Alpha 1-selective Antagonist Research Articles

Microencapsulation for the delivery of terazosin hydrochloride: design, development, and characterization

The aim of the work. Terazosin HCL, which is a selective alpha-1 antagonist, has been recommended for the treatment of benign prostatic hyperplasia-related medical conditions, including hypertension and urinary tract disorders. The purpose of this research was to create microparticles that would have a prolonged release of terazosin hydrochloride (TZ). However, TZ is a medicine that is readily soluble and has a high capability of dissolving in water. Materials and methods. A validated HPLC method was established to assess TZ. The TZ microparticles were produced using the process of melt dispersion by utilising cetyl palmitate (CP), myristic acid (MA), Glycerol monostearate 4055 (type II) or Kolliwax® GMS II (GMS), polyethylene glycol 400 (PEG 400) as a plasticizer, and tween 80 as a stabilizing agent. Different formulations of TZ microparticles were evaluated with regard to particle size, zeta potential, and release, and morphological scanning was performed. Results. A zeta potential that falls between -22.9 and -29.4 mV is possessed by TZ microparticles. Furthermore, the size of TZ microparticles falls between 2.11 and 5.60 µm, and the polydispersity index (PDI) was between 0.24 to 0.41. In addition, the formula (F4) that included CP, GMS, PEG 400, and Tween 80 in the proportions of 0.8:0.2:1:0.5 had the highest zeta potential (ZP) and dissolved more than 85 % of TZ after 8 hours. Therefore, F4 was chosen for the purpose of conducting morphological research. Conclusion. Employing the use of CP, GMS, PEG 400, and Tween 80 in a ratio of 0.8:0.2:1:0.5 could result in the generation of microparticles of TZ that are the most acceptable

The evolution of peri-operative care in the safe management of pheochromocytoma

The use of pre- and intra-operative vasoactive agents for improved blood pressure control has transformed the outcomes following pheochromocytoma (PC) resection. The first agent utilized was phenoxybenzamine, but selective alpha-1 antagonists (SAA) and calcium channel antagonists (CCA) have also been used with success. We sought to define the relationship between pre-operative treatment and intra-operative hemodynamics associated with each of these agents in patients with PC. A retrospective, single-institution review of patients >18 years with resected PC from 1996-2020 was performed. Pre-operative blockade was at the discretion of the treating providers. Adequacy of pre-operative blockade was determined by the attending surgeon prior to proceeding with PC resection. To determine the effectiveness of pre-operative blockade during surgery, vital signs throughout the operation were examined. The final dataset included 166 patients. Phenoxybenzamine (55%) and SAA (24%) were the most commonly used pre-operative medications but phenoxybenzamine use decreased over time. Patients who experienced a hypertensive crisis had a higher initial systolic blood pressure and were older. There was no predilection for developing a hypertensive crisis based on race, sex, tumor size or type of pre-operative medication used. Patients in the early group (2010-2015) were found to have more pronounced hemodynamic instability when compared to patients in the late group (2016-2020). Although there are no demonstrated differences between antihypertensives, the prescription pattern has evolved away from phenoxybenzamine. However, as this is transition happening, patients exhibit better hemodynamic control. We hypothesize that this is due to greater experience by the intra-operative team.

PSUN11 Outcomes of Nonselective or Selective Alpha-Adrenergic Antagonist for Preoperative Management of Intra-adrenal Pheochromocytoma

Abstract Background Pheochromocytoma is a rare neoplasm of the adrenal medulla that leads to catecholamine excess. Adrenalectomy is the standard management for operative candidates. Preoperative alpha-adrenergic antagonism has been traditionally performed with the non-selective irreversible agent phenoxybenzamine. Recently, use of this agent has been limited due to availability and cost. We sought to determine whether type of preoperative antihypertensive management with nonselective alpha-adrenergic antagonist or selective alpha-1 antagonist was associated with differences in patient outcomes for those undergoing adrenalectomy. Methods We performed a retrospective review of adult patients at a single institution undergoing index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma from 2012 through 2021. Exclusion criteria were prior adrenalectomy and extra-adrenal pheochromocytoma or paraganglioma. Clinical and demographic factors were assessed. Our primary outcome was intraoperative hemodynamic stability, secondary outcomes were postoperative hemodynamic instability, and surgical complications. Data were analyzed using Chi-squared, Fisher's exact and Mann Whitney U tests. Results During the study period, 38 patients underwent index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma. Patient age was a mean of 57.8 years (SD 13.6) with 14 male (37%) and 34 (90%) white. On preoperative cross-sectional imaging, the mean tumor size was 3.9cm (IQR 2.5–5.2) with 15 (40%) left sided, 21 (58%) right sided and 1 (3%) bilateral with 32 (87%) undergoing minimally invasive laparoscopic or robotic assisted adrenalectomy. The mean pre-contrast density on computed tomography imaging was 35.4 Hounsfield units (SD 15). Preoperative plasma metanephrines were mean 0.65 (SD 6.7), plasma normetanephrines 11.1 (SD 14.3). For preoperative pharmacologic therapy, 16 (42%) were on phenoxybenzamine, 21 (55%) selective alpha-1 antagonist, and 1 (3%) patient on both who was excluded from comparative analysis. Nine patients overall (24%) had preoperative hypertensive crisis with no difference between the groups. There was no difference between the groups for intraoperative hemodynamic instability with 6 (38%) in the phenoxybenzamine group and 10 (48%) in the selective alpha blockade group (p = 0.74) or postoperative hemodynamic instability with 5 (31%) compared with 9 (45%) respectively (p = 0.50). Groups were also similar with regard to age, sex, body mass index, comorbidities, preoperative catecholamine levels, American Society of Anesthesiologists Physical Status classification, minimally invasive or open surgery, tumor size, estimated surgical blood loss, and postoperative complications. Follow up duration was longer for the phenoxybenzamine group at 55 months (SD 35) compared with 21 months (SD 25) for the selective alpha blockade group (p = 0.003). Conclusions Use of preoperative alpha adrenergic antagonism selective alpha-1 antagonists showed similar outcomes intraoperative and postoperatively compared with irreversible nonselective alpha-adrenergic antagonists in this cohort. Use of selective alpha-1 antagonists should be considered when nonselective agents are not accessible. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PD33-07 ADVERSE EVENTS ASSOCIATED WITH SELECTIVE ALPHA-1 ANTAGONISTS AS REPORTED IN A FOOD AND DRUG ADMINISTRATION DATABASE FROM 2004 TO 2019

INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a prevalent condition in aging men and as many as 14 million men in the US experience symptoms (1). Initial medical therapy consists of selective alpha-1 antagonists (SAA) that improve urinary flow, including terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin. However, few studies have discussed the prevalence of adverse events across a large patient panel (2). Our goal is to employ the FDA Adverse Event Reporting System (FAERS) database for common SAA drugs from 2004-2019 and elaborate on the most frequently reported events, age-specific onset of symptoms, and detail the risks, benefits and safety of these medications. METHODS: FAERS is a government web-based tool that collects and presents data in a user-friendly manner. We reviewed data on the studied drugs from 2004 and 2019, and then categorized based on decade of life. Analysis was performed with IBM SPSS Statistics 25. RESULTS: Data from FAERS yielded a median of n=14188 (3653-77084) adverse events reported for each drug. Statistical analysis of available data reveals dizziness, hypotension, and ineffectiveness among the most frequent adverse events. Our data shows that silodosin and tamsulosin are least associated with hypotensive symptoms while terazosin had the highest incidence of reported drug ineffectiveness. Our analysis reveals the occurrence of adverse events increases with age and peaks for men in the 8th decade of life. CONCLUSIONS: Limited large-scale analysis to date has been performed on SAA. Not only do our findings confirm the known side effects associated with SAA but also provide a more detailed understanding of these side effect profiles, enabling clinicians to better educate their patients. Further analysis with the FAERS database is possible and can provide more information on these commonly prescribed therapies.Source of Funding: N/A

Silodosin: a new subtype selective alpha-1 antagonist for the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia

Introduction: Silodosin is a new uroselective alpha-blocker with high pharmacological selectivity for the 1A adrenoceptor. It is an effective and well-tolerated treatment in men with lower urinary tract symptoms (LUTS), due to presumed bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The efficacy of silodosin is at least equivalent to existing selective alpha-1 antagonists such as tamsulosin. A beneficial consequence of its high selectivity is improved cardiovascular safety and failure to interact with other therapies such as anti-hypertensives and phosphodiesterase type-5 inhibitors.Areas covered: This paper discusses the mechanism of action, uroselectivity and clinical efficacy/tolerability of Silodosin. Additionally, drug interactions and urodynamic effects are reviewed with a focus on ejaculatory dysfunction.Expert opinion: Silodosin is a rapidly efficacious and safe agent in the treatment of LUTS/BPH in men. A lack of clinically important cardiovascular side effects makes it of potential use in the elderly. There is a higher risk of ejaculatory dysfunction, which may lead to discontinuation in younger men. The availability of generic counterparts may make this compound less marketable in countries with social healthcare systems.

Alpha-1 Adrenergic Receptor Signaling Linked to Memory Dysfunction Following Brain Trauma

Alpha-1 Adrenergic Receptor Signaling Linked to Memory Dysfunction Following Brain Trauma

Nimodipine Enhancement of α2 Adrenergic Modulation of NMDA Receptor via a Mechanism Independent of Ca2+Channel Blocking

To further understand alpha2 receptor signaling in the retina and the mechanisms that mediate ocular beneficial effects of brimonidine (an alpha2 agonist) and nimodipine (an L-type Ca(2+) channel blocker). The authors used in situ retinal ganglion cells (RGCs) in the isolated rat retina to characterize alpha2 modulation of NMDA receptor function and a rabbit retinal NMDA excitotoxicity model to verify in vitro findings under in vivo conditions. Electrophysiological (whole-cell patch clamp) recordings and Ca(2+) imaging were used to characterize NMDA receptor function and to verify the effect of various Ca(2+) channel blockers. In vivo drug application in rabbits was achieved by intravitreal injections. Application of NMDA elicited a robust whole-cell inward current in individual in situ RGCs voltage clamped at -70 mV. Pretreatment with brimonidine significantly reduced NMDA-elicited currents in RGCs. This suppressive effect of brimonidine was substantially enhanced by background addition of nimodipine or isradipine, but not by diltiazem, verapamil, or cadmium. This effect of nimodipine was blocked by either a selective alpha2 antagonist, a cyclic adenosine monophosphate (cAMP) analogue, or an adenylate cyclase activator, indicating that nimodipine acts through the alpha2 receptor-G(alphai)-coupled pathway. Brimonidine protects RGCs in the rabbit excitotoxicity model. This brimonidine protection is also enhanced significantly by application of nimodipine but not of diltiazem. These in vitro and in vivo findings demonstrate a novel neural mechanism involving nimodipine enhancement of alpha2 signaling in RGCs. This nimodipine effect appears to be independent of its classic L-type Ca(2+) channel-blocking action.

The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats

We previously showed that systemic administration of the prototypical alpha-2 noradrenaline (NA) receptor antagonist yohimbine increases alcohol self-administration and reinstatement. Yohimbine also acts as an agonist of 5-hydroxytryptamine (5-HT) 5-HT1A receptors, which have been shown to be involved in alcohol seeking. Here, we determined the contributions of the alpha-2 and 5-HT1A properties of yohimbine to its effects on alcohol seeking. The effects of lesions of the dorsal or ventral NA bundles with 6-OHDA on yohimbine-induced alcohol self-administration were first determined in male Wistar rats trained to self-administer alcohol (12% w/v, 0.19 ml per alcohol delivery), and then on reinstatement induced by yohimbine after extinction of the operant response. It was then determined whether the selective alpha-2 antagonist RS-79948 (0.1, 0.2, 0.4 mg/kg) would mimic the effects of yohimbine on self-administration and reinstatement. The effects of the alpha-2 receptor agonist clonidine, or the 5-HT1A antagonist WAY 100,635 were then determined on yohimbine-induced self-administration and reinstatement. Lesions of the NA systems did not affect yohimbine-induced alcohol self-administration or reinstatement, and RS-79948 did not mimic the effects of yohimbine. Clonidine did not significantly affect increased alcohol self-administration induced by yohimbine, but did attenuate its effects on reinstatement. Blockade of 5-HT1A receptors reduced both yohimbine-induced self-administration and reinstatement. These results suggest that alpha-2 antagonist properties of yohimbine may play a role in the reinstatement of alcohol-seeking, but not self-administration. On the other hand, yohimbine's actions on 5-HT1A receptors contribute to its effects on both alcohol self-administration and reinstatement.

Protective effects of carvedilol on ischemia–reperfusion injury in rat epigastric island skin flaps

Carvedilol, a selective alpha-1 and nonselective beta-adrenoceptor antagonist and potent antioxidant, has been shown to provide a significant decrease in neutrophil-mediated tissue injury. Epigastric skin flaps were elevated in rats, rendered ischemic for 10 h, and subsequently reperfused for 12 h. Forty rats were divided into four equal experimental groups: 1—nonischemic group, 2—ischemic saline control group, 3—ischemic control group without any vehicle treatment, and 4—drug-administered ischemic group. The effects of carvedilol on flap necrosis, neutrophil infiltration, and levels of malondialdehyde and nitric oxide in the flap tissue and serum were examined. The authors found that neutrophil numbers were significantly higher in the saline and nontreated groups. Additionally, serum and tissue levels of malondialdehyde were lower in the carvedilol-treated group, and serum nitric oxide was highest in the carvedilol-treated group. Carvedilol-treated animals had significantly lower areas of necrosis compared with controls. We conclude that administration of carvedilol before ischemia and reperfusion can significantly reduce the extent of flap necrosis and flap neutrophil counts because of ischemia–reperfusion injury.

Fluoxetine inhibits arginine vasopressin (AVP)‐stimulated water permeability in rat inner medullary collecting duct (IMCD) via alpha‐2 mechanism

Fluoxetine is widely used as an anti-depressant drug that inhibits reuptake of serotonin. The drug also induces hyponatremia by an unknown mechanism. Evidence shows that fluoxetine does not promote the release of vasopressin that would lead to hyponatremia (Marar IE and Amico JA, Endocrine, 8: 13–18, 1998). Effects of fluoxetine on renal physiology are not known. The purpose of this study was to determine if fluoxetine affects water permeability in the IMCD. Terminal IMCDs from male Wistar rats were isolated and perfused via standard methods. To measure osmotic water permeability (Pf, μm/sec), bath fluid was hypertonic to luminal fluid (545 vs 300 mOsm/Kg H2O). Agents were added to the bath – AVP at 220 pM and fluoxetine at 2.5 μM. In one set of experiments (n=4), fluoxetine reduced AVP-stimulated Pf from 1235±135 to 587±220 (p<.01). This inhibitory effect was reversible. In another protocol (n=5) fluoxetine failed to affect basal Pf (29±9). Subsequent addition of AVP increased Pf to 93±18 and the removal of fluoxetine raised Pf to 591±200 (p<.01). Fluoxetine failed to decrease Pf stimulated by the nonhydrolyzable cAMP analog 8-chlorophenylthio cAMP (n=4). To investigate the inhibitory mechanism, we used the selective alpha-2 antagonist atipamezole. In this protocol (n=4) atipamezole reversed the fluoxetine-induced inhibition of AVP-stimulated Pf from 235±92 to 657±153 (p<05). We conclude that fluoxetine inhibits AVP-stimulated Pf in rat IMCD via a pre-cAMP-dependent mechanism mediated by alpha-2 adrenoceptors. The mechanism for fluoxetine-induced hyponatremia remains unknown.

Ketanserin, a 5-HT2 Antagonist, Directly Inhibits the ATP-Sensitive Potassium Channel in Mouse Ventricular Myocytes

The effects of ketanserin, a 5-HT2 antagonist, on the ATP-sensitive K+ (K(ATP)) channels were studied in mouse ventricular myocytes using patch clamp technique. Under the whole-cell voltage clamp conditions, ketanserin (1-100 microM) reversibly inhibited pinacidil-induced K(ATP) current in a concentration-dependent fashion with a Ki value of 9.36 microM and the Hill coefficient was 0.67. This inhibition was developed even with the presence of 5-hydroxytryptamine (100 microM) in the bath. Prazosin, a selective alpha1-antagonist, also failed to mimic the effect of ketanserin. Ketanserin did not affect the channel activity in inside-out configuration under the ATP-free internal solution. Furthermore, ketanserin applied to the external solution did not affect the pinacidil-induced channel activity in the cell-attached patches, but did inhibit it when applied into the pipette. These results suggest that the inhibitory action of ketanserin observed in this study was probably due to a direct action on the K(ATP) channel rather than to an action through the 5-HT2 receptor or alpha1-adrenoceptor blockade, and that the antiarrhythmic activity of ketanserin against cardiac arrhythmias induced in the ischemic/reperfused heart is at least in part attributable to its inhibition of the K(ATP) channel.

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.

Effect of cyproterone acetate on alpha1-adrenoceptor subtypes in rat vas deferens.

Gonadal hormones regulate the expression of alpha1-adrenoceptor subtypes in several tissues. The present study was carried out to determine whether or not cyproterone acetate, an anti-androgenic agent, regulates the alpha1-adrenoceptor subtypes that mediate contractions of the rat vas deferens in response to noradrenaline. The actions of subtype selective alpha1-antagonists were investigated in vas deferens from control and cyproterone acetate-treated rats (10 mg/day, sc, for 7 days). Prazosin (pA2 approximately 9.5), phentolamine (pA2 approximately 8.3) and yohimbine (pA2 approximately 6.7) presented competitive antagonism consistent with activation of alpha1-adrenoceptors in vas deferens from both control and treated rats. The pA2 values estimated for WB 4101 ( approximately 9.5), benoxathian ( approximately 9.7), 5-methylurapidil (approximately 8.5), indoramin ( approximately 8.7) and BMY 7378 ( approximately 6.8) indicate that alpha1A-adrenoceptors are involved in the contractions of the vas deferens from control and cyproterone acetate-treated rats. Treatment of the vas deferens from control rats with the alpha1B/alpha1D-adrenoceptor alkylating agent chloroethylclonidine had no effect on noradrenaline contractions, supporting the involvement of the alpha1A-subtype. However, this agent partially inhibited the contractions of vas deferens from cyproterone acetate-treated rats, suggesting involvement of multiple receptor subtypes. To further investigate this, the actions of WB 4101 and chloroethylclonidine were reevaluated in the vas deferens from rats treated with cyproterone acetate for 14 days. In these organs WB 4101 presented complex antagonism characterized by a Schild plot with a slope different from unity (0.65 0.05). After treatment with chloroethylclonidine, the complex antagonism presented by WB 4101 was converted into classical competitive antagonism, consistent with participation of alpha1A-adrenoceptors as well as alpha1B-adrenoceptors. These results suggest that cyproterone acetate induces plasticity in the alpha1-adrenoceptor subtypes involved in the contractions of the vas deferens.

Ephedrine in the cat lung vasculature.

Ephedrine is one of the most commonly used non-catecholamine sympathomimetic agents. It is used in operating rooms and critical care settings worldwide. While it has many side effects, its ability to rapidly raise blood pressure makes it an ideal agent to maintain homeostasis as well as in emergency situations. While its effects are known to be mediated by an alpha-mediated mechanism, the exact alpha subtype is unknown. In addition, no studies using ephedrine have been performed in the pulmonary vascular bed of the cat. The effects of phentolamine, a non-selective alpha-receptor blocker, and prazosin, an alpha1-selective antagonist, were investigated on pulmonary arterial responses to ephedrine, phenylepherine, norepinephrine, and U-46619. Lobar arterial perfusion pressure was continuously monitored, electronically averaged, and recorded with constant flow in the isolated left lower lobe vascular bed of the cat. Phentolamine and prazosin significantly reduced vasoconstrictor pulmonary perfusion pressure increases induced by ephedrine. Ephedrine has significant vasopressor activity in the pulmonary vascular bed of the cat meditated predominantly by alpha1 adrenergic receptor activation.

Biochemical and functional characterization of alpha-adrenergic receptors in the rabbit vagina

Vascular and non-vascular smooth muscle within the vagina mediate important physiological changes during sexual arousal in women. In this study, we have characterized alpha-adrenergic receptors (AR) in rabbit vagina by assessment of radioligand binding, contractility of isolated tissue strips and genital hemodynamics. [ 3H]Prazosin and [ 3H]RX821002 (alpha-1 and alpha-2 AR selective antagonists) bound to rabbit vaginal membrane preparations with high affinity and limited capacity. Competition binding assays using both non-selective and subtype selective ligands for AR (phentolamine, prazosin, delequamine, rauwolscine and UK14304) further confirmed the presence of alpha-1 and alpha-2 AR in vaginal tissue. In organ bath preparations of vaginal tissue strips, norepinephrine-induced contraction was attenuated by alpha-1 and alpha-2 AR antagonists (prazosin, tamsulosin, delequamine and phentolamine). In anesthetized rabbits, intravaginal injection of the alpha-1 AR selective antagonist REC 15/2615 (50 and 100 μg/kg) caused a 2 to 3-fold increase in genital tissue oxyhemoglobin (OHb) concentration. Similar increases in tissue OHb were observed with intravaginal injection of phentolamine (500 μg/kg) or a tri-mixture of vasodilators (PGE1, papaverine, phentolamine). REC 15/2615, phentolamine or the tri-mixture also enhanced the amplitude and/or duration of change in genital tissue OHb after pelvic nerve stimulation. Thus, vaginal tissue expresses functional alpha-1 and alpha-2 AR, which modulate vaginal smooth muscle contractility and genital engorgement.

Role of Alpha-Adrenoreceptors in Cerebello-Cortical Transmission in the Rat

We studied the role of alpha-adrenoreceptors (AR) in the modulation of evoked neuronal activity in the primary motor cortex (PMC). Neurons receiving afferent inputs from the cerebellum were examined using a microiontophoretic technique. Activation of alpha-AR with octopamine resulted in most units (71%) on the intensification of background firing and in a prominent rise (in a dose-dependent manner) in the responsiveness of PMC neurons to stimulation of the superior cerebellar peduncle (SCP). A selective postsynaptic alpha1 antagonist, prazosin, evoked significant dose-dependent suppression of the background and evoked activity in 84% of the tested neurons. A selective presynaptic alpha2 antagonist, yohimbine, provided diverse effects. Its application exerted an excitatory effect in 50% of the studied neurons; however, in 33% of the cells qualitatively opposite alterations were observed: in low doses yohimbine increased the neuronal activity, but in high doses suppressed it. Our findings demonstrate the essential role of alpha-AR in the modulation of cerebro-cortical transmission and suggest their considerable involvement in motor functions.

Alpha2-adrenoreceptors profile modulation and high antinociceptive activity of (S)-(-)-2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole.

A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating alpha2-adrenoreceptors selectivity versus both alpha1-adrenoreceptors and I2 imidazoline binding sites. The most potent alpha2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the alpha2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15). (S)-(-)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with alpha2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with alpha2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective alpha2-antagonist RX821002.

Effects of alpha-2 blockade on sexual response: experimental studies with Delequamine (RS15385)

The role of alpha-2 receptors and alpha-2 antagonists in central and peripheral mechanisms of sexual response are discussed. It is concluded that the predominant role of the alpha-2 antagonist centrally is to increase arousal which in certain circumstances, is sexual. It is further concluded that the predominant role of the alpha-2 antagonist peripherally is to modulate (block) the norepinephrine (NE)-induced contractility in the smooth muscle of the penis. How the central arousal mechanisms are specifically linked to sexual response is not understood. Experimental studies with a selective alpha-2 antagonist, delequamine, are briefly reviewed and their complex results discussed. Evidence from sleep studies was consistent with delequamine having both central excitatory and inhibitory effects, dependent on dosage. The possibility that men with psychogenic erectile dysfunction might have increased central alpha-2 tone was considered. The apparent loss of responsiveness to the alpha-2 antagonist in older dysfunctional men was discussed. More questions are raised than answered; further research is needed in this area. International Journal of Impotence Research (2000) 12, Suppl 1, S64-S69

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.

Alpha-2 adrenergic and opioid receptor-mediated gastroprotection

Clonidine inhibited the development of gastric mucosal lesions induced by either acidified ethanol or indomethacin. The ED 50 values were: 7.1 and 5.2 μg.kg –1 orally, respectively. The gastroprotective effect was antagonised by the pre-synaptic alpha-2 antagonist yohimbine, the more selective alpha-2 antagonist Ch-38083 and the pre-synaptic alpha-2B antagonist prazosin. Moreover, the non-selective opioid receptor antagonist naloxone, the delta receptor selective naltrindole also reversed the clonidine-induced mucosal protective action. Clonidine was also effective following intracerebroventricular administration with the ED 50 of 37 ng/rat against ethanol-induced mucosal damage. Our results suggest that: 1) the gastroprotective effect of clonidine is likely to be mediated by alpha-2B adrenoceptor subtype; 2) there is an interaction between pre-synaptic alpha-2 adrenoceptors and opioid system; and 3) clonidine can induce gastroprotection by central mechanism.