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PubMed1989

Effects of indeloxazine hydrochloride on cognitive disturbance in cycloheximide-treated mice.

The effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride] on cognitive disturbance in mice subjected to cycloheximide have been examined. Indeloxazine ameliorated cycloheximide-induced amnesia in mice, indicating a facilitatory effect of this drug on cerebral functions. Piracetam, Cahopantenate, dihydroergotoxine and viloxazine did not show significant effect on the amnesia. These results suggest that indeloxazine possesses a wider pharmacological profile than piracetam, Cahopantenate, dihydroergotoxine and viloxazine in anti-amnesic activities.

Animals↗
PubMed2005

Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes.

Nonsteroidal anti-inflammatory drugs (NSAIDs), used for the treatment of pain and inflammation, are eliminated primarily through conjugation with polar sugar moieties to form glucuronides. Glucuronidation is catalyzed by the UDP-glucuronosyltransferases (UGT) superfamily. An inverse relationship may exist between glucuronidation activity and NSAID efficacy; however, specific UGTs catalyzing conjugation of the structurally diverse NSAIDs have yet to be identified systematically. Therefore, NSAID glucuronidation activity by 12 individually expressed UGTs was investigated by liquid chromatography-tandem mass spectrometry. The relative rates of NSAID glucuronidation varied among UGT enzymes examined, demonstrating specificity of the individual UGTs toward selected NSAIDs. Kinetic parameters were determined for expressed UGT Supersomes and compared with parameters determined in pooled human liver microsomes (HLMs). Comparison of K(m) values suggested roles for UGTs 1A3 and 2B7 in indene glucuronidation and UGTs 1A9, 2B4, and 2B7 in profen glucuronidation. Inhibitory studies in pooled HLMs support the role of UGTs 1A1, 1A3, 1A9, 2B4, and 2B7 in the glucuronidation of ibuprofen, flurbiprofen, and ketoprofen. Bilirubin did not inhibit indomethacin or diclofenac glucuronidation, suggesting that UGT1A1 was not involved in catalysis. Imipramine did not inhibit glucuronidation of sulindac, sulindac sulfone, indomethacin, or naproxen in pooled HLMs, suggesting that UGT1A3 was not a principal hepatic catalyst. Nevertheless, multiple UGT enzymes, most notably UGTs 1A1, 1A9, 2B4, and 2B7, seem to be involved in the hepatic catalysis of NSAID glucuronidation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Activation of beta2- and beta3-adrenergic receptors increases brain tryptophan.

Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by beta-adrenoceptor antagonists. This study aimed to determine the beta-adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective beta-adrenergic antagonists 20 min before subtype-selective beta-agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The beta(2)-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak ( approximately 60%) 1 h following injection and small but statistically significant increases ( approximately 20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The beta(1)-selective agonist dobutamine (10 mg/kg) produced less robust increases ( approximately 40%) in brain tryptophan, whereas the beta(3)-selective agonists BRL 37344 (0.2 mg/kg (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl] phenoxy]acetic acid sodium)) and CL 316243 [0.1 mg/kg disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate)] resulted in larger increases (80 to 100%). Pretreatment with the beta(2)-selective antagonist ICI 118551 (0.5 mg/kg (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)amino]-2-butanol) attenuated the increases in tryptophan induced by both clenbuterol (0.1 mg/kg) and dobutamine (10 mg/kg). Pretreatment with the beta(1/2)-selective antagonist propranolol (2.5 mg/kg), the beta(3)-selective antagonist SR 59230A [1.5, 2.5, 5, or 20 mg/kg (3-(2-ethylphenoxy)-1[1S)-1,2,3,4-tertahydronaphth-1-yl-amino]-(2S)-2-propanol oxalate)], or ICI 118551 (0.5 mg/kg) did not prevent the BRL 37344-induced increase in brain tryptophan, whereas the beta(1/2/3)-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in beta(3)-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that beta-adrenergic modulation of brain tryptophan occurs in the absence of beta(3)-receptors. We conclude that activation of either beta(2)- or beta(3)-adrenergic receptors, but not beta(1)-adrenergic receptors, increases mouse brain tryptophan content.

Adrenergic beta-2 Receptor Agonists↗
PubMed2003

Muscarinic cholinergic and beta-adrenergic contribution to hindquarters vasodilation and cardiac responses to cocaine.

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and beta-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by beta2-adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M2-cholinoceptor activation.

Adrenergic beta-Antagonists↗
PubMed2003

The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways.

Agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively. It also interacted with h5-HT2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors, and negligible (<5.0) affinity for other 5-HT receptors. In antibody capture/scintillation proximity assays, agomelatine concentration dependently and competitively abolished h5-HT2C receptor-mediated activation of Gq/11 and Gi3 (pA2 values of 6.0 and 6.1). As measured by [3H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT2C (pKB value of 6.1) and h5-HT2B (pKB value of 6.6) receptors. In vivo, it dose dependently blocked induction of penile erections by the 5-HT2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[a]inden-3-yl) ethylamine (Ro60,0332). Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected agomelatine, it abolished their inhibition by Ro60,0175. Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely flect blockade of 5-HT2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, distinction to agomelatine, melatonin showed negligible activity 5-HT2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2B and 5-HT2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.

Acetamides↗
PubMed2003

Effect of a beta 2-adrenoceptor stimulation on hyperglycemia-induced endothelial dysfunction.

To investigate whether beta(2)-adrenoceptors exist on endothelial cells and whether a beta(2)-adrenoceptor stimulation might prevent the development of hyperglycemia-induced endothelial dysfunction, porcine aortic endothelial cells (PAECs) were cultured and chronically exposed to either 5 mM D-glucose ("normoglycemia") or 20 mM D-glucose ("hyperglycemia"), with or without 100 nM salbutamol in absence or presence of beta(2)-adrenoceptor antagonist ICI 118,551 [1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)-amino]-2-butanol] or beta(1)-antagonist metoprolol. For osmotic control, PAECs were exposed to 15 mM L-glucose. We measured nitric oxide release using the met-hemoglobin assay and assessed beta-adrenoceptor density and subtypes by radioligand binding. Furthermore, we determined intracellular NADH and NADPH using high-performance liquid chromatography. High D-glucose concentrations but not L-glucose led to significantly reduced basal and stimulated nitric oxide release. Chronic salbutamol treatment significantly antagonized the impairment of the nitric oxide response, which was inhibited by ICI 118,551 but not by metoprolol. The number of giant cells was significantly increased in hyperglycemia, which could be prevented by salbutamol. Binding of the radioligand (-)-[(125)I]iodocyanopindolol revealed a total beta-adrenoceptor density of 29.8 +/- 3.7 (normoglycemic) and 30.3 +/- 3.6 (hyperglycemic) fmol/mg protein. Displacement by ICI 118,551 revealed beta-adrenoceptor subtype distribution with 30.3 +/- 4.4 (normoglycemic) and 29.1 +/- 3.8% beta(2)-adrenoceptors. NADH production increased in hyperglycemia, which was completely prevented by salbutamol. We conclude that hyperglycemia in PAEC induces endothelial dysfunction with impaired nitric oxide release and that this can be prevented by beta(2)-adrenoceptor stimulation.

Adrenergic beta-Agonists↗
PubMed2004

Activation of capsaicin-sensitive sensory neurons by carvedilol, a nonselective beta-blocker, in spontaneous hypertensive rats.

We performed a study in spontaneous hypertensive rats (SHR) to determine whether carvedilol, a nonselective beta-adrenoceptor antagonist, activates capsaicin-sensitive sensory neurons (CSSNs), thereby promoting the release of calcitonin gene-related peptide (CGRP), a neuropeptide with an important role in maintenance of cardiovascular homeostasis. Carvedilol given intravenously at a dose of 0.3 mg/kg transiently decreased the mean arterial blood pressure (MABP) and increased renal tissue blood flow with increases in CGRP levels in plasma and kidney. These effects induced by carvedilol were not seen in animals pretreated with capsazepine, an antagonist of capsaicin. Although 1.0 mg/kg cavedilol markedly decreased MABP, it neither increased renal tissue blood flow nor CGRP levels in plasma and kidney. Prazosin, a selective alpha(1)-adrenoceptor antagonist, and bisoprolol, a selective beta(1)-adrenoceptor antagonist, decreased MABP with capsazepine, showing no antagonistic action in either cases, and these agents increased neither renal tissue blood flow nor levels of CGRP in plasma and kidney. Both ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol], a selective beta(2)-adrenoceptor antagonist, at a dose of 0.25 mg/kg and capsaicin mimicked effects induced by 0.3 mg/kg carvedilol. Administration of 1.0 mg/kg ICI 118,551 produced effects similar to those induced by 1.0 mg/kg carvedilol. These observations strongly suggested that the low dose of carvedilol might activate CSSNs in SHR to increase the release of CGRP, thereby decreasing blood pressure with an increase in renal tissue blood flow. The effects induced by carvedilol seemed to be mediated by its beta(2)-adrenoceptor blockade activity.

Adrenergic alpha-Antagonists↗
PubMed2004

Atypical beta-adrenoceptor subtypes mediate relaxations of rabbit corpus cavernosum.

This study was performed to characterize the beta-adrenoceptor population in rabbit isolated corpus cavernosum (RbCC) by using nonselective and selective beta-adrenoceptor agonists and antagonists in functional assays. Metaproterenol, ritodrine, fenoterol, and 8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(rho-methoxyphenyl)-1-methylethyl]amino]ethyl]carbostyril (TA 2005) (3-100 nmol each) dose dependently relaxed the RbCC preparations. These relaxations were markedly reduced by N(omega)-nitro-L-arginine methyl ester (L-NAME; 10 microM) and 1H-[1,2,4]-oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ) (10 microM), whereas the adenylyl cyclase inhibitor SQ 22,536 [9-(2-tetrahydrofuryl) adenine] (10 microM) had no effect. In contrast, neither L-NAME nor ODQ affected the isoproterenol-induced RbCC relaxations, but SQ 22,536 abolished this response. Sildenafil (1 microM) significantly potentiated the relaxations induced by beta(2)-agonists without affecting the isoproterenol-evoked relaxations. Rolipram (10 microM) enhanced the relaxations elicited by isoproterenol but had no effect on those induced by the selective beta(2) agonists. Propranolol and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551) determined a rightward shift in the concentration-response curves to isoproterenol in a noncompetitive manner with a reduction of maximum response at the highest antagonist concentration, with the slope values significantly different from unity. Propranolol and ICI 118,551 had no effect on the relaxations elicited by fenoterol, TA 2005, metaproterenol, and ritodrine. Atenolol and 1-[2-((3-carbamoyl-4-hydroxy)phenoxy) ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanol methanesulfonate (CGP 20712A) (0.1-10 microM) failed to affect the relaxations induced by all tested beta-adrenoceptor agonists. Our study revealed the existence of two atypical beta-adrenoceptors in the rabbit erectile tissue. Isoproterenol relaxes the rabbit cavernosal tissue by activating atypical beta-adrenoceptors coupled to adenylyl cyclase pathway, whereas the selective beta(2)-adrenoceptor agonists relax the RbCC tissue through another atypical beta-adrenoceptor subtype coupled to nitric oxide release from the sinusoidal endothelium.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Regional hemodynamic effects of the N-(2-benzoylphenyl)-L-tyrosine peroxisome proliferator-activated receptor-gamma ligand, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious rats.

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-gamma activator, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious, male Sprague-Dawley rats. Administration of GI 262570 twice daily for 4 days caused a slowly developing, modest fall in mean arterial blood pressure, associated with a progressive, hyperemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the beta2-adrenoceptor antagonist, ICI 118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride), and was still apparent in the presence of the alpha-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT1) and endothelin (ETA and ETB) receptors unmasked vasodilator responses to GI 262570 in the renal or mesenteric vascular beds. In the presence of GI 262570, vasodilator responses to acetylcholine and vasoconstrictor responses to methoxamine were normal. Furthermore, the cardiovascular responses to nonselective nitric-oxide synthase inhibition were not influenced by GI 262570. Collectively, these results indicate that the vasodilator action of GI 262570 is specific to the hindquarters vascular bed (of those studied), does not involve alpha- or beta2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.

Acetylcholine↗
PubMed2005

Characterization of the T-cell response in a patient with phenindione hypersensitivity.

The oral anticoagulant phenindione [2-phenyl-1H-indene-1,3(2H)-dione] is associated with hypersensitivity reactions in 1.5 to 3% of patients, the pathogenesis of which is unclear. We describe a patient who developed a severe hypersensitivity reaction that involved both the skin and lungs. A lymphocyte transformation test showed proliferation of T-cells from the hypersensitive patient, but not from four controls on exposure to phenindione in vitro. Drug-specific T-cell clones were generated and characterized in terms of their phenotype, functionality, and mechanism of antigen presentation. Forty-three human leukocyte antigen class II restricted CD4(+) alphabeta T-cell clones were identified. T-cell activation resulted in the secretion of interferon-gamma and interleukin-5. Five of seven clones proliferated with phenindione alone, whereas two clones also proliferated with 2-phenylindene. Certain T-cell clones were also stimulated by R- and S-warfarin; computer modeling revealed that warfarin can adopt a phenindione-like structure. Phenindione was presented to T-cells via two pathways: first, bound directly to major histocompatibility complex and second, bound to a processed peptide. Our data show that CD4(+) T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients.

Drug Hypersensitivity↗
PubMed2005

Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.

Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective beta-AR antagonists. ICI-118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [alpha-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the beta2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (K(b)) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective beta1-AR antagonists CGP 20712A [(+/-)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2'-hydroxy-3'-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists indicates that beta2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific beta-AR subtypes.

Action Potentials↗
PubMed2005

Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior.

A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(S)-(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], PD-128,908 [(R)-(-)-(4aS,10bS)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], quinelorane [(5aR-trans)-5,5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(-)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(+)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl) ergotaman-3',6'-18-trione methanesulfonate], and apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole), haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride (N-[(1-butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphtha-lenecarboxamide), U99194 (2,3-dihydro-5,6-dimethoxy-N,N-dipropyl-1H-inden-2-amine maleate), SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on dose-response curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate], and N-[3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptor-mediated activities.

Adrenergic alpha-Antagonists↗
PubMed2005

Induction of beta3-adrenergic receptor functional expression following chronic stimulation with noradrenaline in neonatal rat cardiomyocytes.

This study aimed to characterize beta(3)-adrenergic receptors (ARs) in rat neonatal cardiomyocytes using the noradrenaline (NOR) properties to modulate the expression and function of the three beta-ARs. We assessed the effect of NOR (physiological nonselective agonist), isoprenaline (ISO, beta-nonselective agonist), dobutamine (DOB, beta(1)-selective agonist), and procaterol (PROC, beta(2)-selective agonist) on cAMP accumulation using cardiomyocytes untreated or treated with 100 microM NOR for 24 h. The inhibition of forskolin-stimulated cAMP accumulation was determined using NOR, isoprenaline, and the beta(3)-selective agonists 4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid (BRL 37344) and 5-[-2-([-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243). The experiments were performed in the absence or presence of propranolol or 2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP 20712A) and/or 1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118551) to inhibit beta(1)- and beta(2)-AR stimulation and 1-(2-ethylphenoxy)-3-[[1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino-(2S)-2-propanol hydrochloride (SR 59230A) (beta(3)-selective antagonist). In addition, the level of the three subtypes was determined by reverse transcription polymerase chain reaction and Western blotting. NOR pretreatment decreased the activation of cAMP induced by NOR, isoprenaline, and DOB, whereas PROC response was abolished. The inhibition of NOR response by CGP 20712A or ICI 118551 demonstrated that beta(1)- and beta(2)-ARs are down-regulated and that beta(2)-AR functional activity was also abolished in cardiomyocytes exposed to chronic stimulation. beta(3)-AR function was observed with NOR and ISO when beta(1)-/beta(2)-ARs were blocked and with both beta(3)-selective agonists in NOR-treated cells only. This response was completely inhibited by SR 59230A and involved G(i) protein. Furthermore, the results from functional studies agree well with those from expression experiments. In conclusion, these data provide strong evidence that beta(3)-ARs are functionally up-regulated and coupled to G(i) protein in rat neonatal cardiomyocytes following chronic exposure to NOR when beta(1)- and beta(2)-ARs are down-regulated.

Adrenergic alpha-Agonists↗
PubMed2005

Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats.

The hemodynamic effects of the glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4, and putative underlying mechanisms were assessed in conscious male Sprague-Dawley rats. At a dose of 25 ng kg(-1) i.v., exendin-4 had little effect, but doses of 250 and 2500 ng kg(-1) had significant tachycardic effects (+66 +/- 9 and +95 +/- 16 beats min(-1) at 5 min, respectively) and pressor actions (+10 +/- 2 and +12 +/- 1 mm Hg), accompanied by substantial falls in mesenteric vascular conductance (-38 +/- 3% and -47 +/- 3%) and increases in hindquarters vascular conductance (+82 +/- 14% and +126 +/- 15%). The latter were likely due to adrenaline-mediated activation of beta(2) adrenoceptors since they were abolished by the beta(2) adrenoceptor antagonist, ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) hydrochloride], or propranolol [(RS)-1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol], and absent in adrenal-demedullated rats. In the presence of beta-adrenoceptor antagonism, the tachycardic effects of exendin-4 were suppressed, but the pressor action was enhanced. Enhancement of the pressor action of exendin-4 was not seen in adrenal-demedullated rats or in animals given phentolamine in addition to propranolol, consistent with a component of the pressor action of exendin-4 being due to an adrenaline-mediated positive inotropic effect mediated by alpha-adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of alpha-adrenoceptors, vasopressin receptors, angiotensin receptors, or GLP-1 receptors, although antagonism of the latter substantially inhibited the hindquarter vasodilator effects of exendin-4. These results are consistent with exendin-4 having cardiovascular effects through GLP-1 receptor-dependent and -independent mechanisms, some of which involve sympathoadrenal activation.

Animals↗
PubMed2006

Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil.

In the present study, we examined the interaction of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-inden-1-one hydrochloride (donepezil), a potent cholinesterase inhibitor, with two additional therapeutically relevant targets, N-methyl-d-aspartate (NMDA) and sigma(1) receptors. Donepezil blocked the responses of recombinant NMDA receptors expressed in Xenopus oocytes. The blockade was voltage-dependent, suggesting a channel blocker mechanism of action, and was not competitive at either the l-glutamate or glycine binding sites. The low potency of donepezil (IC(50) = 0.7-3 mM) suggests that NMDA receptor blockade does not contribute to the therapeutic actions of donepezil. Of potential therapeutic relevance, donepezil binds to the sigma(1) receptor with high affinity (K(i) = 14.6 nM) in an in vitro preparation (Neurosci Lett 260:5-8, 1999). Thus, we sought to determine whether an interaction with the sigma(1) receptor may occur in vivo under physiologically relevant conditions by evaluating the sigma(1) receptor dependence effects of donepezil in behavioral tasks. Donepezil showed antidepressant-like activity in the mouse-forced swimming test as did the sigma(1) receptor agonist igmesine. This effect was not displayed by the other cholinesterase inhibitors, rivastigmine and tacrine. The donepezil and igmesine effects were blocked by preadministration of the sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) and an in vivo antisense probe treatment. The memory-enhancing effect of donepezil was also investigated. All cholinesterase inhibitors attenuated dizocilpine-induced learning impairments. However, only the donepezil and igmesine effects were blocked by BD1047 or the antisense treatment. Therefore, donepezil behaved as an effective sigma(1) receptor agonist on these behavioral responses, and an interaction of the drug with the sigma(1) receptor must be considered in its pharmacological actions.

Animals↗
PubMed2006

Regulation of volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following activation of lysophospholipid receptors.

The ability of the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) to promote the release of the organic osmolyte taurine in response to hypoosmotic stress has been examined. Incubation of SH-SY5Y neuroblastoma cells under hypoosmotic conditions (230 mOsM) resulted in a time-dependent release of taurine that was markedly enhanced (3-7-fold) by the addition of micromolar concentrations of either S1P or LPA. At optimal concentrations, the effects of S1P and LPA on taurine efflux were additive and mediated via distinct receptors. Inclusion of 1,9-dideoxyfoskolin, 5-nitro-2-(3-phenylpropylamino benzoic acid, or 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]-butanoic acid blocked the ability of both lysophospholipids to enhance taurine release, indicating the mediation of a volume-sensitive organic osmolyte and anion channel. Both S1P and LPA elicited robust increases in intracellular calcium concentration that were attenuated by the removal of extracellular calcium, abolished by the depletion of intracellular calcium with thapsigargin, and were independent of phosphoinositide turnover. Taurine efflux mediated by S1P and LPA was unaffected by the removal of extracellular calcium but was attenuated by depletion of intracellular calcium (34-38%) and by inhibition of protein kinase C (PKC) with chelerythrine (38-72%). When intracellular calcium was depleted and PKC was inhibited, S1P- or LPA-stimulated taurine efflux was inhibited by 80%. Pretreatment of the cells with pertussis toxin, toxin B, or cytochalasin D had no effect on lysophospholipid-stimulated taurine efflux. The results indicate that both S1P and LPA receptors facilitate osmolyte release via a phospholipase C-independent mechanism that requires the availability of intracellular calcium and PKC activity.

Calcium↗
PubMed2006

Prostanoid receptors regulate the volume-sensitive efflux of osmolytes from murine fibroblasts via a cyclic AMP-dependent mechanism.

The ability of prostanoid receptors to regulate the volume-dependent efflux of the organic osmolyte taurine from murine fibroblasts (L cells) via a cAMP-dependent mechanism has been examined. Incubation of L cells under hypoosmotic conditions resulted in a time-dependent efflux of taurine, the threshold of release occurring at 250 mOsM. Addition of prostaglandin E(1) (PGE(1)) potently (EC(50) = 2.5 nM) enhanced the volume-dependent efflux of taurine at all time points examined and increased the threshold for osmolyte release to 290 mOsM. Maximal PGE(1) stimulation (250-300% of basal) of taurine release was observed at 250 mOsM. Of the PGE analogs tested, only the EP(2)-selective agonist butaprost (9-oxo-11alpha,16S-dihydroxy-17-cyclobutyl-prost-13E-en-1-oic acid) was able to enhance taurine efflux. Inclusion of 1,9-dideoxyfoskolin, 5-nitro-2-(3-phenylpropylamino) benzoic acid, or 4-[(2-butyl-6,7-dicloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]-butanoic acid blocked the ability of PGE(1) to enhance taurine release, indicating the mediation of a volume-sensitive organic osmolyte and anion channel. The ability of PGE(1) to increase osmolyte release from L cells was mimicked by the addition of agents that inhibit cAMP breakdown, directly activate adenylyl cyclase, or are cell-permeant analogs of cAMP. Taurine release elicited by either PGE(1) or 8-(4-chlorophenylthio)-cAMP was attenuated by >70% in L cells that had been stably transfected with a mutant regulatory subunit of cAMP-dependent protein kinase (PKA). PGE(1) stimulation of taurine efflux was not attenuated by either depletion of intracellular calcium or inhibition of protein kinase C. The results indicate that activation of prostanoid receptors on murine fibroblasts enhances osmolyte release via a cAMP and PKA-dependent mechanism.

Alprostadil↗
PubMed2006

Receptor regulation of the volume-sensitive efflux of taurine and iodide from human SH-SY5Y neuroblastoma cells: differential requirements for Ca(2+) and protein kinase C.

The basal (swelling-induced) and receptor-stimulated effluxes of (125)I(-) and taurine have been monitored to determine whether these two osmolytes are released from human SH-SY5Y cells under hypotonic conditions via common or distinct mechanisms. Under basal conditions, both (125)I(-) (used as a tracer for Cl(-)) and taurine were released from the cells in a volume-dependent manner. The addition of thrombin, mediated via the proteinase-activated receptor-1 (PAR-1) subtype, significantly enhanced the release of both (125)I(-) and taurine (3-6-fold) and also increased the threshold osmolarity for efflux of these osmolytes ("set-point") from 200 to 290 mOsM. Inclusion of a variety of broad-spectrum anion channel blockers and of 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid attenuated the release of both (125)I(-) and taurine under basal and receptor-stimulated conditions. Basal release of (125)I(-) and taurine was independent of Ca(2+) or the activity of protein kinase C (PKC). However, although PAR-1-stimulated taurine efflux was attenuated by either a depletion of intracellular Ca(2+) or inhibition of PKC by chelerythrine, the enhanced release of (125)I(-) was independent of both parameters. Stimulated efflux of (125)I(-) after activation of muscarinic cholinergic receptors was also markedly less dependent on Ca(2+) availability and PKC activity than that observed for taurine release. These results indicate that, although the osmosensitive release of these two osmolytes from SH-SY5Y cells may occur via pharmacologically similar membrane channels, the receptor-mediated release of (125)I(-) and taurine is differentially regulated by PKC activity and Ca(2+) availability.

Alkaloids↗