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].

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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.

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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
The peak concentrations of phentolamine are achieved within 10 to 20 minutes following submucosal administration. The Cmax was higher in children with greater weights. Following topical ocular administration of phentolamine ophthalmic solution 0.75%, the peak concentration levels were achieved between 15 minutes and one hour after dosing with the median value of 0.45 ng/mL.
Approximately 13% of a single intravenous dose appears in the urine as unchanged drug.
While there is limited information on phentolamine distribution, the drug is reported to cross the blood-brain barrier.
The Tmax is 30 to 60 minutes. Protein binding is less than 72%. It undergoes extensive hepatic metabolism, 80% renal excretion (10% to 13% excreted as unchanged drug) and 20% fecal excretion.
Phentolamine is only about 20% as active after oral administration as after parenteral administration. About 10% of a parenteral dose can be recovered in the urine as active drug; the fate of the remainder is not known. It is not known whether the drug crosses the placenta or appears in milk.

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Metabolism / Metabolites
Phentolamine has known human metabolites that include [3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylanilino]phenyl] hydrogen sulfate.

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Biological Half-Life
Phentolamine has a half-life of 19 minutes following intravenous administration. The terminal elimination half-life of phentolamine was approximately two to three hours following submucosal administration.
The elimination half life /of phentolamine/ is 19 minutes after intravenous administration, 5 to 7 hours after oral administration.

rat LDLo subcutaneous 275 mg/kg Drugs in Japan, 6(667), 1982
rat LDLo intravenous 75 mg/kg Drugs in Japan, 6(667), 1982
mouse LD50 intravenous 75 mg/kg Journal de Pharmacologie., 5(101), 1974
rabbit LDLo subcutaneous 200 mg/kg Drugs in Japan, 6(667), 1982
rabbit LDLo intravenous 35 mg/kg Drugs in Japan, 6(667), 1982

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Interactions
PIMOZIDE WAS A POTENT ANTAGONIST OF (+)AMPHETAMINE, DIETHYLPROPION, MAZINDOL & PHENTERMINE ANOREXIA IN MOUSE. PHENTOLAMINE & PROPRANOLOL PRODUCED NO SUCH ANTAGONISM, BUT EITHER POTENTIATED OR HAD NO EFFECT ON DRUG-INDUCED ANOREXIA.

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Non-Human Toxicity Values
LD50 Rat oral 1250 mg/kg
LD50 Mouse oral 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-Antagonists; Antihypertensive Agents; Sympatholytics
Phentolamine is used mainly in the diagnosis of pheochromocytoma and to control or prevent paroxysmal hypertension immediately prior to or during pheochromocytomectomy. /Use included in US product label/
OraVerse is indicated for the reversal of soft-tissue anesthesia, i.e., anesthesia of the lip and tongue, and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. /Use included in US product label/
Although no single chemical or pharmacological test is completely reliable, determinations of blood concentrations of catecholamines and/or urinary excretion of catecholamines or their metabolites are the safest and most reliable methods for the diagnosis of pheochromocytoma. The phentolamine test may be used when additional confirmatory evidence of pheochromocytoma is required and the potential benefits of the test outweigh the possible risks. The phentolamine test is more reliable in detecting pheochromocytomas in patients with sustained hypertension than in those with paroxysmal hypertension and is of no value in patients who are not hypertensive at the time of the test. Sudden and marked reduction in blood pressure following parenteral administration of phentolamine to a hypertensive patient suggests the presence of a pheochromocytoma. However, false-negative and false-positive responses to the phentolamine test occur frequently. /Use included in US product label/
For more Therapeutic Uses (Complete) data for Phentolamine (10 total), please visit the HSDB record page.

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Drug Warnings
Phentolamine may cause acute and prolonged hypotension, tachycardia, cardiac arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebrovascular spasm or occlusion, usually in association with marked hypotension and a shock-like state, have been reported occasionally following parenteral administration of phentolamine. Deaths have occurred after IV administration of phentolamine for the diagnosis of pheochromocytoma.
Weakness, dizziness, flushing, orthostatic hypotension, and nasal congestion have been reported in patients receiving phentolamine. Adverse GI effects are common and include abdominal pain, nausea, vomiting, diarrhea, and exacerbation of peptic ulcer; these adverse effects generally prevent long-term administration of phentolamine.
Intracavernous injection /not approved in the US/ of combined phentolamine and papaverine for the treatment of impotence occasionally has caused priapism. Priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, and therefore, patients should be advised to report promptly to their physician or, if unavailable, to seek alternative immediate medical attention if an erection that persists longer than 4 hours or that is extremely painful occurs. ... Other complications of intracavernous injection of combined phentolamine and papaverine have included transient pain, including referred pain to the glans, burning, and paresthesia. Penile ecchymosis has occurred in many patients, and superficial hematoma and bruising of the penis also have occurred. Fibrotic changes (e.g., induration, lumpy areas of the penis but not necessarily at the injection site), including bilateral fibrosis of the corpora cavernosa, also have been reported. Embolus in the glans has been reported rarely, and the development of priapism, deep vein thrombosis, and fatal pulmonary embolus occurred in one patient. Adverse systemic effects of the drugs (e.g., facial flushing, dizziness, decreased systemic blood pressure, metallic taste) also have occurred.
It is not known whether phentolamine mesylate is distributed into milk. Because of the potential for serious adverse reactions to phentolamine mesylate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
For more Drug Warnings (Complete) data for Phentolamine (7 total), please visit the HSDB record page.

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Pharmacodynamics
Phentolamine produces an alpha-adrenergic block of a relatively short duration. Phentolamine induces vasodilatation of vascular smooth muscle and pupils. When used in an ophthalmic solution, the onset of pupil dilation generally occurred in 30 minutes, with the maximal effect seen in 60 to 90 minutes. Pupil dilation lasted for at least 24 hours. Phentolamine also has direct but less marked positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle; however, phentolamine is not believed to affect contractile or adenyl cyclase function. Large doses can lead to a mild sympatholytic action. Some evidence suggests that phentolamine also stimulates beta-adrenergic receptors, thereby causing peripheral vasodilation. Phentolamine was shown to stimulate insulin secretion, possibly related to its blocking actions on ATP-sensitive K⁺ 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.

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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.

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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.

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