To evaluate changes in the effectiveness of phentolamine mesylate in combination with different local anesthetics (LAs) and vasoconstrictors. A prospective randomized double-blind study was conducted with 90 patients divided into three groups, with each group being administered one of three different LAs: lidocaine 2% 1/80,000, articaine 4% 1/200,000, and bupivacaine 0.5% 1/200,000.

Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.

Accidental injection into the digit from an epinephrine autoinjection device can cause discoloration, pain, and paresthesias. Although loss of digit is rare, treatment in the emergency department is commonly aimed at vasodilation of the affected tissue. We report two cases of accidental injection of epinephrine into the digits that were successfully treated with subcutaneous phentolamine injection with no adverse events.

Mental stress reliably induces increases in salivary alpha amylase (sAA), a suggested surrogate marker for sympathetic nervous system (SNS) reactivity. While stress-induced sAA increases correlate with norepinephrine (NE) secretion, a potential mediating role of noradrenergic mechanisms remains unclear. In this study, we investigated for the first time in humans whether a NE-stress-reactivity mimicking NE-infusion with and without alpha-adrenergic blockade by phentolamine would induce changes in sAA.

To observe the effect and mechanism of alpha-adrenergic receptor inhibitor phentolamine (PTL) in a rabbit model of acute pulmonary embolism (APE) combined with shock.

Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD.

Sulfonate esters have been recognized as potential genotoxic impurities (PGIs) in pharmaceuticals. An LC-MS/MS method was developed and validated for the simultaneous determination of 15 sulfonate esters, including methyl, ethyl, propyl, isopropyl, and n-butyl esters of methanesulfonate, benzenesulfonate, and p-toluenesulfonate in drug products. The method utilized atmospheric pressure chemical ionization (APCI) in multiple reaction monitoring (MRM) mode for the quantitation of impurities. The method employed an ODS column as the stationary phase and water-acetonitrile as the solvents for gradient elution without derivatization steps. The method was specific, linear, accurate, precise, and robust. Recoveries of the sulfonic esters from three drug matrices were observed in the range of 91.6∼109.0% with an RSD of not greater than 17.9% at the concentration of the LOQ and in the range of 90.4%∼105.2% with an RSD of not greater than 7.1% at the concentration of 50 ng/mL for the methanesulfonates and 10 ng/mL for the benzenesulfonates and p-toluenesulfonates. The LOD was not greater than 15 ng/mL, 2 ng/mL, and 1 ng/mL for the methanesulfonate, benzenesulfonate, and p-toluenesulfonate esters, respectively. This method was sufficiently sensitive to detect the 15 PGIs in the phentolamine mesylate tablet, amlodipine besylate tablet, and tosufloxacin tosylate tablet. This analytical method is a direct, specific, rapid, and accurate quality control tool for the determination of the 15 sulfonate esters that are most likely to exist in drug products.

Mitochondria are morphologically dynamic organelles which undergo fission and fusion processes. Our previous study found that arterial constriction was always accompanied by increased mitochondrial fission in smooth muscle cells, whereas inhibition of mitochondrial fission in smooth muscle cells was associated with arterial relaxation. Here, we used the typical vasorelaxants, verapamil and phentolamine, to further confirm the coupling between arterial constriction and mitochondrial fission in rat aorta. Results showed that phentolamine but not verapamil induced vasorelaxation in phenylephrine (PE)-induced rat thoracic aorta constriction. Verapamil, but not phentolamine, induced vasorelaxation in high K+ (KPSS)-induced rat thoracic aorta constriction. Pre-treatment with phentolamine prevented PE- but not KPSS-induced aorta constriction and pre-treatment with verapamil prevented both PE- and KPSS-induced aorta constriction. Transmission electron microscopy (TEM) results showed that verapamil but not phentolamine inhibited KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells, and verapamil prevented both PE- and KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells. Verapamil inhibited KPSS-induced excessive mitochondrial fission in cultured vascular smooth muscle cells (A10). These results further demonstrate that arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells.

Multiple mechanisms have been suggested to be responsible for the insulinotropic and blood glucose lowering effects of imidazoline compounds. This study was to unravel which mechanism predominantly accounts for glucose lowering by the prototypical imidazolines idazoxan and phentolamine. To this end, an α2-adrenoceptor agonist (UK14,304) and a KATP channel opener (diazoxide) were used to inhibit insulin release from isolated perifused mouse islets and to induce hyperglycaemia in conscious mice. Potentials of idazoxan and phentolamine to counteract these effects were examined in a comparative manner. In perifused islets, idazoxan increased insulin release only in the presence of the α2-agonist, whereas phentolamine strongly counteracted both inhibitors of insulin release. In vivo, a lower dose of idazoxan was necessary to ameliorate hyperglycaemia induced by the α2-agonist than by the KATP channel opener, indicating α2A-antagonism as the predominant mechanism of action (decrease in incremental area under the glucose curve induced by 0.1mg/kg idazoxan: under diazoxide, -3±7%, vs. under UK14,304, -34±9%, P<0.02). In contrast, identical doses of phentolamine were required to counteract hyperglycaemia induced by the two inhibitors of insulin release, implicating involvement of another mechanism beside α2A-antagonism (2mg/kg phentolamine: diazoxide, -11±8%, vs. UK14,304, -15±9%, ns; 4mg/kg phentolamine: diazoxide, -48±6%, vs. UK14,304, -48±8%, ns). The results show that imidazolines can lower blood glucose via more than one mechanism of action, with the relative contributions of the mechanisms varying considerably between individual compounds. Dissection of the involved mechanisms could help to develop imidazoline drugs for the treatment of type 2 diabetes.

The hypothesis that the amplitude of the myogenic response is modulated by factors released from nerve endings was tested in rat tail small arteries. A pressure myograph in conjunction with direct stimulation of nerve endings by electrical field stimulation (EFS) was used to determine rat small artery contractile reactions. Vessel pretreatment with 10(- 5) M phentolamine abolished EFS-induced reactions completely indicating that they are mediated mainly by an adrenoceptor agonist, probably noradrenaline. In the absence and presence of 10(- 5) M phentolamine, vessel diameter changes in the pressure range from 10 to 120 mmHg were not different. Vessel stimulation by (i) EFS, (ii) noradrenaline, (iii) selective stimulation of alpha1- and alpha2-receptors, (iv) serotonin, or (v) vasopressin significantly reduced the diameter change induced by stepping pressure from 10 to 40 mmHg compared to unstimulated, control vessels. Vessel diameter changes induced by stepping pressure from 40 to 80 and from 80 to 120 mmHg, however, were not different in vessels stimulated with EFS and noradrenaline compared to controls. In conclusion, these data show that factors released from unstimulated adrenergic nerve endings (i.e., not stimulated by EFS) are not involved in the myogenic response. In contrast, factors released upon stimulation of nerve endings can modulate the amplitude of the myogenic response, but only at low pressures. Thus, the pressure range for myogenic blood flow autoregulation is extended to lower pressures. Myogenic autoregulation of blood flow at physiological pressures is unaltered.

In this study, after confirming the suppression of autonomic nervous function by isoflurane anesthesia using autonomic antagonists, we pharmacologically investigated the involvement of vasomotor and cardiac sympathetic functions in systolic blood pressure variability (SBPV) frequency components in conscious rats at rest and during exposure to low-ambient temperature (LT-exposure, 9°C for 90 min). Under unanesthesia, phentolamine administration (α-adrenoceptor antagonist, 10 mg/kg) decreased the mid-frequency component (MF 0.33-0.73 Hz) and inversely increased the high-frequency component (HF 1.3-2.5 Hz). The increased HF was suppressed by subsequent treatment with atenolol (β-adrenoceptor antagonist, 10 mg/kg), but not with atropine (muscarinic receptor antagonist, 10 mg/kg). Moreover, phentolamine administration after atenolol decreased MF, but did not increase HF. LT-exposure increased MF and HF; however, phentolamine pretreatment suppressed the increased MF during LT-exposure, and atenolol pretreatment dose-dependently decreased the increased HF. These results suggest that MF and HF of SBPV may reflect α-adrenoceptor-mediated vasomotor function and β-adrenoceptor-mediated cardiac sympathetic function, respectively, in the conscious state.

It has been shown that noradrenergic activation has great influence on the activities of hypothalamic supraoptic neurons. No direct evidence has been reported on the presynaptic effects of adrenoceptors in the actions of noradrenaline on supraoptic neurons, although postsynaptic mechanisms have been studied extensively. In the present study, we explored presynaptic effects of noradrenaline on the supraoptic neurons by measuring spontaneous inhibitory postsynaptic currents (IPSC) with the whole-cell patch-clamp technique. Noradrenaline reduced the frequency of IPSCs in a dose-dependent (10(-9) to 10(-3) M) and reversible manner. Noradrenaline did not affect the amplitude of IPSCs at concentrations of 10(-9) to 10(-5) M, but reduced the amplitude of IPSCs at high concentrations (10(-4) and 10(-3) M). The inhibitory effects of noradrenaline were mimicked by the alpha2-agonist clonidine (10(-4) M), but not by the alpha1-agonist methoxamine (10(-4) M) nor by the beta-agonist isoproterenol (10(-4) M). Moreover, the inhibitory effects of noradrenaline on IPSCs were blocked by the non-selective alpha antagonist phentolamine (10(-4) M) or the selective alpha2-antagonist yohimbine (10(-4) M), but not by the alpha1-antagonist prazosin (10(-4) M). These results suggest that noradrena-line inhibits release of GABA from the presynaptic GABAergic terminals of the supraoptic neurons by activating presynaptic alpha2-adrenoceptors and such presynaptic mechanisms may play a role in the excitatory control of SON neurons by noradrenergic neurons.

Background We previously reported that pralidoxime facilitated restoration of spontaneous circulation by potentiating the pressor effect of epinephrine. We determined the optimal dose of pralidoxime during cardiopulmonary resuscitation and evaluated the involvement of α-adrenoceptors in its pressor action. Methods and Results Forty-four pigs randomly received 1 of 3 doses of pralidoxime (40, 80, or 120 mg/kg) or saline placebo during cardiopulmonary resuscitation, including epinephrine administration. Pralidoxime at 40 mg/kg produced the highest coronary perfusion pressure, whereas 120 mg/kg of pralidoxime produced the lowest coronary perfusion pressure. Restoration of spontaneous circulation was attained in 4 (36.4%), 11 (100%), 9 (81.8%), and 3 (27.3%) animals in the saline, 40, 80, and 120 mg/kg groups, respectively (P<0.001). In 49 rats, arterial pressure response to 40 mg/kg of pralidoxime was determined after saline, guanethidine, phenoxybenzamine, or phentolamine pretreatment, and the response to 200 mg/kg pf pralidoxime was determined after saline, propranolol, or phentolamine pretreatment. Pralidoxime at 40 mg/kg elicited a pressor response. Phenoxybenzamine completely inhibited the pressor response, but guanethidine and phentolamine did not. The pressor response of pralidoxime was even greater after guanethidine or phentolamine pretreatment. Pralidoxime at 200 mg/kg produced an initial vasodepressor response followed by a delayed pressor response. Unlike propranolol, phentolamine eliminated the initial vasodepressor response. Conclusions Pralidoxime at 40 mg/kg administered with epinephrine improved restoration of spontaneous circulation rate by increasing coronary perfusion pressure in a pig model of cardiac arrest, whereas 120 mg/kg did not improve coronary perfusion pressure or restoration of spontaneous circulation rate. The pressor effect of pralidoxime was unrelated to α-adrenoceptors and buffered by its vasodepressor action mediated by sympathoinhibition.

Oxidative stress and transcriptional pathways of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) are critically involved in the etiopathology of amebic liver abscess (ALA). In this work, we studied the relationship between the adrenergic nervous system and ALA in the hamster. ALA was visible at 12 h of infection. While 6-hydroxidopamine (6-OHDA) decreased infection, propranolol (β-adrenergic blocker) treatment was associated with less extensive liver damage, and phentolamine treatment (α-adrenergic blocker) significantly reduced ALA compared to 6-OHDA and propranolol. Serum enzymatic activities of alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GTP) were increased at 12 h post-infection. Chemical denervation and α and β-adrenergic blockers decreased ALT to normal levels, while 6-OHDA and propranolol showed a trend to decrease γ-GTP but phentolamine significantly reduced γ-GTP. Amebic infection increased oxidized glutathione (GSSG) and decreased both reduced glutathione (GSH) and the GSH/GSSG ratio. Propranolol and 6-OHDA showed a tendency to decrease GSSG. However, GSH, GSSG and GSH/GSSG returned to normal levels with phentolamine. Furthermore, amebic infection increased pNF-κB and interleukin-1β (IL-1β), and showed a tendency to decrease hemoxigenase-1 (HO-1), but not Nrf2. Chemical denervation showed a trend to decrease pNF-κB and IL-1β, and neither Nrf2 nor HO-1 increased significantly. In addition, NF-κB and IL-1β were attenuated by propranolol and phentolamine treatments, although phentolamine showed significant overexpression of Nrf2 and HO-1. This suggests that the adrenergic system may be involved in oxidative stress and in modulation of the Nrf2 and NF-κB pathways during ALA development.

In the present study, we investigated the effect of a nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide [carboxy-PTIO], on endothelium-dependent relaxation of a series of blood vessels from rabbits, such as thoracic aorta and femoral, renal, mesenteric, and pulmonary arteries, using a functional muscle bath technique. Carboxy-PTIO produced concentration-dependent contractions in various vessels. The contractile responses in renal, mesenteric, and pulmonary arteries were significantly greater than those in the aorta and femoral artery. Similarly, phenylephrine-induced contractions in renal, mesenteric, and pulmonary arteries were markedly enhanced after pretreatment with carboxy-PTIO. Also, carboxy-PTIO inhibited acetylcholine-induced relaxation in various blood vessels. The maximum inhibitions in aorta and femoral artery were significantly greater than those in renal, mesenteric, and pulmonary arteries. The present data demonstrate that carboxy-PTIO reduces basal, phenylephrine-, and acetylcholine-induced release of NO in rabbit blood vessels. However, different degrees of inhibition of endothelium-dependent vasorelaxation were observed in various vessels. Specifically, the thoracic aorta and femoral artery are less susceptible to the action of carboxy-PTIO without acetylcholine than renal, mesenteric, and pulmonary arteries. Conversely, the most potent carboxy-PTIO-induced inhibition of acetylcholine-induced vasorelaxation was observed with aorta and femoral arteries. Thus, it is suggested that the contribution of endogenous NO to vascular tone and regional blood flow may vary among different rabbit blood vessels.

1. Direct observations were made of responses to systemic hypoxia (breathing 12 or 6% O2 for 3 min) evoked in terminal arterioles (TA, 14-30 microns internal diameter), precapillary arterioles (PCA, 8-18 microns), collecting venules (CV, 12-30 microns) and small veins (SV, 20-50 microns) of the mesenteric circulation of the anaesthetized rat. Changes in vessel diameter were recorded before and after local blockade of alpha-adrenoreceptors with phentolamine when the mesentery was covered with Saran Wrap, which is impermeable to O2, and then after removal of the Saran Wrap, which would have kept local PO2 relatively high even during systemic hypoxia. 2. The majority of TA showed an initial decrease in diameter of 14 +/- 1% (mean +/- S.E.M.). These responses were reversed to increases in diameter (12 +/- 2%) after phentolamine, but virtually abolished after removal of the Saran Wrap (0.3 +/- 2%). 3. Some PCA showed similar behaviour to the TA; others showed an increase in diameter (11 +/- 1%). The increases in diameter were accentuated after phentolamine (16 +/- 1%), but were reduced after removal of the Saran Wrap (6 +/- 2%). 4. CV and SV showed either a decrease in diameter followed by relaxation towards control levels, or an increase in diameter that waned before hypoxia ceased (6 +/- 1% and 1 +/- 1%, respectively). The responses of CV were not altered by phentolamine (8 +/- 1%), but SV showed larger increases in diameter (5 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology.

The lower and upper incisors of female rats were repeatedly reduced every 48 hr for 21 days. A marked enlargement of the submandibular glands was observed at the end of this period. One day after the final reduction, dose dependent curves to phenylephrine and isoproterenol were obtained in relation to salivary flow rates. Secretory responses, expressed as mg/gland, showed that the dose response curve to the alpha1-adrenomimetic drug was not modified by treatment while that for isoproterenol was shifted to the right of the control. When the responses were expressed as microg of saliva/mg of wet tissue, the dose-response curve to both agonists was shifted to the right in the incisor-reduced group. (Activation of alpha2-adrenergic receptors by clonidine did not inhibit the responses to phenylephrine in the incisor-reduced rats.) Radioligand binding assays of alpha1-, beta- and alpha2-receptors did not show differences between control and experimental glands in terms of densities (Bmax) or affinities (Kd). The lack of correlation between the decrease in alpha2- and beta-mediated responses and the radioligand bindings suggests that postreceptor mechanisms are involved in the diminished secretory responses of the rat submandibular gland after periodic reduction or amputation of incisors.

1. The effects of fetal intravenous treatment with phentolamine or a vasopressinergic V1-receptor antagonist on the fetal cardiovascular responses to acute hypoxaemia in the llama were investigated. 2. Six llama fetuses were surgically prepared between 60 and 70 % of gestation under general halothane anaesthesia with vascular catheters and transit-time ultrasonic flow probes around a carotid artery and a femoral artery. At least 4 days after surgery all fetuses were subjected to a 3 h experiment: 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery while on slow i.v. infusion with saline. On separate days this experiment was repeated with fetal i.v. treatment with either phentolamine or a V1-receptor antagonist dissolved in saline. 3. During saline infusion all llama fetuses responded to acute hypoxaemia with intense femoral vasoconstriction. Phentolamine during normoxia produced hypotension, tachycardia and vasodilatation in both the carotid and the femoral circulations. During hypoxaemia, fetuses treated with phentolamine did not elicit the pronounced femoral vasoconstriction and all died within 20 min of the onset of hypoxaemia. A V1-receptor antagonist produced a femoral vasodilatation during normoxia but did not affect the fetal cardiovascular responses to acute hypoxaemia. 4. In conclusion, alpha-adrenergic and V1-vasopressinergic mechanisms contribute to a basal vasoconstrictor tone in the femoral circulation in the llama fetus. The enhanced femoral vasoconstriction during acute hypoxaemia in the llama fetus is not mediated by stimulation of V1-vasopressin receptors, but is dependent on alpha-adrenergic receptor stimulation. Such alpha-adrenergic efferent mechanisms are indispensable to fetal survival during hypoxaemia in the llama since their abolition leads to cardiovascular collapse and death.

The effects of intrathecal pretreatment with the neurotoxins capsaicin, 6-hydroxydopamine and 5,7-dihydroxytryptamine on spinal antinociception by adenosine analogs (NECA, 5'-N-ethylcarboxamido adenosine and CHA, N6-cyclohexyl adenosine) and morphine were examined using the rat tail flick and hot plate tests. Pretreatment with 50 micrograms capsaicin for 7 to 11 days (which reduced substance P immunoreactivity in the superficial layers of the dorsal spinal cord) produced a slight increase in the action of NECA and CHA, and reduced the action on morphine in the hot plate test but not in the tail flick test. Pretreatment with 50 to 100 micrograms 6-hydroxydopamine for 7 to 14 days (which reduced spinal cord noradrenaline levels by 54-65%) reduced spinal antinociception by NECA and CHA but not that by morphine. Pretreatment with 50 micrograms 5,7-dihydroxytryptamine (which reduced spinal cord serotonin levels by 74-89%) had no effect on any agent. Acute pretreatment with 7.5-30 micrograms phentolamine reduced the spinal antinociceptive action of noradrenaline, NECA and CHA, primarily in the hot plate test. Phentolamine (30 micrograms) also reduced the action of morphine (hot plate greater than tail flick), but did not affect the action of L-baclofen. These results suggest that spinal antinociception by adenosine analogs: 1) occurs primarily at a postsynaptic site of action (capsaicin results), and 2) is dependent on release of endogenous noradrenaline and activation of spinal adrenergic receptors (6-hydroxydopamine and phentolamine results). The reduction in the effect of morphine by capsaicin (removes a source of adenosine release) and phentolamine (antagonizes the action of endogenously released adenosine) can be explained in terms of the adenosine release hypothesis of morphine action within the spinal cord.