RESUMEN
New substances designed for the treatment of anxiety have previously been synthesized, which resulted in the identification of four new pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives structurally designed by using zolpidem as lead compound. Among them, LASSBio-873 was the most potent to produce analgesic, sedative and hypnotic effects. Thus, we investigated the possible mechanisms involved in LASSBio-873-induced sedation, as well as its effects on different models of inflammatory pain. LASSBio-873 (4 mg/kg) reduced locomotor activity of mice in the open field test from 205.2+/-25.6 to 87.6+/-16.2 movements/min. Atropine, a non-selective muscarinic antagonist, prevented the LASSBio-873-induced sedation and increased locomotor activity to 192.9+/-30.2 movements/min. In the formalin test, LASSBio-873 (4 mg/kg) significantly reduced the duration of nociceptive behavior during the inflammatory phase, reducing the control reactivity from 197.6+/-14.5s to 84.4+/-10.3s. Carrageenan reduced the latency for the animal reaction from 5.1+/-0.2s (control) to 2.1+/-0.3s which was completely reverted by LASSBio-873 (6 mg/kg) to 5.6+/-0.6s. Atropine prevented the LASSBio-873-induced antinociceptive and antihyperalgesic activities, indicating the interference of the cholinergic system. LASSBio-873 is a novel prototype of drug that modulates muscarinic activity and could be used for neuropsychiatric and cognitive disorders and other conditions associated to acute and chronic pain.
Asunto(s)
Analgésicos/farmacología , Hipnóticos y Sedantes/farmacología , Dolor/tratamiento farmacológico , Pirazoles/farmacología , Piridinas/farmacología , Pirroles/farmacología , Receptores Muscarínicos/metabolismo , Antagonistas Adrenérgicos alfa/metabolismo , Analgésicos/administración & dosificación , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Antagonistas del GABA/metabolismo , Calor , Hiperalgesia/tratamiento farmacológico , Hipnóticos y Sedantes/administración & dosificación , Inflamación/inducido químicamente , Inflamación/fisiopatología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Antagonistas Muscarínicos/metabolismo , Antagonistas de Narcóticos/metabolismo , Dimensión del Dolor , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Pirroles/administración & dosificaciónRESUMEN
Antecedentes: Los beneficios de algunos antihipertensivos están limitados por sus efectos adversos y baja adhesividad a terapia. El Carvedilol es una beta y alfa-bloqueador, sin efectos metabólicos adversos y además, utilizable como monoterapia y muchas veces en monodosis, mejorando adherencia al tratamiento. Objetivos: Evaluar los efectos del Carvedilol, en hipertensos esenciales no complicados sobre presión arterial (PA), glicemia, lípidos, su tolerabilidad, posibilidad de ser usado en monodosis y adherencia a la terapia. Método: Estudio multicéntrico prospectivo, abierto, de 12 semanas. Los resultados fueron sometidos a análisis estadísticos. Se contemplaron normas éticas de investigación clínica. Resultados: 285 enfermos en 79 consultorios, 66 por ciento mujeres, 53,6 ± 12 años de edad. La PA basal mostró que el 28,8 por ciento tenían HT etapa 1; 49,8 por ciento etapa 2 y el 21,4 por ciento etapa 3, clasificación JNC VI, siendo el 90,6 por ciento de los pacientes HT sisto-diastólicos. En promedio la PAS bajó de 159,9 ± 14,8 a 131,3 ± 13.5 mmHg y la PAD de 98,5 ± 8,1 a 80,9 ± 8,6 mmHg. El 4,2 por ciento alcanzó normotensión. El colesterol total bajó de 219,2 a 202,4 mg/100ml (p<0,001). La glicemia no se modificó. El 90,2 por ciento de los pacientes usó 25 mg diarios en dosis única. Los efectos adversos fueron escasos, los más comunes mareos, cefalea, rubor facial, edema e hipotensión. La adhesividad al tratamiento fue de 85,5 por ciento. Como hallazgos secundarios, el 77 por ciento de los hipertensos tenían IMC > 25 kg/m². Conclusiones: Carvedilol mostró buena eficacia antihipertensiva, sin efectos metabólicos adversos y buena tolerabilidad.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Antagonistas Adrenérgicos beta , Hipertensión/tratamiento farmacológico , Antagonistas Adrenérgicos alfa/uso terapéutico , Antagonistas Adrenérgicos beta , Índice de Masa Corporal , Frecuencia Cardíaca , Lípidos/análisis , Estudios Prospectivos , Presión Sanguínea , Resultado del Tratamiento , Antagonistas Adrenérgicos alfa/efectos adversos , Antagonistas Adrenérgicos alfa/metabolismoRESUMEN
In this work, we characterized alpha(1)-adrenoceptor expression and functionality in rat submandibular gland. Cumulative dose-response curve of methoxamine was constructed to determine the peroxidase secretion by glands from proestrous, estrous, metestrous and diestrous rats. They were compared to those from animals untreated or treated with sex hormones, estradiol and progesterone. The sensitivity of glands to an alpha(1)-adrenoceptor agonist varied depending on hormonal state, i.e. glands from proestrous and estrous were more sensitive to the stimulatory action of methoxamine than those from metestrous, diestrous and ovariectomised animals. The efficacy of the alpha(1) agonist was enhanced in glands from ovariectomised estrogen-treated rats but it was ineffective in glands from ovariectomised progesterone-treated rats. The functional studies correlated with 3H-prazosin binding assays in which estrogen increased alpha(1)-adrenoceptor density while progesterone decreased it. The results demonstrated that alpha(1)-adrenoceptor expression and functionality in rat submandibular glands are apparently under hormonal control and probably represent other examples of bidirectional interactions between neuronal and exocrine systems.
Asunto(s)
Ciclo Estral/efectos de los fármacos , Ciclo Estral/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Peroxidasa/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Glándula Submandibular/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Estradiol/administración & dosificación , Estradiol/metabolismo , Femenino , Metoxamina/farmacología , Ovariectomía , Prazosina/metabolismo , Progesterona/administración & dosificación , Progesterona/metabolismo , Ratas , Ratas Wistar , Regulación hacia ArribaRESUMEN
We have characterized the expression of alpha1-adrenoceptor in epididymis from rats in different stages of sexual maturation: 40 (immature), 60 (young adult), and 120 (adult) days of age. Plasma testosterone levels were low in the immature animals but increased significantly in the 60- and 120-day-old animals. These changes were followed by a progressive increase in rat body weight and in caput and cauda epididymis relative weight. Reverse transcription polymerase chain reaction assay indicated that alpha1a-, alpha1b-, and alpha1d-adrenoceptor transcripts were present in both caput and cauda epididymis from adult rats. Ribonuclease protection assays further indicated that the expression of these alpha1-adrenoceptor transcripts differed with age and epididymal region analyzed. Prazosin (nonselective alpha1 antagonist), 5-methyl urapidil (alpha1A-selective), and BMY 7378 (alpha1D-selective) displaced [3H]prazosin binding curves in caput and cauda epididymis from 40- and 120-day-old rats. The potency order for these antagonists, as calculated from the negative logarithm of the inhibition constant (pK(i)) values for the high-affinity sites, indicated a predominant population of alpha1A-adrenoceptor subtype in caput and cauda epididymis from adult animals. Differences in pK(i) values in caput and cauda epididymis from immature and adult animals also suggested that the relative amount of alpha1-adrenoceptors, at the protein level, is modulated by sexual maturation. Taken together, the changes in alpha1-adrenoceptor expression during sexual maturation may suggest specific roles for these receptors in epididymal function.
Asunto(s)
Epidídimo/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Maduración Sexual/fisiología , Antagonistas Adrenérgicos alfa/metabolismo , Animales , Unión Competitiva , Epidídimo/efectos de los fármacos , Hibridación in Situ , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Ensayos de Protección de Nucleasas , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Prazosina/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/biosíntesis , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testosterona/sangreRESUMEN
1. Age-related changes in the reactivity of postsynaptic alpha-adrenoceptors of isolated portions (epididymal and prostatic) and in whole vas deferens have been studied using 4, 12 and 20 month-old rats. 2. The pD2 values for adrenaline-induced contractions were reduced in the epididymal portion and whole vas deferens of middle-aged and old animals, but not in the prostatic portion. No age related change to phenylephrine or clonidine sensitivity was observed. 3. pA2 values of prazosin and yohimbine were not changed by aging in any preparation. Phentolamine pA2 values were reduced in the epididymal portion and in the whole vas deferens when adrenaline, but not when phenylephrine concentration-response curves were displaced by the antagonist. The mean pA2 value of yohimbine (6.78) indicates that this antagonist blocks alpha(1)-adrenoceptors in the rat vas deferens. 4. The data presented here suggest that age-related decreases in the sensitivity to adrenaline and phentolamine (when measured by displacing adrenaline concentration-effect curves) in the whole vas deferens are probably due to a variation in the proportion of alpha(1)-adrenoceptor subtypes in the epididymal portion of the rat vas deferens.
Asunto(s)
Envejecimiento/fisiología , Epidídimo/ultraestructura , Próstata/ultraestructura , Receptores Adrenérgicos alfa/fisiología , Conducto Deferente/ultraestructura , Agonistas alfa-Adrenérgicos/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Envejecimiento/metabolismo , Animales , Epidídimo/efectos de los fármacos , Epinefrina/farmacología , Cinética , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/ultraestructura , Fenilefrina/farmacología , Próstata/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa/metabolismo , Conducto Deferente/efectos de los fármacosRESUMEN
Although ischemia induces strong coronary vasodilation, some vasoconstrictive tone persists in the ischemic myocardium. To assess whether this tone is mediated through alpha adrenergic receptors, coronary blood flow was measured with radioactive microspheres in the normal and in the ischemic left ventricular wall of the dog before and during alpha blockade with Trimazosin. Ischemia was accomplished by decreasing the coronary perfusion pressure to 22 +/- 1.4 mmHg. Heart rate and aortic pressure were kept constant in each experiment. Trimazosin significantly increased flow in the normal left ventricular wall, but to a greater extent in the subepicardium than in the subendocardium with a decrease of the inner/outer flow ratio from 1.38 +/- 0.12 to 1.20 +/- 0.11 (p less than 0.05). In the ischemic region, Trimazosin did not change total transmural flow, but flow decreased in the subendocardium and increased in the subepicardium with a decrease in the inner/outer flow ratio from 0.63 +/- 0.09 to 0.38 +/- 0.06 (p less than 0.01). These results show that a vasoconstrictive tone mediated through alpha-1 adrenergic receptors persists in the ischemic myocardium, the blockade of which is detrimental for the subendocardium.