Effects of thiopental on endothelium-dependent responses in rat aorta

Effects of pretreatment with thipental on endothelium-dependent vasodilatador responses elicited by drugs in rat aortic rings were investigated. The vasodilators employed were acetylcholine and histamine (endothelium-and receptor-dependent), A23187 (endothelium-dependent but receptor-independent) and sodium nitroprusside (endothelium-independent); they were tested 15 or 60 min to thiopental. Pretreatment with the barbiturate reversibly inhibitied relaxation elicited by either acetylcholine and histamine, but a high concentration of the anesthetic was needed (3.1 mg/ml). On the contrary, thiopental did not modify the relaxation elicited by sodium nitroprusside or A23187. In addition, the barbiturate inhibited basal and acetylcholine-stimulated production of nitrites (an indicator of nitric oxide output) in aortic rings. In conclusion, thiopental inhibited the endothelium-dependent relaxation elicited by either acetylcholine or histamine. Although the bariturate also inhibited nitric oxide production, the reduction in the relaxant response provoked by it does not seem to be the result of direct guanylate cyclase or nitric oxide synthase alterations, since thiopental did not modify the effect of sodium nitroprusside or A23187. Disturbances elicited by thiopenatal on endothelial receptors or on signal transduction elements may indirectly provoke nitric oxide synthase inhibition

Influence of 5-hydroxytryptamine on the pressor responses induced by norepinephrine and electrical sympathetic stimulation in the pithed rat

Serotonin (5-hydroxytryptamine; 5-HT) modifies the responses to several vasoconstrictor stimuli prejunctionally and/or postjunctionally. The pressent study analyzed the effects of 5-HT on the pressor responses induced by norepinephrine (NE) or electrical sympathetic stimulation in pithed rats. Responses to intravenous (i.v.) NE (0.03-3 µg/kg) or electrical stimulation at increasing frequencies (0.1 - 3 Hz) were evaluated before and during continous i.v. infusions of physiological saline (0.01 ml/min) or 5-HT (1 - 10 µg/kg x min). The effects of 5-HT on the tachycardic responses to NE and sympathetic stimulation were studied in parallel. The increases in diastolic blood pressure and heart rate produced by NE were not modified by 5-HT. In contrast, 5-HT significantly and dose-dependently inhibited the increases in diastolic blood pressure but not those in heart rate - produced by stimulation of the appropriate spinal segments. Theses effects of 5-HT were more prononced on the responses to lower frequencies of stimulation. It is suggested that 5-HT inhibits the electrically induced pressor responses by a prejunctional mechanism which would lead to a reduction of neurotransmitter release from the sympathetic nerves supplying the systemic vasculature. The selective stimulation of this inhibitory mechanism might represent a new approach for the development of novel antihypertensive agents

Comparación de los efectos de la serotonina, 2-(2-aminoetil)-quinolina (D-1997) y sumatriptan sobre el flujo sanguíneo carotídeo externo del perro / D-1997 and external carotid blood flow

La 2-(2-aminoetil)-quinolina (D-1997) es un derivado quinolínico capaz de mimetizar el efecto contráctil de la serotonina (5-hidroxitriptamina; 5HT) en la vena safena y la arteria basilar del perro. Debido a la similitud que parece existir en el tipo de receptor serotónergico presente en estas preparaciones y el que media la vasoconstricción de la cirulación carotídea del perro, el presente estudio analiza el perfil hemodinámico del D-1997 en el lecho arterial carotídeo externo de perros vago simpatectomizados anestesiados con pentobarbital. Los efectos del D-1997 se compararon con aquellos producidos por la 5-HT y el agente antimigrañoso, sumatriptan. Las infusiones intracarotídeas (i.c.), durante 1 min, de D-1997 (10, 30, 100, 300 y 1000 µg/min), 5HT (0.3, 1, 3, 10, 30 y 100 µg/min), y sumatriptan (3, 10, 30 y 100 µg/min), produjeron decrementos del flujo sanguíneo carotídeo externo (FSCE) dependientes de la dosis empleada. Debido a que estos efectos no se vieron acompañados de modificaciones en la presión arterial, los agonistas produjeron incrementos dosis-dependientes de la resitencia carotídea externa (RCE). Las respuestas vasoconstrictoras inducidas por el D-1997 y la 5-HT fueron de corta duración (hasta 10 min), mientras que aquellas producidas por el sumatriptan fueron de larga duración (hasta 40 min). Los cambios hemodinámicos producidos por el D-1997 y la 5-HT y el sumatriptan en la carótida externa no modificaron los valores basales de resitencia en el lecho arterial de la carótida común contralateral, hecho que indica un efecto local. El orden de potencia agonista aparente fue 5-HT>sumatriptan>D-1997, mientras que el orden de eficacia, representada aquí como la respuesta máxima observada, siguió un patrón diferente, es decir, D-1997 ò sumatriptan > 5-HT. La administración repetida o la administración previa de 5-HT y sumatriptan no modificó las respuestas inducidas por este nuevo agonista; en consecuencia, el D-1997 se comportó como un agonista completo sin inducción de taquifilaxia. Los resultados de este estudio indican que, al igual que en la arteria basilar y en la vena safena del perro, el D-1997 es capaz de producir contracción del músculo liso vascular en el lecho arterial carotídeo externo del perro

Pharmacological screening of some quinoline derivatives in canine vascular smooth muscle

In order to develop drugs wich can discriminate vascular 5-HT1-like receptos, this study aalyzed the agonist/antagonist interactions of several quinoline derivatives in vascular tissues containing these receptors. 5/HT and several substituted quinolines were evaluated and compared in canine basilar artery rings and saphenous vein helical strips wich were mounted in organ baths for monitoring isometric tension changes. Based upon the molecular features of quipazine, the main assayed variations included some substitutions at the 4-position of piperazine and miscellaneous substitutions at the 2-position of the quinoline nucleus. The rsults, in terms of agonist-induced contraction and-or antagonism of 5-HT-induced contraction revealed that: a) 4-alylation of the piperazinyl mioety moderately increases the agonist efficacy; b) halogenation or methylation at 5-or 6-position of both 1-piperazinyl-and 4-methyl-1-piperazinyl quinolines completely abolishes agonist activity; c) introduction of larger substituents (i.e., alkyl, carbethoxy, acethoxyalkyl, aromatic and non/aromatic rings) at the 4-position of the piperazinyl moiety, notably decreases or even abolishes the agonist activity; d) replacement of the piperainyl group by an aminoethyl moiety impotantly increases potency (more than threefold) and efficacy (more than twofold). These findings represent leads which may aid the subsequent desing of vascular 5-HT1-like-selective agents

Propiedades antiadrenérgicas alfa de la espiroxatrina, un ligando de los receptores serotonérgicos 5-HT1A / Antiadrenergic properties of spiroxatrine

La espiroxatrina, un ligando 5-HT1A, tiene muy baja afinidad por los sitios de unión Ó1-adrenérgicos y una afinidad relativamente alta por los sitios Ó2. No obstante, estudios funcionales recientes indican que la espiroxatrina es un potente antagonista de los receptores adrenérgicos a1 que median la contracción de la aorta de rata in vitro. Tomando en consideración las notables diferencias en la interacción de los fármacos con los receptores adrenérgicos Ó presentes en los diferentes modelos experimentales, el presente estudio fue diseñado para analizar las propiedades antagonistas Ó-adrenérgicas de la espiroxatrina en la rata descerebrada y desmedulada montada para el registro de la presión arterial. La norepinefrina y los agonistas adrenérgicos Ó1 y Ó2 metoxamina y clonidina, respectivamente, produjeron incrementos de la presión arterial en forma dependiente de la dosis. La espiroxitrina (1 mg/kg, i.v.) produjo un desplazamiento significativo de las curvas dosis-respuesta a los tres agonistas. La magnitud de dicho desplazamiento fue similar en los tres casos. Los resultados presentes sugieren que, aunque la espiroxatrina presenta propiedades antiadrenérgicas Ó1 y Ó2 en el modelo in vivo utilizado en este estudio, su potencia antagonista no parece corresponder con la encontrada en la aorta de rata. La posible participación de subtipo del receptor adrenérgico Ó1 es discutida

Influence of sympathetic tone on the reactivity to indorenate in the external carotid vascular bed of the dog

The present study was designed to analyze the effects of drugs th at interfere with sympathetic transmission on the external carotid vasodilator response induced by the 5-HT1A receptor agonist, indorenate, in pentobarbital-anesthetized dogs. Intracarotid (i.c.) infusions of indorenate (1000 µg/lmin) produced an increase in external carotid blood flow (external C.B.F.) without modifying mean arterial blood pressure or heart rate. This effect of indorenate was dose-dependently antagonized by intravenous (i.v.) administration of the Ó1-adrenoceptor antagonist, prazosin (1, 3.1, 10, 31 and 100 µg/kg), the ganglionic blocking agent, mecamylamine (0.31, 0.1, 0.31, 1, 3.1 and 10 mg/kg) or the 5-HT2 receptor and Ó1-adrenoceptor antagonist, ketanserin (10, 31 and 100 µ/kg). It is concluded that indorenate.induced increase in canine external C.B.F. is dependent on the vascular neurogenic tone