Adrenoceptor Inhibition Research Articles

WP1.1 - Examining the effectiveness of prescribing Tamsulosin before elective surgery for inguino-scrotal hernias - a case series

Abstract Aims Urinary retention following surgery is a common issue that can result in significant morbidity and prolonged hospital admissions. Tamsulosin is commonly used to manage patients at risk of urinary retention in the community but its usefulness at preventing retention following surgery is currently unclear. This case series describes the effectiveness of using short courses of tamsulosin to prevent post-operative urinary retention at a single centre. Methods Males aged over 70 who underwent elective surgery for an inguino-scrotal hernia between January 2022 and January 2024 were included in this series. Inclusion also required the patients to be planned as day case procedures under general anaesthetic. Patients with a known history of prostatic disease and/or who were already taking Tamsulosin or another alpha-1 adrenoceptor inhibitor were excluded. Results 67 patients who took 400 micrograms of Tamsulosin once daily for 2 days before and on the day of surgery were included in this series. The patients were aged between 70 - 89 years and all underwent elective open mesh hernia repairs under the same surgeon with the same materials. None of the patients suffered post-operative urinary retention and so were able to be discharged as day cases. Conclusions The absence of any instances of post-operative urinary retention in this series suggests that a course of Tamsulosin before elective inguino-scrotal hernia repair can effective as prophylaxis against the condition. This data alongside additional randomised control trials demonstrating the benefits of pre-operative Tamsulosin may result in it being used more widely.

α1A Adrenoreceptor blockade attenuates myocardial infarction by modulating the integrin-linked kinase/TGF-β/Smad signaling pathways

BackgroundMyocardial infarction (MI) is considered a public health problem. According to the World Health Organization, MI is a leading cause of death and comorbidities worldwide. Activation of the α1A adrenergic receptor is a contributing factor to the development of MI. Tamsulosin, an α1A adrenergic blocker, has gained wide popularity as a medication for the treatment of benign prostatic hyperplasia. Limited evidence from previous studies has revealed the potential cardioprotective effects of tamsulosin, as its inhibitory effect on the α1A adrenoceptor protects the heart by acting on the smooth muscle of blood vessels, which results in hypotension; however, its effect on the infarcted heart is still unclear. The mechanisms of the expected cardioprotective effects mediated by tamsulosin are not yet understood. Transforming growth factor-beta (TGF-β), a mediator of fibrosis, is considered an attractive therapeutic target for remodeling after MI. The role of α1A adrenoceptor inhibition or its relationships with integrin-linked kinase (ILK) and TGF-β/small mothers against decapentaplegic (Smad) signaling pathways in attenuating MI are unclear. The present study was designed to investigate whether tamsulosin attenuates MI by modulating an ILK-related TGF-β/Smad pathway.MethodsTwenty-four adult male Wistar rats were randomly divided into 4 groups: control, ISO, TAM, and ISO + TAM. ISO (150 mg/kg, intraperitoneally) was injected on Days 20 and 21 to induce MI. Tamsulosin (0.8 mg/kg, orally) was administered for 21 days, prior to ISO injection for 2 consecutive days. Heart-to-body weight ratios and cardiac and fibrotic biomarker levels were subsequently determined. ILK, TGF-β1, p-Smad2/3, and collagen III protein expression levels were determined using biomolecular methods.ResultsTamsulosin significantly attenuated the relative heart-to-body weight index (p < 0.5) and creatine kinase-MB level (p < 0.01) compared with those in the ISO control group. While ISO resulted in superoxide anion production and enhanced oxidative damage, tamsulosin significantly prevented this damage through antioxidant defense mechanisms, increasing glutathione and superoxide dismutase levels (p < 0.05) and decreasing lipid peroxide oxidation levels (p < 0.01). The present data revealed that tamsulosin reduced TGF-β/p-Smad2/3 expression and enhanced ILK expression.ConclusionTamsulosin may exert a cardioprotective effect by modulating the ILK-related TGF-β/Smad signaling pathway. Thus, tamsulosin may be a useful therapeutic approach for preventing MI.

Overlooked switch from transient sedation to sustained excitement in the Biphasic effects of Ephedra Herb extract administered orally to mice

Ethnopharmacological relevanceIn our previous study, we reported that Ephedra Herb extract (EHE) increased the locomotor activity of mice in the open-field test and reduced the immobility time in the forced swim test. Ephedrine alkaloids (EAs) are thought to be responsible for the adverse effects of Ephedra Herb. However, there are no reports to verify that the adverse effects of Ephedra Herb are caused by the amount of EAs in the herb. Therefore, we investigated whether these adverse effects of EHE are caused by the amounts of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract. In a preliminary study of the time course analysis of the open field test, we newly observed that EHE evoked switching from transient sedation to sustained excitement. Aim of the studyWe aimed to confirm whether EHE evokes switching from transient sedation to sustained excitement, investigate whether these actions of EHE are caused by the amount of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract, and clarify the molecular mechanism of the transient sedative effect. Materials and methodsThe locomotor activity of mice was tested using the open-field test. The immobility times were measured using a forced swim test, and the motor dysfunction in mice was tested using the rotarod test. ResultsEHE, Eph, and Pse induced transient motionlessness between 0 and 15 min after oral administration, however, they did not induce depression-like behavior and motor dysfunction in mice, suggesting that the motionlessness induced by EHE, Eph, or Pse resulted from sedation. The α2a adrenoceptor inhibitor, atipamezole, decreased their sedative effects. Thus, immediately after EHE administration, the transient sedative effect is mediated through the activation of the α2a adrenoreceptor by Eph and Pse. EHE and Eph increased total locomotor activity for 15–120 min after oral administration; however, Pse had no effect. Therefore, the slow-onset and sustained excitatory effects of EHE are mediated by Eph. ConclusionsWe discovered for the first time that EHE evokes diphasic action by switching from transient sedation to sustained excitement. The transient sedation was evoked by the Eph and Pse in the herbal extract via activation of the α2a adrenoceptor and the sustained excitement was caused by the Eph in the herbal extract.

Dexmedetomidine-Induced Aortic Contraction Involves Transactivation of the Epidermal Growth Factor Receptor in Rats.

In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH2-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10−6 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.

Dexmedetomidine attenuates sevoflurane‑induced neurocognitive impairment through α2‑adrenoceptors.

It has been reported that sevoflurane induces neurotoxicity in the developing brain. Dexmedetomidine is an α2 adrenoceptor agonist used for the prevention of sevoflurane-induced agitation in children in clinical practice. The aim of the present study was to determine whether dexmedetomidine could prevent sevoflurane-induced neuroapoptosis, neuroinflammation, oxidative stress and neurocognitive impairment. Additionally, the involvement of α2 adrenoceptors in the neuroprotective effect of dexmedetomidine was assessed. Postnatal day (P)6 C57BL/6 male mice were randomly divided into four groups (n=6 in each group). Mice were pretreated with dexmedetomidine, either alone or together with yohimbine, an α2 adrenoceptor inhibitor, then exposed to 3% sevoflurane in 25% oxygen. Control mice either received normal saline alone or with sevoflurane exposure. Following sevoflurane exposure, the expression of cleaved caspase-3 was detected by immunohistochemistry in hippocampal tissue sections. In addition, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and malondialdehyde, as well as superoxide dismutase (SOD) activity in the hippocampus were measured. At P35, the learning and memory abilities were assessed in each mouse using a Morris water maze test. Dexmedetomidine significantly decreased the expression of activated caspase-3 following sevoflurane exposure. Moreover, dexmedetomidine significantly decreased the levels of TNF-α, IL-1β and IL-6 in the hippocampus. SOD activity also increased in a dose-dependent manner in dexmedetomidine-treated mice. MDA decreased in a dose-dependent manner in dexmedetomidine-treated mice. Lastly, sevoflurane-induced learning and memory impairment was reversed by dexmedetomidine treatment. By contrast, co-administration of yohimbine significantly attenuated the neuroprotective effects of dexmedetomidine. These findings suggested that dexmedetomidine exerted a neuroprotective effect against sevoflurane-induced apoptosis, inflammation, oxidative stress and neurocognitive impairment, which was mediated, at least in part, by α2 adrenoceptors.

Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo

Background: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β₃-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. Objective: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of β₃-adrenoceptors and adiponectin. Method: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). Results: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using β₃-adrenoceptor inhibition, and activation of β₃-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The β₃-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon β₃-adrenoceptor activation. Conclusions: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte β₃-adrenoceptors, which may trigger release of the vasodilator adiponectin.

Naftopidil reduced the proliferation of lung fibroblasts and bleomycin-induced lung fibrosis in mice.

Naftopidil, an α‐1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α‐1 adrenoceptor inhibitor. We examined the incorporation of 5‐bromo‐2ʹ‐deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme‐linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound‐healing assay, and mRNA expressions of type IV collagen and α‐smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin‐induced lung fibrosis in mice were evaluated using histology, micro‐computed tomography, and surfactant protein‐D levels in serum. Naftopidil, dose‐dependently but independently of phenoxybenzamine, inhibited 5‐bromo‐2ʹ‐deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α‐smooth muscle actin in one normal lung fibroblast line. Histological and micro‐computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein‐D levels in bleomycin‐induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

Dexmedetomidine-induced contraction involves c-Jun NH2 -terminal kinase phosphorylation through activation of the 5-lipoxygenase pathway in the isolated endothelium-denuded rat aorta.

Vasoconstriction induced by dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist, mainly involves c-Jun NH2 -terminal kinase (JNK) phosphorylation in the isolated endothelium-denuded aorta. We carried out an in vitro study to determine the main arachidonic acid metabolic pathway that is involved in dexmedetomidine-induced JNK activation. Cumulative dexmedetomidine concentration-contractile response curves were generated in the endothelium-denuded rat aorta in the presence or absence of the following inhibitors: the JNK inhibitor SP600125, the phospholipase A2 inhibitor quinacrine dihydrochloride, the non-specific lipoxygenase (LOX) inhibitor nordihydroguaiaretic acid, the 5-LOX inhibitor AA-861, the dual 5-LOX and cyclooxygenase (COX) inhibitor phenidone, the non-specific COX inhibitor indomethacin, the cytochrome p450 epoxygenase inhibitor fluconazole, the COX-1 inhibitor SC-560, and the COX-2 inhibitor NS-398. The effect of the alpha-2 adrenoceptor inhibitor rauwolscine and other inhibitors, such as quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone, indomethacin and the protein kinase C inhibitor GF 109203X, on dexmedetomidine-induced JNK phosphorylation was investigated in rat aortic vascular smooth muscle cells with western blotting. The effect of dexmedetomidine on 5-LOX and COX-2 expression was investigated in vascular smooth muscle cells. SP600125, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone, rauwolscine and chelerythrine attenuated dexmedetomidine-induced contraction. Indomethacin slightly attenuated dexmedetomidine-induced contraction. Fluconazole and SC-560 had no effect on dexmedetomidine-induced contraction, whereas NS-398 attenuated contraction. SP600125, rauwolscine, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone and GF 109203X attenuated dexmedetomidine-induced JNK phosphorylation. 5-LOX and COX-2 were upregulated by dexmedetomidine. Thus, dexmedetomidine-induced alpha-2 adrenoceptor-mediated contraction is mediated mainly by 5-LOX and partially by COX-2, which leads to JNK phosphorylation.

Effects of hippadine on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats

Ethnopharmacological relevanceHippadine is an alkaloid isolated from Crinum macowanii. Crinum macowanii is used in South Africa to treat oedema, ‘heart disease’, rheumatic fever, cancer and skin diseases, and belongs to the plant family Amaryllidaceae, assumed to have originated in the South African region. The aim of this study was to evaluate the effect of hippadine, an alkaloid extracted from Crinum macowanii, on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive Wistar rats (SHR); and to find out if α1 and⧸or β1 adrenoceptors contribute to its effects. Materials and methodsHippadine (2.5–12.5mg/kg), adrenaline (0.05–0.20mg/kg), atenolol (0.5–40mg/kg) and prazosin hydrochloride (100–500µg/kg) were infused intravenously, and the BP and HR measured via a pressure transducer connecting the femoral artery and the PowerLab.Adrenaline increased the systolic, diastolic and mean arterial BP, while hippadine, atenolol and prazosin respectively decreased the systolic, diastolic and mean arterial BP. Increases in HR were observed with both adrenaline and prazosin, while reductions in HR were observed with atenolol and hippadine. Infusion of adrenaline in rats pre-treated with atenolol (30mg/kg), prazosin (400µg/kg), and hippadine (10mg/kg) led to similar increases in BP and HR in all groups. All changes in HR or BP were significant (p<0.05) and dose dependent. ConclusionHippadine decreases the BP and HR in SHR, and these effects may be due to α1 and β1 adrenoceptor inhibition.

Dexmedetomidine-induced contraction involves phosphorylation of caldesmon by JNK in endothelium-denuded rat aortas.

Caldesmon, an inhibitory actin binding protein, binds to actin and inhibits actin-myosin interactions, whereas caldesmon phosphorylation reverses the inhibitory effect of caldesmon on actin-myosin interactions, potentially leading to enhanced contraction. The goal of this study was to investigate the cellular signaling pathway responsible for caldesmon phosphorylation, which is involved in the regulation of the contraction induced by dexmedetomidine (DMT), an alpha-2 adrenoceptor agonist, in endothelium-denuded rat aortas. SP600125 (a c-Jun NH2-terminal kinase [JNK] inhibitor) dose-response curves were generated in aortas that were pre-contracted with DMT or phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Dose-response curves to the PKC inhibitor chelerythrine were generated in rat aortas pre-contracted with DMT. The effects of SP600125 and rauwolscine (an alpha-2 adrenoceptor inhibitor) on DMT-induced caldesmon phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) were investigated by western blot analysis. PDBu-induced caldesmon and DMT-induced PKC phosphorylation in rat aortic VSMCs was investigated by western blot analysis. The effects of GF109203X (a PKC inhibitor) on DMT- or PDBu-induced JNK phosphorylation in VSMCs were assessed. SP600125 resulted in the relaxation of aortas that were pre-contracted with DMT or PDBu, whereas rauwolscine attenuated DMT-induced contraction. Chelerythrine resulted in the vasodilation of aortas pre-contracted with DMT. SP600125 and rauwolscine inhibited DMT-induced caldesmon phosphorylation. Additionally, PDBu induced caldesmon phosphorylation, and GF109203X attenuated the JNK phosphorylation induced by DMT or PDBu. DMT induced PKC phosphorylation in rat aortic VSMCs. These results suggest that alpha-2 adrenoceptor-mediated, DMT-induced contraction involves caldesmon phosphorylation that is mediated by JNK phosphorylation by PKC.

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Blockade of α2 adrenoceptors and histamine H1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine. However, it remains unclear how mirtazapine's actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei. Using dual-probe microdialysis, we determined the roles of α2 and H1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices. Mirtazapine (<30μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α2 adrenoceptor blockade was attenuated by concurrent DRN H1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α2 adrenoceptor inhibition was unaffected by concurrent MRN H1 receptor blockade. These results suggest that enhanced serotonergic transmission resulting from α2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.

Dexmedetomidine-induced contraction of isolated rat aorta is dependent on extracellular calcium concentration

BackgroundDexmedetomidine is a highly selective α2-adrenoceptor agonist that is widely used for sedation and analgesia during the perioperative period. Intravenous administration of dexmedetomidine induces transient hypertension due to vasoconstriction via the activation of the α2-adrenoceptor on vascular smooth muscle. The goal of this in vitro study is to investigate the calcium-dependent mechanism underlying dexmedetomidine-induced contraction of isolated endothelium-denuded rat aorta.MethodsIsolated endothelium-denuded rat thoracic aortic rings were suspended for isometric tension recording. Cumulative dexmedetomidine concentration-response curves were generated in the presence or absence of the following inhibitors: α2-adrenoceptor inhibitor rauwolscine; voltage-operated calcium channel blocker verapamil (5 × 10-7, 10-6 and 5 × 10-5 M); purported inositol 1,4,5-trisphosphate receptor blocker 2-aminoethoxydiphenylborate (5 × 10-6, 10-5 and 5 × 10-5 M); phospholipase C inhibitor U-73122 (10-6 and 3 × 10-6 M); and store-operated calcium channel inhibitor gadolinium chloride hexahydrate (Gd3+; 5 × 10-6 M). Dexmedetomidine concentration-response curves were also generated in low calcium concentrations (1 mM) and calcium-free Krebs solution.ResultsRauwolscine, verapamil, and 2-aminoethoxydiphenylborate attenuated dexmedetomidine-induced contraction in a concentration-dependent manner. Low calcium concentrations attenuated dexmedetomidine-induced contraction, and calcium-free Krebs solution nearly abolished dexmedetomidine-induced contraction. However, U-73122 and Gd3+ had no effect on dexmedetomidine-induced contraction.ConclusionsTaken together, these results suggest that dexmedetomidine-induced contraction is primarily dependent on extracellular calcium concentrations that contribute to calcium influx via voltage-operated calcium channels of isolated rat aortic smooth muscle. Dexmedetomidine-induced contraction is mediated by α2-adrenoceptor stimulation. Dexmedetomidine-induced contraction appears to be partially mediated by calcium release from the sarcoplasmic reticulum.

The Synergistic Interaction Between Morphine and Maprotiline After Intrathecal Injection in Rats

Antidepressant drugs act as potent inhibitors of norepinephrine and/or serotonin reuptake and are widely used with opioids for the treatment of chronic pain. The mechanism of this increased analgesic action is unclear. We compared the antinociceptive effects of the intrathecal administration of morphine with that of a nonselective (amitriptyline) or selective (maprotiline or citalopram) antidepressant drug using the thermal withdrawal test in rats. We also investigated the possible mechanisms involved in the interactions of these drugs. Male Wistar rats were anesthetized with sevoflurane and administered morphine and antidepressant drugs, or saline, through intrathecal injection. The antinociceptive effect was evaluated using the thermal withdrawal test before and after drug administration. The time for the withdrawal reaction was expressed as percentage of maximum possible effect (MPE). Animals were also pretreated with yohimbine (a nonselective alpha2-adrenergic antagonist) and naloxone (a nonselective opioid antagonist) for mechanism of action studies. Pharmacologic interaction was evaluated using isobolographic analysis of simultaneous administration of fixed proportions of maprotiline and morphine. Single intrathecal administration of morphine (2 microg), amitriptiline (125 microg), citalopram (144 microg), and maprotiline (1.25 microg) produced 51.6% +/- 8.9%, 10.3% +/- 3.2%, 33.8% +/- 5.2%, and 48.5% +/- 9.2% MPE, respectively. The antinociceptive effect of morphine was increased when combined with amitriptyline (91.3% +/- 4.6% MPE) and maprotiline (86.9% +/- 9.2% MPE) but not with citalopram (40.6% +/- 4.6% MPE). Coadministration of maprotiline increased the antinociceptive duration of morphine by 4-fold (from 120 to 480 min), which was reversed by pretreatment with the alpha-2 adrenoceptor inhibitor, yohimbine, and the mu-type opioid receptor antagonist, naloxone. Isobolographic analysis demonstrated a synergistic interaction between morphine and maprotiline. Selective norepinephrine reuptake inhibitors can significantly increase the intensity and duration of morphine antinociceptive activity via both alpha(2)-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.

Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the β3-adrenoceptor inhibitor SR-59230A

Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

Role of α 2-Adrenoceptors and Glutamate Mechanisms in the External Urethral Sphincter Continence Reflex in Rats

We investigated the role of alpha(2)-adrenoceptors and glutamate mechanisms in the urethral continence reflex in response to abdominal pressure increases. Under urethane anesthesia external urethral sphincter electromyogram activity was evaluated in spinal cord transected (T8-T9) female rats during lower abdominal wall compression before and after intravenous application of test drugs. The effects of the N-methyl-D-aspartate glutamate receptor antagonist MK-801 (Sigma) or the alpha(2)-adrenoceptor agonist medetomidine (Tocris Cookson, Ellisville, Missouri) (each 0.03, 0.3 and 3 mg/kg intravenously) on external urethral sphincter activity were examined. A 0.3 mg/kg intravenous dose of the alpha(2)-adrenoceptor antagonist idazoxan (Sigma) was then administered before or after the application of 1 mg/kg MK-801 intravenously. In addition, 0.3 mg/kg idazoxan were administered intravenously following the application of 1 mg/kg of the serotonin/norepinephrine reuptake inhibitor duloxetine (Kemprotec, Middlesbrough, United Kingdom) intravenously. MK-801 and medetomidine dose dependently decreased external urethral sphincter activity. Idazoxan significantly increased external urethral sphincter activity by 64% but the increase in activity after idazoxan was abolished by MK-801. On the other hand, idazoxan did not reverse the inhibitory effects of MK-801. In addition, idazoxan significantly potentiated the duloxetine effects on external urethral sphincter activity by 120%. These results indicate that 1) glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases, 2) alpha(2)-adrenoceptor activation suppresses external urethral sphincter activity, probably via presynaptic inhibition of glutamate release and 3) the effects of serotonin/norepinephrine reuptake inhibitors are enhanced by alpha(2)-adrenoceptor inhibition. Therefore, alpha(2)-adrenoceptor antagonists could be beneficial for treating stress urinary incontinence.

Clinical Effect of alpha 1D/A adrenoceptor inhibitor naftopidil on Benign Prostatic Hyperplasia: An International Prostate Symptom Score and King's Health Questionnaire assessment

To examine the effect of alpha 1D/A adrenoceptor inhibitor naftopidil on health-related quality of life (QOL) in men with benign prostatic hyperplasia (BPH). A total of 56 newly diagnosed patients with symptomatic BPH were prospectively enrolled and treated with 50 mg naftopidil daily for more than 12 weeks. All underwent pre-treatment documentation of lower urinary tract symptoms, QOL assessment using the international prostate symptom score (IPSS) and King's Health Questionnaire (KHQ), and uroflowmetry. A post-treatment assessment was performed at 12 weeks. IPSS scores as well as QOL index showed a significant improvement after naftopidil administration. Similarly, all seven domains except general health perceptions and social limitations in the KHQ questionnaire were significantly improved. When dividing the patients into overactive bladder (OAB) and non-OAB groups, only the OAB group showed significant improvement in almost all the domains of KHQ. Change ratios of the IPSS were not associated with those of KHQ domain scores in the OAB group. On the other hand, in the non-OAB group more domains presented improvements, which were associated with those of IPSS scores. Twelve-week treatment with naftopidil for symptomatic BPH patients is associated with significant improvement in the IPSS, QOL index, maximum urinary flow rate, post-void residual urine volume (PVR) and almost all domains in KHQ. KHQ is useful for the evaluation of clinical response in BPH patients, particularly in those with associated OAB.

Effects of chronic systemic hypoxia on contraction evoked by noradrenaline in the rat iliac artery.

Comparisons were made between responses evoked by noradrenaline (NA) in iliac artery rings from normoxic (N) rats and chronically hypoxic (CH) rats kept in 12 % O(2) for 3-4 weeks. At P(O(2)) of 100 mmHg, cumulative concentration-response curves (CCRC) to NA were greatly depressed in endothelium-intact (E+) rings, but not endothelium-denuded (E-) rings, of CH rats relative to N rats. However, CCRCs evoked by NA in E+ and E- rings during nitric oxide (NO) synthase inhibition were similar in N and CH rats. Reducing P(O(2)) to 55 mmHg depressed CCRCs to NA in E+ and E- rings of CH and N rats in the absence and presence of NO synthase inhibition. At P(O(2)) of 100 mmHg, CCRCs evoked by phenylephrine were comparable in E+ and E- rings of N and CH rats as were CCRCs for the relaxation evoked by isoprenaline, which were similarly rightward shifted by NO synthase inhibition. However, CCRCs evoked by the NO donor sodium nitroprusside were leftward shifted in E- rings of CH rats relative to N rats. Further, in the presence of the alpha(2) adrenoceptor inhibitor rauwolscine, CCRCs to NA were comparable in E+ rings of CH and N rats. Thus, the depressive effects of chronic hypoxia on NA-evoked contractions of iliac artery are additional to those of acute hypoxia. We propose that they reflect a facilitation of the contribution of NO to alpha(2) adrenoceptor-evoked relaxation that includes an increased sensitivity of the vascular smooth muscle of arteries from CH rats to NO.

Effects of Nipradilol on Alpha-Adrenoceptor Function in Ocular Arteries

The effects of nipradilol, a drug used in the treatment of glaucoma, on the contractions induced by noradrenaline and phenylephrine in isolated dog central retinal, external and internal ophthalmic arteries and pig ciliary arteries were investigated. In dog ocular arteries treated with oxyhemoglobin (1.6 × 10^–5 mol/l) to adsorb nitric oxide, noradrenaline (2 × 10^–8 to 10^–5 mol/l) produced a concentration-related contraction which was markedly inhibited by prazosin but not by yohimbine. Nipradilol (10^–9 to 10^–7 mol/l) slightly but significantly inhibited the noradrenaline-induced contraction in a concentration-related manner, but the inhibitory potency and efficacy were much less than those of prazosin. However, nipradilol inhibited the phenylephrine-induced contraction with a similar PA₂ value of prazosin. In pig ciliary arteries treated with oxyhemoglobin, noradrenaline-induced contraction was slightly inhibited by prazosin but markedly inhibited by yohimbine. Nipradilol, similarly to timolol, did not inhibit, but rather tended to potentiate, the contraction elicited by noradrenaline. The contraction induced by phenylephrine was significantly inhibited by prazosin and nipradilol. It is concluded that nipradilol acts as an α₁-adrenoceptor antagonist (but not as an α₂-adrenoceptor antagonist) in the ocular arteries, which may partially explain its ocular-pressure-lowering mechanism. Taken together with the results of our previous studies, the potencies of the nipradilol-induced vascular actions in ocular arteries are found to be in the following order: β-adrenoceptor inhibition > α₁-adrenoceptor inhibition ≒ direct vasodilation via a release of nitric oxide.

Changes in blood glucose and plasma insulin levels induced by bradykinin in anaesthetized rats.

1. The influence of bradykinin (BK) on blood glucose and plasma insulin levels was investigated in anaesthetized rats. 2. Blood glucose level was dose-dependently increased by intravenous infusion of BK. This effect of BK was enhanced by captopril, an inhibitor of angiotensin-converting enzyme (ACE). Des-Arg9-bradykinin (DABK), a kinin B1 receptor agonist, did not modify blood glucose levels while the effect of BK was inhibited by Hoe-140, a kinin B2 receptor antagonist. 3. The effect of BK was reduced by the NO-synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), and by the cyclo-oxygenase inhibitor, indomethacin. The effect of BK was suppressed by the association of propranolol with phentolamine or phenoxybenzamine. It was also reduced by hexamethonium, a ganglion-blocking drug. In adrenalectomized rats, the infusion of BK slightly decreased blood glucose levels. 4. The hyperglycaemic effect of adrenaline was suppressed by propranolol associated with phentolamine or phenoxybenzamine, but it was not modified by L-NAME. 5. Infusion of BK did not modify plasma insulin levels. However, after phentolamine and propranolol, BK induced a transient 2 fold rise in plasma insulin levels. The release of insulin was dose-dependent and inhibited by Hoe-140. 6. We conclude that infusion of BK induces, via a stimulation of B2 receptors, the release of NO and of prostanoids. The latter agents activate through a reflex pathway the release of catecholamines from the adrenal medulla. This release increases blood glucose levels and reduces plasma insulin levels. After adrenoceptor inhibition, BK induces a secretion of insulin, via the stimulation of B2 receptors.

PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway

The objective of this work was to assess the role of alpha 2–adrenoceptors in emesis induced by inhibitors of type 4 phosphodiesterase (PDE4) in ferrets. Pre-treatment with yohimbine, MK–912 or MK–467 (alpha 2–adrenoceptor antagonists) caused sudden and unexpected vomiting. In contrast, clonidine (alpha 2–adrenoceptor agonist) did not induce emesis at doses ranging from 62.5–250 μg/kg s.c. At the dose of 250 μg/kg, clonidine also provided protection against emesis induced by the PDE4 inhibitors, PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline, CT–2450 and R–rolipram. It was postulated that PDE4 inhibitors trigger emesis by mimicking the pharmacological actions of alpha 2–adrenoceptor antagonists. This hypothesis was strengthened by the demonstration that PDE4 inhibitors can reverse the hypnotic effect of an alpha 2–adrenoceptor mediated anaesthetic regimen in rats and ferrets. Similar to alpha 2–adrenoceptor antagonists, PMNPQ, R–rolipram and S–rolipram dose-dependently decreased the duration of anaesthesia in rats injected with the combination xylazine/ketamine. While subcutaneous injections of CT–2450 (3–30 mg/kg) were without effect, a central infusion (6 μg i.c.v.) decreased the duration of anaesthesia. These studies suggest that the ferret is an appropriate model to study emesis induced by PDE4 inhibitors and that these compounds trigger the emetic reflex via a noradrenergic pathway, mimicking the pharmacological actions of a pre-synaptic alpha 2–adrenoceptor inhibition.