RESUMEN
The goal of the present study was to determine if nitric oxide (NO) acting on the brain of bullfrog (Lithobates catesbeianus) is involved in arterial pressure and heart rate (HR) control by influencing sympathetic activity. We investigated the effect of intracerebroventricular injections of L-NMMA (a nonselective NO synthase inhibitor) on mean arterial blood pressure (MAP), HR and cutaneous vascular conductance (CVC) of pelvic skin after intravenous injection of α or ß adrenergic blockers, prazosin or sotalol, respectively. Arterial pressure was directly measured by a telemetry sensor inserted in the aortic arch of animals. L-NMMA increased MAP, but did not change HR. This hypertensive response was inhibited by the pre-treatment with prazosin, but accentuated by sotalol. The effect of L-NMMA on MAP was also inhibited by i.v. injections of the ganglionic blocker, hexamethonium. Thus, NO acting on the brain of bullfrog seems to present a hypotensive effect influencing the sympathetic activity dependent on α and ß adrenergic receptors in the periphery.
Asunto(s)
Presión Sanguínea/fisiología , Encéfalo/fisiología , Óxido Nítrico/fisiología , Rana catesbeiana/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Óxido Nítrico/metabolismo , Prazosina/administración & dosificación , Prazosina/farmacología , Rana catesbeiana/metabolismo , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Sotalol/administración & dosificación , Sotalol/farmacología , omega-N-Metilarginina/administración & dosificación , omega-N-Metilarginina/farmacologíaRESUMEN
The influence of Glu298Asp endothelial nitric oxide synthase (eNOS) polymorphism in exercise-induced reflex muscle vasodilatation is unknown. We hypothesized that nonexercising forearm blood flow (FBF) responses during handgrip isometric exercise would be attenuated in individuals carrying the Asp298 allele. In addition, these responses would be mediated by reduced eNOS function and NO-mediated vasodilatation or sympathetic vasoconstriction. From 287 volunteers previously genotyped, we selected 33 healthy individuals to represent three genotypes: Glu/Glu [n = 15, age 43 +/- 3 yr, body mass index (BMI) 22.9 +/- 0.3 kg/m(2)], Glu/Asp (n = 9, age 41 +/- 3 yr, BMI 23.7 +/- 1.0 kg/m(2)), and Asp/Asp (n = 9, age 40 +/- 4 yr, BMI 23.5 +/- 0.9 kg/m(2)). Heart rate (HR), mean blood pressure (MBP), and FBF (plethysmography) were recorded for 3 min at baseline and 3 min during isometric handgrip exercise. Baseline HR, MBP, FBF, and forearm vascular conductance (FVC) were similar among genotypes. FVC responses to exercise were significantly lower in Asp/Asp when compared with Glu/Asp and Glu/Glu (Delta = 0.07 +/- 0.14 vs. 0.64 +/- 0.20 and 0.57 +/- 0.09 units, respectively; P = 0.002). Further studies showed that intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA) did not change FVC responses to exercise in Asp/Asp, but significantly reduced FVC in Glu/Glu (Delta = 0.79 +/- 0.14 vs. 0.14 +/- 0.09 units). Thus the differences between Glu/Glu and Asp/Asp were no longer observed (P = 0.62). l-NMMA + phentolamine increased similarly FVC responses to exercise in Glu/Glu and Asp/Asp (P = 0.43). MBP and muscle sympathetic nerve activity increased significant and similarly throughout experimental protocols in Glu/Glu and Asp/Asp. Individuals who are homozygous for the Asp298 allele of the eNOS enzyme have attenuated nonexercising muscle vasodilatation in response to exercise. This genotype difference is due to reduced eNOS function and NO-mediated vasodilatation, but not sympathetic vasoconstriction.
Asunto(s)
Ejercicio Físico/fisiología , Contracción Isométrica/fisiología , Óxido Nítrico Sintasa de Tipo III/genética , Polimorfismo Genético , Adulto , Sustitución de Aminoácidos , Análisis de Varianza , Presión Sanguínea , Índice de Masa Corporal , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Femenino , Antebrazo/irrigación sanguínea , Frecuencia de los Genes , Genotipo , Fuerza de la Mano/fisiología , Frecuencia Cardíaca , Humanos , Infusiones Intraarteriales , Contracción Isométrica/efectos de los fármacos , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Vasodilatación/efectos de los fármacos , omega-N-Metilarginina/administración & dosificación , omega-N-Metilarginina/farmacologíaRESUMEN
1. Nitric oxide has been described either as pronociceptive or antinociceptive. In this investigation, using an electronic pressure-metre, the intradermal and the subcutaneous effects of prostaglandin E(2) (PGE(2)) and agents that mimic or inhibit the arginine/NO/cGMP pathway were compared. 2. The hypernociceptive effect of the intradermal injection of PGE(2) (100 ng) was immediate, peaking within 15-30 min and returning to basal values in 45-60 min. The subcutaneous injection of PGE(2) induced a hypernociception with a delayed peak (3 h) plateauing for 4-6 h. 3. Intradermal administration of 3-morpholino-sydnonimine-hydrochloride (SIN-1) enhanced, while its subcutaneous administration inhibited, subcutaneous hypernociception induced by PGE(2). This inhibition was prevented by ODQ (8 micro g) but not by NG-monomethyl-L-arginine (L-NMMA) (50 micro g). 4. Intradermal but not subcutaneous administration of L-arginine (1-100 micro g), SIN-1 (1-100 micro g) and dibutyrylguanosine 3':5'-cyclic monophosphate (db cGMP) (0.1-100 micro g) induced an early (15-30 min) dose-dependent hypernociceptive effect. Intradermal pretreatment with NG-monomethyl-L-arginine (L-NMMA; 50 micro g) inhibited the hypernociception induced by L-Arg (10 micro g), but not that induced by SIN-1 (10 micro g) or db cGMP (10 micro g). 5. Intradermal injection of ODQ (8 micro g) antagonized the hypernociception induced by L-arginine and SIN-1, but not that induced by db cGMP. 6. Considering (a) the different time course of intradermal and subcutaneous PGE(2)-induced hypernociception, (b) the opposite nociceptive effect of intradermal and subcutaneous administration of SIN-1 (db cGMP) as well as the arginine/NO/cGMP pathway, the existence of different subsets of nociceptive primary sensory neurons in which the arginine/NO/cGMP pathway plays opposing roles is suggested. This hypothesis would explain the apparent contradictory observations described in the literature.
Asunto(s)
Arginina/antagonistas & inhibidores , Arginina/farmacología , GMP Cíclico/administración & dosificación , Dermis/fisiopatología , Dinoprostona/administración & dosificación , Hiperalgesia/inducido químicamente , Molsidomina/análogos & derivados , Nociceptores/efectos de los fármacos , Nociceptores/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Tejido Subcutáneo/fisiopatología , Animales , Bucladesina/administración & dosificación , Bucladesina/antagonistas & inhibidores , GMP Cíclico/fisiología , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Masculino , Molsidomina/administración & dosificación , Molsidomina/antagonistas & inhibidores , Óxido Nítrico/fisiología , Oxadiazoles/administración & dosificación , Quinoxalinas/administración & dosificación , Ratas , Ratas Wistar , Factores de Tiempo , omega-N-Metilarginina/administración & dosificaciónRESUMEN
NG-nitro-L-arginine methyl ester (L-NAME) has been used extensively as a paradigmatic inhibitor of NO synthase and has been shown to cause antinociception in several experimental models. We describe here how L-NAME produced a dose-dependent antinociceptive effect when injected intraperitoneally in the mouse after acetic acid induced writhings, or intraplantarly in the rat paw pressure hyperalgesia induced by carrageenin or prostaglandin E2. In contrast another NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), had no significant effect per se but inhibited L-NAME systemic induced antinociception in mice and local induced antinociception in the rat paw hyperalgesia test. D-NAME had no antinociceptive effect upon carrageenin-induced hyperalgesia. Pretreatment of the paws with two inhibitors of guanylate cyclase, methylene blue (MB) and 1H-:[1,2,4]-oxadiazolo-:[4,3-a] quinoxalin-1-one (ODQ) abolished the antinociceptive effect of L-NAME. L-Arginine and the cGMP phosphodiesterase inhibitor, MY 5445 significantly enhanced the L-NAME antinociceptive effect. The central antinociceptive effect of L-NAME was blocked by co-administration of L-NMMA, ODQ and MB. The present series of experiments shows that L-NAME, but not L-NMMA, has an antinociceptive effect. It can be suggested that L-NAME causes the antinociceptive effect by stimulation of the arginine/ NO/ cGMP pathway, since the antinociceptive effect of L-NAME can be antagonized by L-NMMA and abolished by the guanylate cyclase inhibitors (MB and ODQ). In addition, the NO synthase substrate, L-arginine and the cGMP phosphodiesterase inhibitor, MY5445 were seen to potentiate the effects of L-NAME. Thus, L-NAME used alone, has limitations as a specific inhibitor of the arginine-NO-cGMP pathway and may therefore be a poor pharmacological tool for use in characterising participation in pathophysiological processes.
Asunto(s)
Analgésicos/metabolismo , Arginina/metabolismo , GMP Cíclico/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Carragenina/inmunología , Dinoprostona/inmunología , Hiperalgesia/inmunología , Masculino , Azul de Metileno/farmacología , Ratones , NG-Nitroarginina Metil Éster/administración & dosificación , NG-Nitroarginina Metil Éster/farmacología , Oxadiazoles/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Ftalazinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Wistar , omega-N-Metilarginina/administración & dosificación , omega-N-Metilarginina/farmacologíaRESUMEN
The objective of this study was to investigate the site of action of dipyrone in rat paw prostaglandin-induced hyperalgesia. The intracerebroventricular (i.c.v.) injection of dipyrone had no effect on the hyperalgesic response to prostaglandins. In contrast, intraplantar (i.pl.) and intrathecal (i.t.) injections produced dose-dependent analgesic effects. The analgesia observed following the intraperitoneal (i.p.), i.t., i.pl. or combined i.t. and i.pl. administration of dipyrone was abolished by pretreating the paws with L-NMMA (a nitric oxide synthase inhibitor) or methylene blue (MB, an inhibitor of soluble guanylate cyclase). These results support the suggestion that dipyrone-mediated antinociception results from a combined spinal and peripheral effect in the primary peripheral sensory neuron via stimulation of the arginine/cGMP pathway.