Dissociable effects of systemic and orbitofrontal administration of adrenoceptor antagonists on yohimbine-induced motor impulsivity.

The α2-adrenoceptor antagonist, yohimbine, is commonly used as a pharmacological stressor. Its behavioural effects are typically attributed to elevated noradrenaline release via blockade of central, inhibitory autoreceptors. We have previously reported that yohimbine increases motor impulsivity in rats on the five-choice serial reaction time task (5CSRTT), a cognitive behavioural assessment which measures motor impulsivity and visuospatial attention. Furthermore, this effect depended on cyclic adenomonophosphate (cAMP) signalling via cAMP response element binding (CREB) protein in the orbitofrontal cortex (OFC). However, the role of specific adrenoceptors in this effect is not well-characterised. We therefore investigated whether the pro-impulsive effects of systemic yohimbine could be reproduced by direct administration into the OFC, or attenuated by intra-OFC or systemic administration of prazosin and propranolol-antagonists at the α1- and ß-adrenoceptor, respectively. Male Long-Evans rats were trained on the 5CSRTT and implanted with guide cannulae aimed at the OFC. Systemically administered α1- or ß-adrenoceptor antagonists attenuated yohimbine-induced increases in premature responding. In contrast, local infusion of yohimbine into the OFC reduced such impulsive responding, while blockade of α1- or ß-adrenoceptors within the OFC had no effect on either basal or yohimbine-stimulated motor impulsivity. Direct administration of selective antagonists at the α1-, α2- or ß-adrenoceptor into the OFC therefore produce clearly dissociable effects from systemic administration. Collectively, these data suggest that the pro-impulsivity effect of yohimbine can be modulated by adrenergic signalling in brain areas outside of the OFC, in addition to non-adrenergic signalling pathways within the OFC.

Evidence for the involvement of peripheral -adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg·kg−1·day−1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 µg PRO or V. The groups were treated iv with saline or with 240 µmol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean±SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7±1.6 vs 47.1±2.3%) and of At (33.2±2.3 vs 54.7±3.6%) on GE and significantly reduced the effect of AA (48.1±3.2 vs 67.2±3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean±SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1±1.7 vs 46.9±2.7%) and At (30.5±1.7 vs 49±3.2%) and significantly reduced the effect of AA (48.4±2.6 vs 59.5±3.1%). These data suggest activation of peripheral β-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.

The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters.

Kisspeptins are G protein-coupled receptor ligands originally identified as human metastasis suppressor gene products that have the ability to suppress melanoma and breast cancer metastasis and recently found to play an important role in initiating the secretion of gonadotropin-releasing hormone at puberty. Kisspeptin-13 is an endogenous isoform that consists of 13 amino acids. The action of kisspeptin in the regulation of gonadal function has been widely studied, but little is known as concerns its function in limbic brain structures. In the brain, the gene is transcribed within the hippocampal dentate gyrus. This paper reports on a study the effects of kisspeptin-13 on passive avoidance learning and the involvement of the adrenergic, serotonergic, cholinergic, dopaminergic and GABA-A-ergic, opiate receptors and nitric oxide in its action in mice. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α2-adrenergic receptor antagonist, yohimbine, a ß-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, D2, D3, D4 dopamine receptor antagonist, haloperidol, a γ-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, naloxone, a nonselective opioid receptor antagonist and nitro-l-arginine, a nitric oxide synthase inhibitor. Kisspeptin-13 facilitated learning and memory consolidation in a passive avoidance paradigm. Phenoxybenzamine, yohimbine, propranolol, methysergide, cyproheptadine, atropine, bicuculline and nitro-l-arginine prevented the action of kisspeptin-13 on passive avoidance learning, but haloperidol and naloxone did not block the effects of kisspeptin-13. The results demonstrated that the action of kisspeptin-13 on the facilitation of passive avoidance learning and memory consolidation is mediated, at least in part, through interactions of the α2-adrenergic, beta-adrenergic, 5-HT2 serotonergic, muscarinic cholinergic and GABA-A-ergic receptor systems and nitric oxide.

Reduction of oedema formation after preconditioning with dopamine in an isolated rat lung model is mediated by adrenergic receptors.

BACKGROUND: Donor treatment with dopamine (DA) is an effective modality to improve organ quality by reduction of hypothermic, ischemic and reperfusion (I/R) injury. It is unknown by which mechanism DA reduces oedema formation and inflammation. Therefore we tested the first time in an isolated rat lung model if dopaminergic or adrenergic receptors are involved. MATERIAL/METHODS: Rats were treated for 1 hr with NaCl, DA or simultaneously with DA alpha- beta- D1- or D2-receptor blockers. Thereafter lungs were explanted, flushed with Perfadex-solution and stored at 4°C. Peak inspiratory pressure (PIP), pulmonary arterial pressure (PAP) and lung weight were measured during reperfusion of 3 hrs. Inflammatory mediators and the expression of adhesion molecules were measured after perfusion. RESULTS: Up to 6 hours of hypothermia did not influence oedema formation or PIP and PAP during reperfusion time. However, hypothermia after 8 hrs significantly increased PIP, PAP and pulmonary oedema in NaCl, alpha- and beta-blocker treated lungs, but significantly not in DA, D1- or D2-blocker treated lungs. Perfusion and ventilation alone induced a strong upregulation of cytokine-induced neutrophil chemoattractant-1 and adhesion molecules in untreated, alpha- and beta-blocker treated lungs, while in DA, D1- and D2-blocker treated lungs significant lower levels were found. CONCLUSIONS: Our study suggests that dopamine mediated protective effects on I/R damage and inflammation in donor lungs are most likely mediated via adrenergic receptors. These findings are highly relevant because new strategies for organ preservation are necessary in terms of long donation waiting lists.

Safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia.

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are highly prevalent in older men. Medical therapy is the first-line treatment for LUTS associated with BPH. Mainstays in the treatment of male LUTS and clinical BPH are the α(1)-adrenergic receptor antagonists. Silodosin is a new α(1)-adrenergic receptor antagonist that is selective for the α(1A)-adrenergic receptor. By antagonizing α(1A)-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. Since silodosin has greater affinity for the α(1A)-adrenergic receptor than for the α(1B)-adrenergic receptor, it minimizes the propensity for blood pressure-related adverse effects caused by α(1B)-adrenergic receptor blockade. In the clinical studies, patients receiving silodosin at a total daily dose of 8 mg exhibited significant improvements in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving placebo. Silodosin showed early onset of efficacy for both voiding and storage symptoms. Furthermore, long-term safety of silodosin was also demonstrated. Retrograde or abnormal ejaculation was the most commonly reported adverse effect. The incidence of orthostatic hypotension was low. In conclusion, silodosin, a novel selective α(1A)-adrenergic receptor antagonist, was effective in general and without obtrusive side effects. This review provides clear evidence in support of the clinical usefulness of silodosin in the treatment of LUTS associated with BPH.

The effects of carvedilol administration on cardiopulmonary resuscitation in a rat model of cardiac arrest induced by airway obstruction.

BACKGROUND: Carvedilol is a nonselective ß-adrenoceptor and selective α(1)-adrenoceptor blocker and is widely used in the treatment of patients with hypertensive and/or chronic heart failure because, unlike classic ß-blockers, this drug has additional endothelium-dependent vasodilatory effects. We evaluated the effects of oral administration of carvedilol on cardiopulmonary resuscitation (CPR) in a rat model of cardiac arrest (CA) induced by airway obstruction. METHODS: Twenty-four rats were randomly assigned to 2 groups: control group (no medication) and treatment group (oral administration of carvedilol [10 mg/kg/d] for 5 days) (n = 12 per group). All the animals were anesthetized, and CA was induced by obstructing the airway. Three minutes after CA, the animals were revived by administering CPR. The rate of chest compressions (CCs) was 240 to 260 CCs/min and the depth of CCs was adjusted to maintain the diastolic arterial blood pressure between 25 to 30 mm Hg in both groups. Epinephrine (0.02 mg/kg) was administered after 5 minutes of CPR. No other therapy was administered before, during, or after CA. RESULTS: The time interval between airway obstruction and CA in the treatment group was significantly longer than in the control group (230 ± 27 vs 203 ± 24 seconds; P < 0.05). The rate of return of spontaneous circulation in the treatment group was significantly higher than in the control group (92% vs 50%; P < 0.05). Acidosis and increased glucose and tumor necrosis factor-α concentrations in the treatment group were significantly lower than in the control group. CONCLUSIONS: The results of our study showed that rats that had been administered oral carvedilol for several days were more resistant to CA induced by airway obstruction, and when CA did occur, were more likely to be resuscitated. These findings suggest that carvedilol may prolong the safe ischemic time induced by respiratory failure.

UGT2B7*3 did not affect the pharmacokinetics of R- and S-carvedilol in healthy Japanese.

We previously investigated the pharmacokinetics of R- and S-carvedilol in 54 healthy Japanese subjects, and reported that the oral clearance (CL/F) and apparent volume of distribution (V/F) of both enantiomers in subjects with the CYP2D6*10 allele were significantly lower than those in subjects without the CYP2D6*10 allele. In the present study, we examined the genotype of UGT2B7 in these 54 subjects, and investigated the effect of UGT2B7*3 on the pharmacokinetics of R- and S-carvedilol. Forty-three subjects did not have the UGT2B7*3 allele, and 11 subjects had one UGT2B7*3 allele. CL/F and V/F values of R- and S-carvedilol in the subjects with one UGT2B7*3 allele were similar to those without the UGT2B7*3 allele, indicating that the UGT2B7*3 allele did not significantly affect the systemic clearance (CL) and bioavailability (F) of the two enantiomers.

Activation of BKCa channels via cyclic AMP- and cyclic GMP-dependent protein kinases by eugenosedin-A in rat basilar artery myocytes.

BACKGROUND AND PURPOSE: The study investigated whether eugenosedin-A, a 5-hydroxytryptamine and alpha/beta adrenoceptor antagonist, enhanced delayed-rectifier potassium (K(DR))- or large-conductance Ca(2+)-activated potassium (BK(Ca))-channel activity in basilar artery myocytes through cyclic AMP/GMP-dependent and -independent protein kinases. EXPERIMENTAL APPROACH: Cerebral smooth muscle cells (SMCs) were enzymatically dissociated from rat basilar arteries. Conventional whole cell, perforated and inside-out patch-clamp electrophysiology was used to monitor K(+)- and Ca(2+)-channel activities. KEY RESULTS: Eugenosedin-A (1 microM) did not affect the K(DR) current but dramatically augmented BK(Ca) channel activity in a concentration-dependent manner. Increased BK(Ca) current was abolished by charybdotoxin (ChTX, 0.1 microM) or iberiotoxin (IbTX, 0.1 microM), but not affected by a small-conductance K(Ca) blocker (apamin, 100 microM). BK(Ca) current activation by eugenosedin-A was significantly inhibited by an adenylate cyclase inhibitor (SQ 22536, 10 microM), a soluble guanylate cyclase inhibitor (ODQ, 10 microM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100 microM and Rp-cGMP, 100 microM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3 microM and KT5823, 0.3 microM). Eugenosedin-A reversed the inhibition of BK(Ca) current induced by the protein kinase C activator, phorbol myristyl acetate (PMA, 0.1 microM). Eugenosedin-A also prevented BK(Ca) current inhibition induced by adding PMA, KT5720 and KT5823. Moreover, eugenosedin-A reduced the amplitude of voltage-dependent L-type Ca(2+) current (I(Ca,L)), but without modifying the voltage-dependence of the current. CONCLUSIONS AND IMPLICATIONS: Eugenosedin-A enhanced BK(Ca) currents by stimulating the activity of cyclic nucleotide-dependent protein kinases. Physiologically, this activation would result in the closure of voltage-dependent calcium channels and thereby relax cerebral SMCs.

Glomus jugulare tumors with intracranial extension.

Glomus tumors provide unique surgical challenges for both tumor resection and defect reconstruction. Tumors with intracranial extension compound these challenges. Surgical techniques have evolved, and now, with a multidisciplinary team, single-stage surgeries are the standard. In this paper the authors will report the results of the Otology Group protocol for surgical management of glomus tumors with intracranial extension. Particular attention will be paid to prevention of cerebrospinal fluid leaks with the use of vascularized tissue for defect reconstruction.

Uso de los antagonistas Beta-adrenérgicos en la hipertensión arterial / Antagonist adrenergic beta use in the arterial hypertension

Los Betabloqueantes son drogas que inhiben competitivamente a los receptores beta-adrenérgicos, modulando la actividad de el sistema nervioso simpático. Estos son normalmente clasificados en base a su selectividad por los receptores beta. Los beta bloqueantes no selectivos, como propanolol, pindolol, nadolol, timolol y labetalol antagonizan los receptores B1 y B2. Los beta-bloqueantes selectivos, como el metoprolol, atenolol, esmolol y acebutolol tienen mayor afinidad por los receptores B-1. Los beta-bloqueantes selectivos están indicados en pacientes en quienes el bloqueo B-2 puede asociar un aumento en el riesgo de efectos adversos. Como en pacientes asmáticos o diabéticos, así como en pacientes con enfermedad vascular periférica o enfermedad de Raynaud. Algunos betabloqueantes tienen actividad agonista parcial (actividad simpático mimétrica intrínseca). Los beta-bloqueantes, como monoterapia o combinados con otras drogas han probado que tienen efectividad en la reducción de síntomas de angina de pecho y reducción de la morbi-mortalidad después del infarto al miocardio. Además son las drogas de elección en pacientes con hipertensión arterial e infarto al miocardio o angina. Muchos beta-bloqueantes son comúnmente usados en el tratamiento de pacientes con migraña recurrente, cardiomiopatía hipertrófica obstructiva, ansiedad aguda y en casos de glaucoma. En este artículo se presenta una revisión detallada sobre los beta-bloqueantes en el tratamiento de la hipertension arterial

[NO synthase activity in epitheliocytes of the rat bronchi following inhalation administration of adrenergic agonists and guanosine triphosphate]. / Aktivnost' NO-sintazy épiteliotsitov bronkhov krys pri ingaliatsionnom vvedenii adrenoagonistov i guanozintrifosfata.

NO synthase was studied in intact rats and in rats with bronchial asthma epitheliocytes after inhalation of phenotherol, propranolol, guanosine triphosphate (GTP) and combined inhalation of GTP with phenotherol. NO synthase mediator action on bronchial patency during adrenoagonists and GTP inhalation was demonstrated.

Pituitary-adrenal, hormonal changes during induced hypotension with labetol or isoflurane for middle-ear surgery.

BACKGROUND: Pituitary-adrenal secretion during induced hypotension for middle-ear surgery has received little attention. Previous work failed to differentiate the effects of induced hypotension from surgical stimulation. We have undertaken a preliminary study examining the effects of hypotension, achieved with labetalol or isoflurane, on pituitary-adrenal secretion before, during and after middle-ear surgery. METHODS: Twenty-four patients were allocated randomly to 3 groups. The control group were anaesthetised with isoflurane, and normotension maintained for 30 min before hypotension was induced with isoflurane and surgery started. In the labetalol group, this drug was given i.v. to obtain a mean arterial pressure (MAP) of 60 mm Hg for 30 min before surgery and hypotension maintained with labetalol during the operation. In the isoflurane group, hypotension was induced to a MAP of 60 mm Hg for 30 min before surgery and continued throughout the procedure. All 3 groups received metoprolol i.v. before hypotension was established. Blood samples were collected before induction of anaesthesia, during anaesthesia alone (normotensive or hypotensive), surgery with hypotension, and recovery. They were analysed for adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP), cortisol and aldosterone. RESULTS: Induced hypotension before surgery failed to stimulate release of ACTH, AVP and cortisol. No significant increase in these hormones occurred until the postoperative period. Aldosterone concentrations increased significantly during anaesthesia and hypotension in the labetalol and isoflurane groups (P<0.05) and continued to rise significantly in all 3 groups during surgery. However, there was no significant difference in aldosterone concentration before surgery between the control and the 2 hypotensive groups. CONCLUSION: ACTH, AVP and cortisol secretion were not stimulated by induced hypotension to MAP of 60 mm Hg before surgery. Increased aldosterone secretion occurred and a further study with a larger sample size is needed.