Selective Alpha 1-adrenergic Antagonist Research Articles

FORMULATION AND IN VITRO CHARACTERIZATION OF THE SOLID LIPID NANOPARTICLES OF NAFTOPIDIL FOR ENHANCING ORAL BIOAVAILABILITY

Objective: Naftopidil (NAF) is a selective alpha1-adrenergic receptor antagonist with a nearly 20% bioavailability due to poor aqueous solubility, permeability, and extensive first-pass metabolism. To improve the bioavailability of the NAF, the solid lipid nanoparticles (SLN) of NAF were prepared. Methods: SLNs NAF were prepared using the solvent emulsification/evaporation method with excipients Compritol 888 ATO and Poloxamer 188. Formulation F10 shows better entrapment efficiency (EE) as compare to other formulations so, it has selected to optimize the particle size, zeta potential, surface morphology, Fourier transform infrared spectroscopy (FTIR), and in vitro drug release and stability studies were assessed. Results: The results showed that NAF was successfully incorporated in SLN. Having EE of all formulations ranged from 56% to 88%, drug loading ranged from 17% to 20%, drug content ranged from 77% to 98%, particle size and zeta potential of F10 were 270.2 nm and 21.7 mV, respectively, and FTIR revealed no interaction between drug and lipid in the formulation. The release of NAF-SLNs increased significantly, reaching a maximum of 4.547–82.418% in pH 6.8 buffer, the release data were fitted into the Korsmeyer-Peppas model yielding the highest correlation coefficient (R2=0.916). The stability study revealed that the formulation stability and bioavailability might be improved. Conclusion: It can be concluded that SLN could be effective nanoplatforms for increasing NAF oral bioavailability.

COVID-19-associated Guillain–Barrè Syndrome and Urinary Dysfunction: A case report

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can cause multiple systemic and neurological complications, including Guillain- Barrè Syndrome (GBS). In this report we describe for the first time, urinary dysfunction in a patient with COVID- 19. We reported a 41-years- old female patient with complaints of an increased generalized muscular weakness associated with progressive difficulty in walking. Four days earlier, patient complained of fever, diarrhea, and general weakness, and the RT-PCR was positive for COVID-19 infection. Due to the worsening of neurological symptoms, a neurophysiological examination on nervous conduction was performed and the diagnosis was suggestive of GBS. Two weeks later, patient developed two consecutive episodes of acute urinary retention that requested the placement of indwelling transurethral catheter. Patient started assuming selective alpha-1 adrenergic antagonist in association with 4 clean intermittent catheterization/ die. Four months later, women continued the therapy and the ultrasound evaluation revealed non- pathologic post- void residual volume. Therefore, patient started to void spontaneously again and alpha- blockers were discontinued. We report for the first time a case of severe voiding disorder in a patient with COVID-19 associated GBS. Timely bladder drainage should be adopted to avoid irreversible detrusor damage.

Impact of intraoperative floppy IRIS syndrome in cataract surgery by phacoemulsification: Analysis of 622 cases

BackgroundSmall pupil syndromes, including IFIS, increase the risk of complications during cataract surgery if proper surgical planning is not performed. Tamsulosin is associated with a very significant increase in the risk of IFIS, due to the prolonged inactivation of alpha-1 adrenergic receptors in the smooth muscle fiber of the iris. Material and methodsSingle-center prospective observational study, carried out at the Hospital de l'Esperança - Parc de Salut Mar. Results622 eyes of 502 patients were included, of which 337 (62%) were women. The mean age of the sample is 74.8 years. 61 cases of IFIS (11%) were observed, of which 13 received treatment with Tamsulosin and 1 with Doxazosin. 23 cases of IFIS were observed in female patients. The female:male ratio was approximately 1:3. 19 cases (3%) of severe IFIS were observed, of which 6 received treatment with alpha-antagonists, with no statistically significant correlation.The mean surgical time was 13.80 min (Standard Deviation - SD: 4.01 min) in patients without IFIS and 16.93 min (SD: 4.32 min) in patients with IFIS. The relationship between the duration of the surgical procedure in minutes and the presence of IFIS was statistically significant, applying a 'two-tailed' or bilateral t-Student test with a p value of 0.01. ConclusionRegardless of the degree of severity, the diagnosis of IFIS lengthens the surgical time in cataract surgery. This represents yet another piece of evidence that supports the use of less selective alpha-1 adrenergic antagonist treatments than Tamsulosin or the performance of cataract surgery before starting these treatments.

Impacto del síndrome de iris flácido intraoperatorio (IFIS) en cirugía de cataratas mediante facoemulsificación: análisis de 622 casos

BackgroundSmall pupil syndromes, including intraoperative-floppy iris syndrome (IFIS), increase the risk of complications during cataract surgery if proper surgical planning is not performed. Tamsulosin is associated with a very significant increase in the risk of IFIS, due to the prolonged inactivation of alpha-1 adrenergic receptors in the smooth muscle fiber of the iris. Material and methodsSingle-center prospective observational study, carried out at the Hospital de l’Esperança – Parc de Salut Mar. ResultsSix hundred and twenty-two eyes of 502 patients were included, of which 337 (62%) were women. The mean age of the sample is 74.8 years. Sixty-one cases of IFIS (11%) were observed, of which 13 received treatment with Tamsulosin and 1 with Doxazosin. Twenty-three cases of IFIS were observed in female patients. The female:male ratio was approximately 1:3. Nineteen cases (3%) of severe IFIS were observed, of which 6 received treatment with alpha-antagonists, with no statistically significant correlation.The mean surgical time was 13.80min (standard deviation – SD: 4.01min) in patients without IFIS and 16.93min (SD: 4.32min) in patients with IFIS. The relationship between the duration of the surgical procedure in minutes and the presence of IFIS was statistically significant, applying a ‘two-tailed’ or bilateral t-Student test with a p value of 0.01. ConclusionRegardless of the degree of severity, the diagnosis of IFIS lengthens the surgical time in cataract surgery. This represents yet another piece of evidence that supports the use of less selective alpha-1 adrenergic antagonist treatments than tamsulosin or the performance of cataract surgery before starting these treatments.

Development and In-Vitro Evaluation of Plantago ovata Based Rapid Disintegrating Tablets of Labetalol Hydrochloride

Objectives: To avoid swallowing problems of conventional tablets and improved patient compliance Plantago Ovata based Labetalol HCl Rapid disintegrating tablets have been prepared. Methods: Six different (F1 to F6) batches of Labetalol HCl Rapid disintegrating tablets were developed by ‘direct compression method’ using Plantago ovata as a natural super-disintegrating agent. The formulated RDT were tested for angle of repose’, densities like tapped and bulk density, Hausner’s ratio, Carr’s index like pre-compression parameters and for thickness, weight variation or weight uniformity, tablet hardness, % drug content or content uniformity, water absorption ratio’, time require for wetting of tablets’ means wetting time, in-vitro drug disintegration time and in-vitro drug dissolution studies under post-compression parameters of evaluation. Results: It was found that the all the results of these pre-compression and post-compression parameters comply with official standards. The drug release was determined using dissolution media of pH 6.8 phosphate buffer through in-vitro dissolution of drug. This study showed that a rapid drug release by prepared tablets. The optimized formulation F6 showed higher water absorption ratio`, lower wetting time, minimum in-vitro disintegration time’ and higher drug release amongst all the formulations. The F6 formulation was considered the best among all formulations. Conclusion: The prepared rapid disintegrating tablets shows rapid onset of action by quick drug release, minimize side effects and enhanced patient compliance. These prepared tablets containing selective alpha-1 and non-selective beta adrenergic antagonist’ drug candidate Labetalol HCl, will be very useful in the treatment of high blood pressure with enhanced bioavailability.
 Keywords: Rapid disintegrating tablets, Labetalol Hydrochloride, Bioavailability Enhancement, Natural Superdisintegrant, Plantago Ovata, High Blood Pressure, RDT, Patient Compliance

The AAHKS Clinical Research Award: Prophylactic Tamsulosin Does Not Reduce the Risk of Urinary Retention Following Lower Extremity Arthroplasty: A Double-Blinded Randomized Controlled Trial

BackgroundPostoperative urinary retention (POUR) is common. Selective alpha-1 adrenergic antagonists, such as tamsulosin, are effective for treating urinary retention. The purpose of this study is to determine whether perioperative prophylactic tamsulosin reduces the incidence of POUR following total hip and knee arthroplasty. MethodsMale patients 35 years of age and older undergoing primary total hip or knee arthroplasty at a single center from 2015 to 2018 were eligible for inclusion. Patients were randomized to receive tamsulosin 0.4 mg or placebo daily for 5 days preoperatively, the morning of surgery, and the first postoperative day. The incidence of POUR was determined during the postoperative hospitalization. ResultsA total of 176 patients were enrolled in the study. Two patients were withdrawn prior to randomization. The remaining 174 were randomized to tamsulosin (n = 87) or placebo (n = 87). After an additional 43 patients were withdrawn prior to surgery, 131 patients completed the study (tamsulosin, n = 64; placebo, n = 67). A total of 42 patients (32.1%) developed POUR, with 18 cases (28.1%) in the tamsulosin group and 24 cases (35.8%) in the placebo group (P = .345), resulting in an odds ratio of 0.701 and a risk difference of 7.69%. ConclusionProphylactic tamsulosin did not reduce the incidence of POUR after hip and knee arthroplasty compared to placebo. The odds ratio indicates an approximately 30% decreased odds of developing POUR in the tamsulosin group, albeit not statistically significant. Tamsulosin does not appear to be effective as a prophylactic measure for reducing POUR in male hip and knee arthroplasty patients.

Doxazosin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in military veterans

Posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD) are two of the most common mental health disorders affecting civilians as well as military populations. If left untreated, individuals with co-occurring PTSD/AUD are at increased risk for developing other mental health problems (e.g., depression, anxiety), physical health problems, reduced resiliency and military readiness, and vocational and social impairment. Substantial gaps in the treatment of co-occurring PTSD/AUD exist and there is a critical need to develop more effective pharmacological treatments. The current study addresses this gap in the literature by testing the efficacy and safety of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared to placebo in reducing PTSD and AUD severity among U.S. military veterans. Noradrenergic dysregulation has been implicated in the development and maintenance of PTSD and AUD, and pilot studies examining doxazosin in PTSD-only or AUD-only samples have shown promise. This is the first study, however, to evaluate doxazosin in a comorbid PTSD/AUD sample. This paper describes the rationale, design and methodology of a randomized, double-blind, placebo-controlled trial of doxazosin (16 mg/day) delivered over 12 weeks among military veterans with current PTSD and AUD. In addition, functional magnetic resonance imaging (fMRI) is applied at pre- and post-treatment to investigate the underlying pathophysiology of comorbid PTSD/AUD and identify prognostic indicators of treatment outcome. This study is designed to accelerate research on co-occurring PTSD/AUD and provide empirical evidence to inform clinical practice.

Adverse drug reaction with silodosin: a case report of an unusual skin rash

Silodosin is a selective alpha-1 adrenergic receptor antagonist approved for the treatment of lower urinary tract symptoms associated with benign prostatic hypertrophy. Adverse events include retrograde ejaculation, dizziness, diarrhea, vasodilator symptoms, and postural hypotension. Skin adverse reactions to silodosin such as eruption, purpura, and jaundice are uncommon. This article reports a case of unusual silodosin-related skin rash, Naranjo score 5, which regressed after applying combined intense pulsed light (IPL)/fractional CO2 laser/chemical treatments and drug interruption. Level of evidence: Level V, risk/prognostic.

Pseudoallergic conjunctivitis induced by tamsulosin, a selective alpha-1 adrenergic receptor antagonist

Pseudoallergic conjunctivitis induced by tamsulosin, a selective alpha-1 adrenergic receptor antagonist

Abstract 641: Renal Denervation does not Lower Blood Pressure in Spontaneously Hypertensive Rats Treated with a Beta-1 Adrenergic Receptor Antagonist.

We have used the SHR as an animal model to understand how renal denervation (RDN) lowers blood pressure. In order to determine how concomitant antihypertensive drug therapy could affect the blood pressure response to RDN, we performed RDN both before and after chronic (several days) treatment via the drinking water with the selective alpha-1 adrenergic antagonist prazosin and the selective beta-1 adrenergic antagonist atenolol. In the presence of prazosin treatment, RDN (n=7) significantly (p<0.05) lowered mean arterial pressure (MAP) compared to sham operated (SO; n=6) SHR (Δ=–4.0±1.7mmHg in RDN-SHR vs +1.5±1.3 in SO-SHR). Subsequent addition of atenolol during prazosin treatment reduced MAP significantly in both groups, but MAP in SO-SHR fell to the same level as in RDN-SHR, i.e. the antihypertensive effect of RDN was lost. After discontinuation of all drug treatment, the change in MAP from pre-treatment baseline was –7.7±3.5mmHg in RDN-SHR and +3.0±4.0mmHg in SO-SHR, p=0.06). To test whether the BP response to RDN would be lost during blockade of beta-1 adrenergic receptors alone, we performed RDN in SHR (n=5) pre-treated with atenolol. Atenolol alone significantly reduced MAP (Δ=-20.7±2.5mmHg). Steady-state MAP was not further reduced by RDN (Δ=+2.1±0.9mmHg). When atenolol was withdrawn MAP rose but remained reduced from baseline (Δ= -9.5±0.9mmHg). This magnitude of BP reduction is comparable to what we have previously observed after RDN in untreated SHR. In summary, in SHR RDN does not lower BP in the presence of an effective antihypertensive dose of a beta-1 antagonist. This indicates that RDN is reducing BP in SHR by interrupting a mechanism also affected by beta-1 adrenergic receptor signaling. Although further investigation is necessary, the data suggest that possibility that patients on clinically effective antihypertensive doses of beta-blockers may not exhibit a good response to RDN.

Combination therapy with dutasteride and tamsulosin for the treatment of symptomatic enlarged prostate

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5alpha-reductase inhibitors, 2) the alpha1-adrenergic antagonists, and 3) the combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist. Selective alpha1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that alpha1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5alpha-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. Interim results of the ongoing Combination of Avodart and Tamsulosin (CombAt) study have shown combination therapy with the 5alpha-reductase inhibitor dutasteride and the alpha1-adrenergic antagonist tamsulosin offer significant improvements from baseline compared with either drug alone.

The involvement of urothelial α1A adrenergic receptor in controlling the micturition reflex

The current study was undertaken in an attempt to characterize the functional properties of urothelial alpha1A adrenergic receptors, especially in modulating the micturition reflex. The expression of alpha1A receptors in rat bladder was analyzed by immunohistochemistry and Western blotting. As a functional study, we obtained continuous infusion cystometrograms in conscious rats using noradrenaline (NA) and subtype selective alpha1 adrenergic receptor antagonists, tamsulosin (alpha1A/alpha1D selective) and silodosin (alpha1A superselective). Alpha1A receptors were immunohistochemically detected in rat urothelium. Intravesical infusion of NA (60 microM) significantly shortened the intercontraction interval (ICI). Pretreatment with tamsulosin at a dose of 0.4 microg/kg i.v. abolished intravesical NA infusioninduced reduction of ICI. Neither intravesical infusion of tamsulosin (20 microM) nor that of silodosin (0.2 microM) significantly altered ICI. After intravesical infusion of silodosin, intravesical NA infusion did not affect ICI. Urothelial alpha1A receptors might modulate bladder afferent activity under pathophysiological conditions with augmented concentrations of NA in blood or urine.

Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats

Among antipsychotics, clozapine ranks highest in terms of the risk for weight gain and developing diabetes. However, the mechanism by which clozapine induces weight gain and diabetes remains unclear. The aim of this study was to determine the mechanism of clozapine-induced weight gain and hyperglycemia, and to clarify whether clozapine-induced hyperglycemia results from impairment of the system regulating appetite. Circulatory glucose, insulin, leptin and ghrelin levels were analyzed after acute administration of clozapine in rats. Clozapine (10 mg/kg) or a vehicle was injected intraperitoneally and blood samples were collected at 0, 15, 30, and 60 min after the injection. Clozapine (5, 10 or 20 mg/kg) or the vehicle was given, and blood samples were collected at 30 min after the injection. Since clozapine has receptor affinity for multiple neurotransmitters, selective antagonists of it, including dopamine, serotonin, alpha-adrenergic, muscarine and histamine were administered to clarify the pathway of clozapine-induced blood glucose and changes in plasma ghrelin. Clozapine administration increased the blood glucose level at all time points (p<0.05) compared to controls. Plasma ghrelin was elevated at 30 min (p=0.0124) and 60 min (p=0.00152). Blood glucose was increased in rats given 5 (p=0.0344), 10 (p<0.0001), or 20 mg/kg (p<0.0001) clozapine, while plasma ghrelin was increased in rats treated with 10 mg/kg (p=0.0009) or 20 mg/kg (p=0.0059) clozapine. Blood glucose was increased in rats treated with a selective alpha1-adrenergic receptor antagonist (p<0.0001), while plasma ghrelin was significantly increased in rats given a selective alpha1- (p=0.025) or alpha2-adrenergic receptor antagonist (p=0.0003). Clozapine impairs glucose metabolism and the appetite-regulation system. Clozapine increases blood glucose independent of insulin. The antagonistic action of alpha-adrenergic receptors is one of the mechanisms that induces both hyperglycemia and elevation of ghrelin.

Effects of adrenergic and cholinergic antagonists on diameter of nasolacrimal drainage system

To determine the effect of an adrenergic and a cholinergic antagonist on the diameter of the lumen of the nasolacrimal drainage system. The asymptomatic side of 38 patients (29 women, nine men) with unilateral stenosis/obstruction of the nasolacrimal drainage system was studied. The tear meniscus height (TMH) of the asymptomatic side was normal, and the lacrimal drainage system was patent as revealed by dacryocystography. The nasolacrimal drainage system of the asymptomatic side was infused with 100 mul of 0.01% bunazosin hydrochloride, a selective alpha-1 adrenergic antagonist, or 100 mul of 0.4% tropicamide, a muscarinic and cholinergic antagonist. Dacryocystography was performed to determine the diameter of the lumen of the nasolacrimal drainage system before and after the antagonists. Bunazosin reduced the diameter of the lumen significantly, and the changes were more marked in the nasolacrimal duct (NLD), especially the middle and the lower regions. The diameter of the lumen of the lacrimal sac was not changed significantly. In contrast, tropicamide did not cause any significant change in the diameter of the lumen of the nasolacrimal drainage system. The alterations of the size of the lumen of the nasolacrimal drainage system, especially the NLD, by an adrenergic antagonist suggest that the lumen diameter is under continuous sympathetic tone, and the parasympathetic tone is weak.

Update on the use of dutasteride in the management of benign prostatic hypertrophy

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection, and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5alpha-reductase inhibitors, 2) the alpha1-adrenergic antagonists, and 3) the combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist. Selective alpha1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that alpha1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5alpha-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. The combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist reduces the clinical progression of BPH over either class of drug alone.

Long-term reduction of intimal hyperplasia by the selective alpha-1 adrenergic antagonist doxazosin.

Studies have shown that alpha 1-adrenergic blockade reduces intimal hyperplasia in the rabbit aorta. In this study a selective alpha 1-adrenergic antagonist, doxazosin, has been used to examine whether this effect is persistent and dose dependent. Forty-eight New Zealand White rabbits underwent endothelial denudation of the abdominal aorta using a Fogarty balloon catheter. Test rabbits were given low-dose (2 mg) or high-dose (8 mg) doxazosin daily and all animals killed at either 1 or 12 weeks after the procedure. The aortas were harvested after fixation in situ with 4 per cent glutaraldehyde and neointimal hyperplasia was measured, using an x-y digitizer, as the percentage reduction in luminal cross-sectional area. At 1 week after surgery, rabbits receiving the low dose had a median area reduction of 7.7 per cent and those receiving the high dose a reduction of 8.2 per cent; both had significantly less intimal hyperplasia than control rabbits, which had a median area reduction of 14.8 per cent (P < 0.01). However, at 12 weeks, when compared with the 32.6 per cent reduction in the control group, only those rabbits receiving high-dose doxazosin had significantly less intimal hyperplasia, with a reduction of 5.5 per cent (P < 0.001). It is concluded that selective alpha 1-adrenergic blockade significantly reduces neointimal hyperplasia, that this effect is dose dependent, and that it persists for at least 3 months.

Phenylpropanolamine Constricts Mouse and Human Blood Vessels by Preferentially Activating α2-Adrenoceptors

Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an alpha1-adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor alpha2-adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular alpha2-adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective alpha1-adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective alpha2-adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective alpha2-adrenergic antagonist, rauwolscine (10(-7) M) but was abolished by the selective alpha1-adrenergic antagonist, prazosin (3 x 10(-7) M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential alpha2-adrenergic agonist. At low concentrations, it constricts blood vessels that express functional alpha2-adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular alpha1-adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.

Buspirone raises blood pressure through activation of sympathetic nervous system and by direct activation of alpha1-adrenergic receptors after severe hemorrhage.

5-Hydroxytryptamine 1A (5-HT1A) receptor agonists reverse the hypotensive and sympathoinhibitory responses to severe hemorrhage in rats. To determine whether 5-HT1A receptor-mediated pressor responses in hypovolemic animals are due to sympathoexcitation and/or direct vasoconstriction, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to the partial 5-HT1A receptor agonist buspirone or the more selective, full 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were compared in intact and ganglionic blocked, hemorrhaged Sprague-Dawley rats. Buspirone produced dose-dependent increases in BP (110 +/- 4(**), 86 +/- 4(**), 65 +/- 7 mm Hg), HR [369 +/- 10(**), 337 +/- 14, 277 +/- 16 beats per minute (bpm)], and RSNA (114 +/- 36(**), 34 +/- 21, -23 +/- 25% baseline for 0.2, 0.1, and 0 mg/kg; (**)p < 0.01 versus 0 mg/kg, 3 min after injection). Ganglionic blockade with hexamethonium chloride blocked the pressor effect of 9.9 microg/kg 8-OH-DPAT and attenuated, but did not block, the pressor response to 0.2 mg/kg buspirone (85 +/- 7 versus 46 +/- 6 mm Hg for buspirone + ganglionic blockade versus saline + ganglionic blockade; p < 0.01). In subsequent tests, rats treated with the selective alpha1-adrenergic receptor antagonist prazosin (25 microg/kg) continued to show extensive tachycardic (+73 +/- 26 bpm) and sympathoexcitatory (128 +/- 55% baseline) responses to 0.2 mg/kg buspirone. Ganglionic blockade combined with prazosin completely blocked all responses to buspirone. Buspirone (0.2 mg/kg) produced significant bradycardic (-89 +/- 12 bpm; p < 0.01) and sympathoinhibitory (-72 +/- 7% baseline; p < 0.01) responses in euvolemic rats 3 min after injection. It is concluded that the pressor effect of buspirone is unique to hypovolemic animals and is mediated by sympathetic activation as well as direct activation of vascular alpha1-adrenergic receptors.

Visceral Afferent Bias on Cortical Processing: Role of Adrenergic Afferents to the Basal Forebrain Cholinergic System.

Intraperitoneal epinephrine enhances the cerebral auditory evoked potential (AEP), an effect that is dependent on the basal forebrain cortical cholinergic system. The present study examined the hypothesis that ascending noradrenergic projections from brainstem autonomic substrates to the basal forebrain cholinergic system represent an essential component of the ascending pathway mediating this effect of epinephrine. Epinephrine again enhanced the AEP in rats, and this effect was attenuated by infusion of the selective alpha1 adrenergic antagonist terazosin into the basal forebrain. Moreover, infusions of the selective alpha1 adrenergic agonist phenylephrine into the basal forebrain mimicked the priming effects of epinephrine. Results support the hypothesis that noradrenergic afferents to the basal forebrain cholinergic system represent a component of an ascending visceral afferent system.

Alpha Blocker Therapy for Children With Dysfunctional Voiding and Urinary Retention

Alpha blocker therapy has been successfully used to decrease residual urine in children with complex neuropathic and nonneuropathic voiding dysfunction. We evaluated the safety and efficacy of using selective alpha blocker therapy for children with uncomplicated voiding dysfunction and underlying poor bladder emptying. A total of 55 patients with a mean age of 7.9 years presented with symptoms of urinary incontinence, urgency and urinary tract infection. All patients had increased post-void residual (PVR) on bladder ultrasound, with a mean residual volume of 65 ml (22% of age expected capacity). All patients were treated with doxazosin, a selective alpha-1 adrenergic antagonist, at dosages of 0.5 mg to 2.0 mg daily. Of the patients 38 were treated at presentation with a regimen of anticholinergics, timed voiding and antibiotic prophylaxis before initiating alpha blocker therapy. Patients were reevaluated with post-void ultrasound of the bladder 6 weeks after initiating alpha blocker therapy. After starting doxazosin average PVR decreased to 8 ml (p <0.0001), representing an 88% reduction in residual urine (or reduction to only 2.7% of age expected bladder capacity). Medication was discontinued in 2 patients due to minor side effects. Selective alpha blocker therapy appears to be effective for improving bladder emptying in children with an overactive bladder, wetting, recurrent infection and increased PVR urine. This therapy may be used as either a replacement or in addition to biofeedback in patients with urinary retention. Further investigation, including a prospective randomized trial of alpha blocker therapy in children with urinary tract dysfunction, is warranted based on the findings of our study.