Pharmacological Characterization of the Presynaptic Α‐Adrenoceptors Regulating Cholinergic Activity in the Guinea‐Pig Ileum (original) (raw)
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Naunyn-Schmiedeberg's Archives of Pharmacology, 1985
The effects of noradrenaline and isoprenaline were examined on preparations of guinea-pig ileum, in which contractions were induced by three different methods; by transmural electrical stimulation, by exogenous carbachol and by potassium depolarization. Alpha-or beta-adrenoceptor-mediated responses were examined by construction of cumulative concentration-response curves in the presence of propranolol (10 -6 M) and phentolamine (5• 10 -6 M) respectively. Stimulation of alpha-adrenoceptors by noradrenaline virtually abolished the twitches from transmural stimulation, but only partially inhibited the carbachol-and potassium-induced contractions. The effects on the last two preparations were attributed to a postsynaptic inhibition at alpha-adrenoceptors on the longitudinal smooth muscle. In the transmurally-stimulated preparation there was an additional pre-synaptic alphaadrenoceptor-mediated inhibition of cholinergic transmission. The maximum beta-adrenoceptor-mediated inhibition of all three preparations to noradrenaline and isoprenaline was of the same magnitude and attributed only to a post-synaptic action on longitudinal smooth muscle.
British Journal of Pharmacology, 1988
The receptors for glutamic acid (L-Glu) present in the guinea-pig myenteric plexus-ileal longitudinal muscle preparation have been studied by measuring the muscle contraction induced by numerous putative endogenous agonists acting at these receptors. Furthermore, the actions of different concentrations of antagonists, glycine, Mg2 + and Ca2+ on the ileal contractions induced by L-Glu have been evaluated. 2 The EC5o values of the most common putative endogenous agonists of these receptors were: L-Glu 1.9 x 10-5M; L-aspartate 8 x 10-'M; quinolinate 5 x 10-4M; L-homocysteate 1.4 x 10-4M; the dipeptide aspartyl-glutamate 8 x 10-M, while N-acetyl-aspartyl-glutamate was inactive. Among the molecules used to classify excitatory amino acid receptors, N-methyl-D-aspartate (NMDA) was the most potent (EC50 5 x 10-M). Kainic and quisqualic acids were almost completely inactive. 3 The responses to L-Glu were competitively antagonized by 2-amino-5-phosphonovaleric acid. They were, also, prevented by hyoscine (10-7M) and by tetrodotoxin (3 x 10-7M), suggesting that the L-Glu-induced ileal contraction was in some way dependent upon an action on the myenteric cholinergic neurones. Kynurenic acid was a non-competitive antagonist, y-D-glutamyl-taurine (10-4M) and aminophosphonobutyric acid (10-M) did not modify the L-Glu-induced contractions. 4 Glycine (10 5 M) significantly potentiated the effects of glutamate especially when the ionic composition of the superfusion medium contained concentrations of Ca2+ in the range of 0.6-1.2 mm. Strychnine 3 x 10-5 M did not modify the actions of glycine. 5 The data presented here confirm the presence of NMDA receptors in the guinea-pig myenteric plexus, and show that these receptors, similar to those present in primary neuronal cultures may be modulated by glycine. ' Author for correspondence. ileal muscle which appeared to be mediated by the myenteric cholinergic neurones (Moroni et al., 1986). In the present studies we further investigated the actions of numerous putative endogenous agonists and antagonists possibly acting at the NMDA receptor level. Furthermore, since it has been clearly shown that glycine significantly potentiates the electrophysiological actions of L-Glu at the level of the NMDA receptor-ion-channel complex (Johnson & Ascher, 1987; Ascher & Nowak, 1987), we studied the effects of glycine on the actions of L-Glu. Methods Male guinea-pigs weighing 300-500 g were used for the study. The longitudinal muscle of their ilea with
Life Sciences, 1992
carboxamide hydrochloride) and cisapride was studied on the electrically-induced neurogenic cholinergic twitch contractions in the guinea pig ileum circular muscle. These compounds caused a concentration-dependent increase in the amplitude of submaximal twitch contractions with the following rank order of potency: 5-HT > BIMU 8 = cisapride. The effect of 5-HT was competitively antagonized by tropisetron (ICS 205-930) (apparent pA2 value: 6.4), suggesting an interaction at 5-hydroxytryptamine4 (5-HT4) receptors. The novel benzimidazolone derivative DAU 6285 (endo-6-methoxy-8methyl-8-azabicyclo [3.2.1 .] oct-3-yl-2,3-dihydro-2-oxo-1H-benzimidazole-l-carboxylate hydrochloride), antagonized the effect of 5-HT, BIMU 8 and cisapride with apparent pA2 values in the range 7.1-7.3. Our findings demonstrate that cholinergic neurones innervating the circular coat are endowed with excitatory 5-HT4 receptors. DAU 6285 is approximately 5-9-fold more potent than tropisetron as antagonist at these receptors.
Effect of morphine and acetylcholine on contractile activity and cyclic AMP in guinea-pig ileum
Bioscience Reports, 1990
Neither acute nor prolonged exposure to morphine altered cAMP content or spontaneous movements of longitudinal muscle-myenteric plexus strips of the guinea-pig ileum. By contrast, exogenous acetylcholine or electrical stimulation of the strips elicited both a decrease of cAMP concentration and a twitch response. Atropine blocked the effects of stimulation on these parameters. Addition of morphine to electrically stimulated strips inhibited the twitch response but did not affect cAMP levels. Incubation with morphine led to the development of tolerance to the inhibitory effect on twitch activity and prevented the fall in cAMP normally elicited by electrical stimulation. These results suggest that muscarinic activation is associated with a reduction of cAMP content, an effect which would be impaired in opiate-tolerant tissues.
Neuroscience Letters, 1983
The substance P (SP) analog, I~ProZ,v-TrypT'9-SP attenuated in a dose-dependent fashion noncholinergic excitatory responses of the guinea pig ileum to the exogenous administration of SP, but did not affect the atropine-resistant contractures produced by serotonin (I ~tM), histamine (1 ~M), bradykinin (0.01 pM) or prostaglandin FT~ (10 ~tM). Pretreatment with •-ProZ, D-TrypT'9-SP also significantly reduced the magnitude of the non-cholinergic contracture evoked by field stimulation at 20 Hz. These results suggest that enteric SP-containing neurons can function in an efferent motor capacity to bring about non-cholinergic excitation of the longitudinal muscle layer of the guinea pig small bowel.
The cholinergic response is increased in isolated ileum from gastroschisis rat model
Pediatric Surgery International
Introduction Babies with gastroschisis (G) have high morbidity rate and long hospital stay due to bowel hypomotility caused by chronic exposure of the bowel to the amniotic fluid. Our aim was to evaluate the reactivity of isolated ileum in fetal rats selected for experimental gastroschisis. Method G was surgically created at 18.5 days of gestation (term = 22 days). Concentration-dependent curve to the muscarinic agonist methacholine (1–30 μM) and contractions induced by electrical field stimulation (EFS, 1–16 Hz, 50 V, 1 ms) were carried out in isolated ileum of groups control (C), sham (S) and gastroschisis (G) (n = 30). Protein expression for M3 was assessed by western blot analysis. Results The frequency and amplitude of spontaneous contractions were decreased in G (p < 0.001). Methacholine produced concentration-dependent contractions being the maximal response values higher in G (p < 0.01). EFS-induced frequency-dependent contractions showed 1.8 times higher in G as well as an increase of M3 expression. Conclusion The frequency and the amplitude of rhythmic contractions were reduced along with an increase in the contraction induced by mucarinic agonist and by EFS in G. These results suggest the occurrence of an adaptative supersensitivity to cholinergic response via increases in the protein expression for M3 receptor.
Digestive Diseases and Sciences, 1985
Nociceptive stimulation of the peritoneum inhibits colonic motility via a sympathoadrenergic reflex. This sympathetic reflex most probably induces the inhibition indirectly via a presynaptic blockade of cholinergic transmission. To further clarify this reflex, colonic motility was continuously recorded by a volume method in rats exposed to nociceptive abdominal stimulation and intravenous drug administration. Intraabdominally applied HCl inhibited colonic motility, which was unaffected by nonselective beta-adrenoceptor blockade (propranolol). However, the nonselective alpha-adrenoceptor antagonist phentolamine and the selective alpha 2-adrenoceptor antagonist yohimbine restored motility. Spontaneous colonic motility was unaffected by the nonselective beta-adrenoceptor agonist (isoproterenol) and the selective alpha 1-adrenoceptor agonist (L-phenylephrine). On the other hand, a nonselective alpha-agonist (noradrenaline) and a selective alpha 2-adrenoceptor agonist (clonidine) inhibited spontaneous colonic motility. It is suggested that in the rat sympathetic reflex inhibition of colonic motility caused by abdominal nociception is mediated via presynaptic alpha 2-adrenoceptors inhibiting the excitatory cholinergic neurons.