RESUMEN
A novel adenosine A(3) receptor antagonist (SSR161421) was characterized by both receptor binding assays and pharmacological tests. Binding studies on cloned human adenosine receptors showed that SSR161421 has high affinity for adenosine hA(3) receptors (K(i)=0.37 nM) with at least 1000-fold selectivity compared to hA(1), hA(2A) and hA(2B) receptors. The receptor antagonist nature of SSR161421 was determined in a functional study on Chinese hamster ovarian cells (CHO) cells expressing human adenosine A(3) receptors. SSR161421 competitively antagonized the effect of 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) on cAMP production with a pA2 value in a luciferase reporter gene construct. In mice, intravenously administered SSR161421 inhibited the N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride (AB-MECA) induced increase in plasma histamine levels (ED(50)=2.0mg/kg) and the Cl-IB-MECA evoked plasma extravasation (ID(50)=2.9 mg/kg) and oedema formation (ID(50)=4.6 mg/kg) in mouse ear.
Asunto(s)
Agonistas del Receptor de Adenosina A3/farmacología , Antagonistas del Receptor de Adenosina A3/farmacología , Adenosina/análogos & derivados , Aminoquinolinas/farmacología , Benzamidas/farmacología , Edema/tratamiento farmacológico , Adenosina/administración & dosificación , Adenosina/farmacología , Antagonistas del Receptor de Adenosina A3/administración & dosificación , Aminoquinolinas/administración & dosificación , Animales , Benzamidas/administración & dosificación , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Edema/patología , Histamina/sangre , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Plasma/metabolismo , Receptores Purinérgicos P1/efectos de los fármacos , Receptores Purinérgicos P1/metabolismoRESUMEN
The effects of a novel adenosine A(3) receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10(-5)M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride] (10(-7)M) increased the antigen response up to 61 ± 3.0% and 88 ± 5.2% of maximal contraction, respectively. The agonists of adenosine A(1) and A(2) adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5'-N-ethylcarboxamidoadenosine], R-PIA [N(6)-R-phenylisopropyladenosine], and CGS21680 (10(-7)M) were ineffective. In vivo intravenous adenosine (600 µg/kg) and AB-MECA (30 µg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214 ± 13.0% and 220 ± 15.2%, respectively. SSR161421 in vitro (IC(50)=5.9 × 10(-7)M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED(50)=0.008 mg/kg) or oral (ED(50)=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3 × 10(-6)M) decreased the AUC of the antigen-induced contraction-time curve to 20.8 ± 5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC(50) values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.
Asunto(s)
Antagonistas del Receptor de Adenosina A3/farmacología , Aminoquinolinas/farmacología , Antígenos/inmunología , Benzamidas/farmacología , Broncoconstricción/efectos de los fármacos , Adenosina/administración & dosificación , Adenosina/análogos & derivados , Adenosina/farmacología , Antagonistas del Receptor de Adenosina A3/administración & dosificación , Administración Oral , Aminoquinolinas/administración & dosificación , Animales , Benzamidas/administración & dosificación , Broncoconstricción/inmunología , Relación Dosis-Respuesta a Droga , Cobayas , Concentración 50 Inhibidora , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Tráquea/efectos de los fármacos , Tráquea/inmunologíaRESUMEN
Central and peripheral mechanisms modulate food intake and energy balance in mammals and the precise role of the type 1 cannabinoid receptor (CB1) in these processes is still being explored. Using the zebrafish, Danio rerio, we show that rimonabant, a CB1-specific antagonist with an EC(50) of 5.15 × 10(-8) m, decreases embryonic yolk sac reserve use. We reveal a developmental overlap between CART genes and CB1 expression in the hypothalamus and medulla oblongata, two brain structures that play crucial roles in appetite regulation in mammals. We show that morpholino knockdown of CB1 or fasting decreases cocaine- and amphetamine-related transcript (CART)-3 expression. Strikingly, this down-regulation occurs only in regions coexpressing CB1 and CART3, reinforcing the link between CB1, CART, and appetite regulation. We show that rimonabant treatment impairs the fasting-induced down-regulation of CART expression in specific brain regions, whereas vehicle alone-treated embryos do not display this rescue of CART expression. Our data reveal that CB1 lies upstream of CART and signals the appetite through the down-regulation of CART expression. Thus, our results establish the zebrafish as a promising system to study appetite regulation.
Asunto(s)
Regulación del Apetito , Encéfalo/metabolismo , Regulación hacia Abajo , Privación de Alimentos , Receptor Cannabinoide CB1/metabolismo , Pez Cebra/metabolismo , Animales , Encéfalo/embriología , Agonistas de Receptores de Cannabinoides/farmacología , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Larva/metabolismo , Datos de Secuencia Molecular , Obesidad/metabolismo , Obesidad/fisiopatología , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Rimonabant , Saco Vitelino/metabolismo , Pez Cebra/genética , Pez Cebra/fisiologíaRESUMEN
Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.
Asunto(s)
Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Ingestión de Energía/efectos de los fármacos , Obesidad/metabolismo , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/metabolismo , Adiponectina/sangre , Adiposidad/efectos de los fármacos , Adiposidad/genética , Animales , Fármacos Antiobesidad/uso terapéutico , Biomarcadores/sangre , Peso Corporal/genética , Sistema Nervioso Central/efectos de los fármacos , Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/genética , Tránsito Gastrointestinal/fisiología , Hipotermia/prevención & control , Insulina/sangre , Leptina/sangre , Ratones , Ratones Noqueados , Ratones Transgénicos , MicroARNs , Mutación , Obesidad/tratamiento farmacológico , Obesidad/genética , Sistema Nervioso Periférico/efectos de los fármacos , Sistema Nervioso Periférico/metabolismo , Fenotipo , Piperidinas/uso terapéutico , Regiones Promotoras Genéticas , Pirazoles/uso terapéutico , Receptor Cannabinoide CB1/genética , Rimonabant , Triglicéridos/sangreRESUMEN
Recent studies suggested the involvement of the endocannabinoid pathway on insulin secretion in RINm5F cells or rat islets. Animal and clinical studies have reported beneficial effects of the selective cannabinoid 1 receptor antagonist rimonabant on glucose homeostasis. The aim of this study was to investigate the in vivo effects of rimonabant on pancreatic function in Zucker Fatty rats. Zucker Fatty rats were treated with rimonabant (10 mg kg(-1) day(-1)) or vehicle for up to 3 months. Pancreatic function was assessed by oral glucose tolerance test and by static incubation of islets in the presence of different glucose concentrations. Islet morphology was assessed by immuno-histochemistry on pancreatic sections. After 3 months, there was no difference in fasting glycaemia or AUC(glucose) during oral glucose tolerance test between rimonabant- and vehicle-treated animals. However, vehicle-treated rats developed a marked hyperinsulinaemia with time in contrast to rimonabant-treated animals, which maintained at 3 months significantly lower fasting insulin levels (7.76+/-0.67 microg l(-1) vs. 5.59+/-0.59 microg l(-1), P<0.01) and lower AUC(insulin) (1380+/-98 microg l(-1)min vs. 926+/-58 microg l(-1)min, respectively, P<0.001). In static incubation, rimonabant significantly decreased insulin secretion in response to low glucose concentration (3 months: 7.68+/-1.29 vs. 12.25+/-2.01 microg l(-1) 5 islets(-1) 45 min(-1) in rimonabant and vehicle respectively, P<0.01), resulting in a trend to increase stimulation index in the presence of 16.7 mM glucose (10.64+/-0.92 vs. 8.52+/-1.70 respectively). Morphological analysis at 3 months showed that rimonabant reduced islet-cell surface (-60%) and the percentage of disorganized islets (-54%).In conclusion, our data suggest that rimonabant has a protective role against the development of hyperinsulinaemia, beta-cell dysfunction and islet modification in Zucker Fatty rats.
Asunto(s)
Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/fisiología , Piperidinas/farmacología , Pirazoles/farmacología , Animales , Peso Corporal/efectos de los fármacos , Moduladores de Receptores de Cannabinoides/metabolismo , Bovinos , Ingestión de Alimentos/efectos de los fármacos , Ayuno , Glucosa/metabolismo , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Homeostasis/efectos de los fármacos , Hiperinsulinismo/inducido químicamente , Hiperinsulinismo/tratamiento farmacológico , Hiperinsulinismo/patología , Hiperinsulinismo/fisiopatología , Hiperplasia/prevención & control , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Páncreas/metabolismo , Páncreas/fisiopatología , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Ratas , Ratas Zucker , Rimonabant , Factores de TiempoRESUMEN
The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions. Six-week-old Ad(-/-) male mice and their wild-type littermate controls (Ad(+/+)) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad(-/-) mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad(+/+) and Ad(-/-) mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad(+/+) mice compared with Ad(+/+) vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad(-/-) mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.
Asunto(s)
Fármacos Antiobesidad/farmacología , Hiperinsulinismo/prevención & control , Resistencia a la Insulina , Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Pirazoles/farmacología , Pérdida de Peso/efectos de los fármacos , Adiponectina/deficiencia , Adiponectina/genética , Adiponectina/metabolismo , Animales , Grasas de la Dieta , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Hiperinsulinismo/etiología , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatología , Insulina/sangre , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Rimonabant , Grasa Subcutánea/efectos de los fármacos , Grasa Subcutánea/metabolismoRESUMEN
The mechanisms by which the CB1 receptor antagonist rimonabant exerts its appetite-suppressing and energy-dissipating effects are still incompletely resolved. To shed further light on the central pathways influenced by CB1 receptor modulation we examined the expression of the immediate early gene c-fos in male Sprague-Dawley rats at 60, 120 and 240 min after intraperitoneal administration of the CB1R antagonist rimonabant (10 mg/kg) and the CB1R agonist WIN55,212-2 (3 mg/kg). Perfusion-fixed brains were processed for immunohistochemistry and the localization of c-Fos immunoreactive neuronal profiles was assessed qualitatively throughout the brain. Nine areas, including specific hypothalamic and brainstem nuclei known to be involved in appetite regulation, were selected for quantitative analyses. Whereas WIN55,212-2 induced c-Fos immunoreactivity in a time-specific manner in the striatum, the central nucleus of amygdala, the hypothalamic paraventricular nucleus and the arcuate nucleus, no significant increases in c-Fos positive nuclei were found in any forebrain areas following rimonabant administration. In contrast, rimonabant and WIN55,212-2 were both found to significantly increase c-Fos immunoreactivity in the brainstem lateral parabrachial nucleus, the nucleus of the solitary tract and the area postrema. To characterize the phenotype of activated neurons in the nucleus of the solitary tract, a triple immunohistochemical staining technique was used to simultaneously label c-Fos protein and tyrosine hydroxylase (TH), GLP-1 or CART. Interestingly, rimonabant was found to significantly increase c-Fos protein expression in TH-positive neurons. Collectively, these results suggest that brainstem areas including ascending catetholaminergic A2/C2 neurons could play a role in rimonabant-induced inhibition of food intake.
Asunto(s)
Benzoxazinas/farmacología , Tronco Encefálico/efectos de los fármacos , Morfolinas/farmacología , Naftalenos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Benzoxazinas/administración & dosificación , Tronco Encefálico/citología , Tronco Encefálico/metabolismo , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Inyecciones Intraperitoneales , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Piperidinas/administración & dosificación , Prosencéfalo/citología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Pirazoles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Rimonabant , Núcleo Solitario/citología , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismo , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: The visceral (VAT) and subcutaneous (SCAT) adipose tissues play different roles in physiology and obesity. The molecular mechanisms underlying their expansion in obesity and following body weight reduction are poorly defined. METHODOLOGY: C57Bl/6 mice fed a high fat diet (HFD) for 6 months developed low, medium, or high body weight as compared to normal chow fed mice. Mice from each groups were then treated with the cannabinoid receptor 1 antagonist rimonabant or vehicle for 24 days to normalize their body weight. Transcriptomic data for visceral and subcutaneous adipose tissues from each group of mice were obtained and analyzed to identify: i) genes regulated by HFD irrespective of body weight, ii) genes whose expression correlated with body weight, iii) the biological processes activated in each tissue using gene set enrichment analysis (GSEA), iv) the transcriptional programs affected by rimonabant. PRINCIPAL FINDINGS: In VAT, "metabolic" genes encoding enzymes for lipid and steroid biosynthesis and glucose catabolism were down-regulated irrespective of body weight whereas "structure" genes controlling cell architecture and tissue remodeling had expression levels correlated with body weight. In SCAT, the identified "metabolic" and "structure" genes were mostly different from those identified in VAT and were regulated irrespective of body weight. GSEA indicated active adipogenesis in both tissues but a more prominent involvement of tissue stroma in VAT than in SCAT. Rimonabant treatment normalized most gene expression but further reduced oxidative phosphorylation gene expression in SCAT but not in VAT. CONCLUSION: VAT and SCAT show strikingly different gene expression programs in response to high fat diet and rimonabant treatment. Our results may lead to identification of therapeutic targets acting on specific fat depots to control obesity.
Asunto(s)
Grasa Abdominal/metabolismo , Matriz Extracelular/metabolismo , Obesidad/genética , Obesidad/metabolismo , Grasa Subcutánea/metabolismo , Transcripción Genética , Adipocitos/efectos de los fármacos , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Antagonistas de Receptores de Cannabinoides , Grasas de la Dieta/administración & dosificación , Regulación de la Expresión Génica , Insulina/sangre , Leptina/sangre , Lipoproteínas VLDL/sangre , Ratones , Ratones Endogámicos C57BL , Piperidinas/farmacología , Pirazoles/farmacología , RimonabantRESUMEN
OBJECTIVE: To investigate the in vitro and in vivo effects of 5-hydroxytryptamine (5-HT) on the rat urinary bladder and to characterize the receptors involved in mediating these pharmacological effects by using selective antagonists. MATERIALS AND METHODS: Female Wistar rats (250-350 g) were used for all studies. In vitro, detrusor muscle strips were mounted between two platinum electrodes in organ baths filled with a modified Krebs' solution bubbled with 95% O(2) and 5% CO(2) at 37 degrees C. After equilibration and a contraction to 80 mmol/L KCl, strips were exposed to electrical field stimulation for 30 min and incubated with the antagonist or vehicle for a further 30 min, then a 5-HT concentration-response curve (CRC) was obtained. In vivo, rats were anaesthetized with pentobarbital, and the ureters and urethra ligated, the bladder catheterized and infused with saline. 5-HT (3-100 microg/kg intravenous) dose-dependently increased intravesical pressure (IVP). After administering 5-HT at 30 microg/kg three times at 10 min intervals (controls), one dose of antagonist was perfused for 5 min and, after a further 5 min, 30 microg/kg 5-HT was tested again. This cycle was repeated four times using increasing doses of the antagonist to be tested. RESULTS: In vitro, 5-HT (0.01-100 micromol/L) induced a concentration-dependent enhancement of the neurogenic response, with a mean (sd) pEC(50) of 6.36 (0.15) and E(max) of 41.1 (4.6)% KCl (eight rats). In unstimulated tissues, 5-HT induced no contractile effect. Selective 5-HT(4), 5-HT(3) and 5-HT(1A) receptor antagonists had no effect on the 5-HT potentiating effects. The potentiating effect of 5-HT was antagonized by mesulergine at 0.3 micromol/L, R(+)lisuride at 0.3 micromol/L and the selective 5-HT(7) receptor antagonist SB-258741 at 0.3 micromol/L. In vivo, in anaesthetized rats, IVP increases induced by repeated doses of 30 microg/kg 5-HT were reproducible. R(+)lisuride (3-100 microg/kg) dose-dependently inhibited the 5-HT-induced increase of IVP. At the maximum dose tested, R(+)lisuride almost totally inhibited the 5-HT effect. CONCLUSIONS: In rat isolated detrusor muscle the 5-HT(7) receptor antagonists SB-258741, R(+)lisuride and mesulergine blocked the 5-HT potentiating effect with the expected potency. Moreover, in anaesthetized rats, R(+)lisuride abolished 5-HT effects on IVP at doses that antagonize physiological effects known to be mediated by 5-HT(7) receptor activation in several animal species. These results suggest the involvement of 5-HT(7) receptors in the modulation of rat bladder contraction both in vitro and in vivo.
Asunto(s)
Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Vejiga Urinaria/metabolismo , Animales , Atropina/farmacología , Estimulación Eléctrica , Femenino , Técnicas In Vitro , Contracción Muscular , Red Nerviosa/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas WistarRESUMEN
OBJECTIVES: Growing evidence suggest that BPH is a risk factor for ED. Since alfuzosin is a cornerstone in the treatment of BPH patients, we assessed the effect of alfuzosin on erectile function in rats when combined with a pro-erectile drug such as apomorphine. METHODS: Potencies of alfuzosin, apomorphine or the combination to relax norepinephrine (NE) precontracted corpus cavernosum tissue of spontaneous hypertensive rats (SHR) were determined. In anaesthetized rats, intracavernous and blood pressures were recorded after administration of apomorphine (10-250microg/kg s.c.) and alfuzosin (3-30microg/kg i.v.). RESULTS: Alfuzosin fully relaxed the NE-precontracted penile tissue (pIC(50)=6.62+/-0.7) while apomorphine, up to 10microM, did not produce any relaxation. The potency of alfuzosin to relax erectile tissue was not further enhanced with 10microM apomorphine. Apomorphine induced erections in rat while alfuzosin alone did not. However, alfuzosin (30microg/kg) significantly enhanced the potency of apomorphine, to induce erections (ED(50)=25microg/kg versus 57microg/kg). In addition, alfuzosin even at 3microg/kg, significantly increased the intracavernous pressure (ICP) during erectile events up to 52-55mmHg when compared to ICP values of 29mmHg with 50microg/kg apomorphine alone. CONCLUSION: These results show that alfuzosin enhances the number and amplitude of erections induced by apomorphine in SHR. Therefore, clinical evaluation of alfuzosin in association with apomorphine is warranted.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Erección Peniana/efectos de los fármacos , Quinazolinas/farmacología , Animales , Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Masculino , Ratas , Ratas Endogámicas SHRRESUMEN
(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.