mg/kg, i.p.)-pretreated animals. 11. These results indicate that enhancement of noradrenergic neurotransmission potentiates strychnine seizures in mice[2].

The binding activity of phentolamine was investigated in a cell-free system by displacement of specific and selective radiolabelled ligands to alpha 1 and 2 adrenergic receptors. The physiologic activity of phentolamine-mediated relaxation of adrenergic and non-adrenergic pre-contracted erectile tissue strips of human and rabbit corpus cavernosum were studied in organ bath chambers. Int J Impot Res . 1998 Dec;10(4):215-23.

The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 microM) and yohimbine (30 microM) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of alpha-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of alpha-adrenergic receptor blockade.Fundam Clin Pharmacol . 2001 Feb;15(1):1-7.

Animal/Disease Models: WT mice [3]
Doses: 1 mg/kg
Route of Administration: IP
Experimental Results: Blood glucose diminished and insulin levels increased.

---

Effects of (+/-)-efaroxan, 5 mg kg(-1), and phentolamine, 1 mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha2-adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine (RS79948-197), 1 mg kg(-1), and the sulphonylurea glibenclamide, in alpha2A-KO and control (wild type (WT)) mice. Key results: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha2A-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha2A-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha2A-KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide. Conclusions and implications: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha2A-adrenoceptors, and demonstrate a critical role for alpha2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.[3]

Absorption, Distribution and Excretion
Phentolamine reaches peak plasma concentration within 10 to 20 minutes after submucosal administration. Peak plasma concentrations (Cmax) are higher in larger children. After topical instillation of 0.75% phentolamine eye drops, peak plasma concentrations are reached within 15 minutes to 1 hour, with a median of 0.45 ng/mL. Approximately 13% of a single intravenous dose is excreted unchanged in the urine. Although information on the distribution of phentolamine is limited, it has been reported to cross the blood-brain barrier. The time to peak concentration (Tmax) is 30 to 60 minutes. Protein binding is less than 72%. It is primarily metabolized in the liver, with 80% excreted by the kidneys (of which 10% to 13% is excreted unchanged) and 20% by feces. The activity of orally administered phentolamine is only about 20% of that of parenteral administration. Approximately 10% of the parenteral dose is recovered in the urine as the active drug; the fate of the remainder is unknown. It is currently unknown whether this drug crosses the placenta or appears in breast milk. Metabolites/Metabolites: Known metabolites of phentolamine include [3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylaniline]phenyl]hydrosulfate. Biological Half-Life: The half-life of intravenously administered phentolamine is 19 minutes. The terminal elimination half-life of submucosal administration of phentolamine is approximately 2 to 3 hours. The elimination half-life of intravenously administered phentolamine is 19 minutes, and the elimination half-life of oral administration is 5 to 7 hours.

Subcutaneous injection of LDLo 275 mg/kg in rats, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LDLo 75 mg/kg in rats, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LD50 75 mg/kg in mice, Pharmacology Journal, 5(101), 1974
Subcutaneous injection of LDLo 200 mg/kg in rabbits, Japanese Pharmacopoeia, 6(667), 1982
Intravenous injection of LDLo 35 mg/kg in rabbits, Japanese Pharmacopoeia, 6(667), 1982
Interactions
Pimozide is a potent antagonist of (+) amphetamine, diethylacetone, malindole, and phentermine in anorexia in mice. Phentolamine and propranolol did not produce such antagonistic effects, but either enhanced or had no effect on drug-induced anorexia.

---

Non-human toxicity values
Oral LD50 in rats: 1250 mg/kg
Oral LD50 in mice: 1000 mg/kg

[1]. Goldstein I I. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res. 2000 Mar;12(S1):S75-S80.

[2]. Strychnine-induced seizures in mice: the role of noradrenaline. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Jul;18(4):753-63.

[3]. alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice. Br J Pharmacol. 2008 Jul;154(6):1287-96.

Therapeutic Uses
Adrenergic alpha receptor blocker; antihypertensive drug; sympathetic nerve blocker. Phentolamine is primarily used for the diagnosis of pheochromocytoma and for controlling or preventing paroxysmal hypertension before or during pheochromocytoma resection. /See US product label for usage details/ OraVerse is indicated for reversing soft tissue anesthesia, i.e., lip and tongue anesthesia, and for corresponding functional impairments caused by submucosal injection of local anesthetics containing vasoconstrictors in the oral cavity. /See US product label for usage details/ While no single chemical or pharmacological assay is entirely reliable, measuring the concentration of catecholamines in the blood and/or the excretion of catecholamines or their metabolites in the urine is the safest and most reliable method for diagnosing pheochromocytoma. A phentolamine test may be used when further confirmation of pheochromocytoma is required and the potential benefit of the test outweighs the possible risks. The phentolamine test is more reliable in detecting pheochromocytoma in patients with persistent hypertension than in patients with paroxysmal hypertension, but has no diagnostic value in patients with normal blood pressure at the time of the test. A sudden and significant drop in blood pressure following parenteral administration of phentolamine in hypertensive patients may indicate the presence of pheochromocytoma. However, false negative and false positive results in the phentolamine test are common. /See US product label for usage details/
For more complete data on the therapeutic uses of phentolamine (10 types), please visit the HSDB record page.

---

Drug Warnings
Pentolamine may cause acute or persistent hypotension, tachycardia, arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebral vasospasm or occlusion have been reported occasionally after parenteral administration of phentolamine, usually accompanied by significant hypotension and shock-like status. There have been cases of death following intravenous administration of phentolamine for the diagnosis of pheochromocytoma.
Patients receiving phentolamine treatment have reported symptoms such as fatigue, dizziness, flushing, orthostatic hypotension, and nasal congestion. Gastrointestinal adverse reactions are common, including abdominal pain, nausea, vomiting, diarrhea, and exacerbation of peptic ulcers; these adverse reactions usually limit the long-term use of phentolamine. When phentolamine and papaverine are used in combination (not approved in the US) to treat erectile dysfunction, priapism may occasionally occur. Priapism is a medical emergency that, if left untreated, can lead to penile tissue damage and permanent loss of sexual function. Therefore, if an erection lasts longer than 4 hours or is accompanied by severe pain, the patient should be advised to seek immediate medical attention; if medical attention is not available, other emergency medical assistance should be sought. Other complications of the combined use of phentolamine and papaverine include transient pain (including referred pain to the glans penis), burning sensation, and paresthesia. Many patients have experienced penile ecchymosis, and superficial penile hematoma and bruising have also been reported. Fibrotic changes (e.g., penile induration, lumps, but not necessarily located at the injection site) have been reported, including bilateral corpora cavernosa fibrosis. Reports of penile embolism are rare; one patient experienced priapism, deep vein thrombosis, and a fatal pulmonary embolism. Systemic adverse reactions to the drug have also been reported (e.g., facial flushing, dizziness, decreased blood pressure, metallic taste in the mouth). It is currently unknown whether phentolamine mesylate is excreted into breast milk. Because phentolamine mesylate can cause serious adverse reactions in breastfeeding infants, the importance of the drug to the mother should be weighed when deciding whether to discontinue breastfeeding or discontinue the drug. For more complete data on phentolamine (7 of 7), please visit the HSDB record page.

---

Pharmacodynamics
Phentolamine produces a relatively short-duration alpha-adrenergic blockade. Phentolamine can cause vascular smooth muscle and pupillary dilation. When used in ophthalmic solutions, pupillary dilation typically begins within 30 minutes and reaches its maximum effect within 60 to 90 minutes. Pupil dilation lasts for at least 24 hours. Phentolamine also has direct but less pronounced positive inotropic and positive chronotropic effects on the myocardium, and vasodilatory effects on vascular smooth muscle; however, phentolamine is not considered to affect contractile function or adenylate cyclase function. High doses can lead to mild sympathetic nerve blockade. Some evidence suggests that phentolamine can also stimulate β-adrenergic receptors, thereby causing peripheral vasodilation. Phentolamine has been shown to stimulate insulin secretion, which may be related to its blocking effect on ATP-sensitive potassium channels.

C17H19N3O.HCL

317.8132

317.129

C, 64.25; H, 6.34; Cl, 11.15; N, 13.22; O, 5.03

73-05-2

Phentolamine;50-60-2;Phentolamine-d4 hydrochloride;1346599-65-2;Phentolamine mesylate;65-28-1

5775

Off-white to light yellow solid powder

569ºC at 760 mmHg

>230ºC(dec.)

297.9ºC

3.406

2

3

4

21

363

0

MRBDMNSDAVCSSF-UHFFFAOYSA-N

InChI=1S/C17H19N3O/c1-13-5-7-14(8-6-13)20(12-17-18-9-10-19-17)15-3-2-4-16(21)11-15/h2-8,11,21H,9-10,12H2,1H3,(H,18,19)

3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylanilino]phenol

Phentolamine hydrochloride; 73-05-2; Phentolamine HCl; Phentolamine chloride; Phentolamine hydrochloride [USP]; Phentolamine (hydrochloride); UNII-86DRW83R1H; NSC-757431;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~393.32 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: 2.08 mg/mL (6.54 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (6.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)