RESUMEN
The in vitro pharmacology of inosine (Ino), a putative anti-inflammatory compound, has been investigated in smooth muscle preparations, with emphasis on its possible interaction with known inflammatory mediators, as well as capsaicin, an inducer of "neurogenic inflammation". The highest concentration of Ino routinely studied was 1 mM, since 10 mM nonspecifically inhibited many types of smooth muscle motor responses. In the guinea pig isolated ileum or trachea, Ino (1 mM) failed to influence the excitatory effect of capsaicin. The nitric oxide (NO)-mediated relaxant effect of capsaicin in the human colonic circular muscle was not influenced by Ino. Ino only weakly reduced the contractile effect of histamine on the guinea pig ileum. Substance P-mediated nonadrenergic, noncholinergic (NANC) contractions evoked by electrical stimulation in the guinea pig ileum were inhibited by half by Ino (1 mM). Ino showed no or only a weak inhibitory effect on NANC relaxation of the rat ileum. Arachidonic acid- or leukotriene D(4)-induced contractions of the guinea pig ileum were only moderately inhibited by Ino. Collectively, these results indicate that Ino (up to 1 mM) shows no major antagonist activity at histamine H(1) receptors, leukotriene CysLT(1) receptors, the transient receptor potential channel TRPV1 or tachykinin NK(1) or NK(2) receptors, or cyclooxygenase-inhibitory activity. Therefore, its anti-inflammatory activity is probably not associated with these mechanisms. The in vitro methods used in this study are capable of detecting a wide range of biological effects and hence may be recommended as a screening procedure for potential drugs or natural products.
Asunto(s)
Antiinflamatorios/farmacología , Inosina/farmacología , Músculo Liso/efectos de los fármacos , Animales , Antiinflamatorios/administración & dosificación , Capsaicina/farmacología , Colon/efectos de los fármacos , Colon/metabolismo , Relación Dosis-Respuesta a Droga , Cobayas , Histamina/farmacología , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Técnicas In Vitro , Inosina/administración & dosificación , Contracción Muscular/efectos de los fármacos , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Tráquea/efectos de los fármacos , Tráquea/metabolismoRESUMEN
Capsaicin-sensitive extrinsic afferent nerves have been demonstrated to release biologically active substances in the gastrointestinal (GI) tract. This fact may be useful for identifying sensory transmitter substances in isolated organ experiments. In the GI tract of animals neuropeptides like tachykinins and calcitonin gene-related peptide (CGRP) mediate specific excitatory and inhibitory effects of capsaicin; some evidence indicates a participation of purinergic mechanisms as well. The human gut (especially the circular musculature) is powerfully relaxed by capsaicin, and this effect seems to have a completely different transmitter background (nitric oxide (NO) and maybe VIP, neither of them of intrinsic neuronal origin). We propose that NO may be a sensory neurotransmitter. The "local efferent" (mediator-releasing) effect of extrinsic afferent neurons can also be demonstrated in vivo, both in animals and man. Yet, nearly normal motility of the small and large intestines (i.e., the most "autonomous" part of the GI tract) is maintained in animals with functionally inhibited capsaicin-sensitive nerves. The importance of this system in regulating GI movements may be exaggerated under pathopysiological conditions, first of all inflammation. The afferent function of capsaicin-sensitive nerves plays a role in sympathetic reflexes, such as the inhibition of GI motility after laparotomy or by peritoneal irritation.
Asunto(s)
Motilidad Gastrointestinal/fisiología , Neuronas Aferentes/fisiología , Animales , Capsaicina/farmacología , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/fisiopatología , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Neuronas Aferentes/efectos de los fármacosRESUMEN
Neurotransmitters released by myenteric neurons regulate movements of intestinal smooth muscles. There has been little pharmacological evidence for a role of purinergic mechanisms in the non-adrenergic, non-cholinergic (NANC) relaxation of the human large intestine. We used P(2) purinoceptor antagonists to assess whether such receptors are involved in the NANC relaxation of the circular muscle of the human sigmoid colon. It was also investigated whether the guanylate cyclase enzyme mediates the NANC response. Human colonic circular strips were tested in organ bath experiments with isotonic recording. NANC, non-nitrergic relaxations induced by electrical field stimulation (1 and 10 Hz, in the presence of atropine, guanethidine, and 100 microM N(G)-nitro-L-arginine [L-NOARG]) were strongly inhibited by a combination of the P(2) purinoceptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-sulfonic acid (PPADS) (50 microM) and suramin (100 microM). PPADS plus suramin was ineffective in the absence of L-NOARG. L-NOARG alone significantly reduced the NANC relaxation to electrical stimulation. PPADS plus suramin strongly inhibited the relaxation in response to exogenous alpha,beta-methylene ATP. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 microM) inhibited the NANC relaxation, but did not add to its reduction by L-NOARG. L-NOARG was still slightly effective in the presence of ODQ. Vasoactive intestinal polypeptide tachyphylaxis failed to influence the non-nitrergic NANC relaxation. It is concluded that nitric oxide (NO) and ATP co-mediate, in a non-additive manner, the NANC relaxation. NO probably acts through the guanylate cyclase, though a small fraction of its effect might be mediated by other mechanisms. Activators of the guanylate cyclase other than NO do not seem to participate in the NANC relaxation.
Asunto(s)
Colon Sigmoide/fisiología , Relajación Muscular/fisiología , Músculo Liso/fisiología , Neuronas Nitrérgicas/fisiología , Receptores Purinérgicos P2/fisiología , Adenosina Trifosfato/fisiología , Colon Sigmoide/efectos de los fármacos , Colon Sigmoide/inervación , Interacciones Farmacológicas , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/metabolismo , Humanos , Técnicas In Vitro , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Plexo Mientérico/fisiología , Neurotransmisores/farmacología , Neuronas Nitrérgicas/efectos de los fármacos , Ácido Nítrico/metabolismo , Óxido Nítrico/fisiología , Nitroarginina/farmacología , Oxadiazoles/farmacología , Antagonistas del Receptor Purinérgico P2 , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Quinoxalinas/farmacología , Estadísticas no Paramétricas , Suramina/farmacologíaRESUMEN
Two achalasia patients with former complaints of heartburn were examined. Antisecretory drugs were used by the patients when dysphagia occurred. Barium X-ray and esophageal manometry were performed and achalasia was diagnosed in both patients. Twenty-four-hour pH-metry showed significant and long-lasting acid reflux during supine position. Prolonged reflux episodes can be explained not only by the swallow-unrelated transient relaxation of lower esophageal sphincter (LES) and mechanical damage of the esophageal body, but also by its chemical insensitivity. Thus preoperative detection of reflux should determinate either the operational procedure and the postoperative follow up of the patient.