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Caffeic acid phenethyl ester (CAPE) exerts pharmacological actions (e.g. anti-inflammatory, chemopreventive) which are relevant for potential clinical application in the digestive tract. However, no study has been published on its possible effects on intestinal motility, to date. In the present study, we investigated the effect of this plant-derived polyphenolic compound on the spontaneous contractions of the rat isolated ileum. CAPE reduced (in a tetrodotoxin-insensitive manner) spontaneous ileal contractions and this effect was reduced by the l -type Ca 2+ channel blocker nifedipine and the chelant of calcium ethylenediaminetetraacetic acid. However, the effect of CAPE was not modified by a number of inhibitors/antagonists such as of phentolamine plus propranolol, atropine, tetrodotoxin, cyclopiazonic acid, ω-conotoxin, apamin, N G -nitro- l -arginine methyl ester, 3-isobutyl-1-methylxanthine, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or a combination of SR 140333, SR48968 and SR142801. In conclusion our study shows that (i) CAPE relaxed myogenic contractions of rat ileum and that (ii) this effect occurs, at least in part, throughout a mechanism involving l -type Ca 2+ channels.

1. Electrical field stimulation (EFS) (0.5 ms in train of 2-32 Hz for 300 ms) in smooth muscle of pigeon oesophagus, in the presence of atropine (1 microm) and guanethidine (1 microm), elicited an inhibitory response consisting of a transient hyperpolarization (inhibitory junction potential, IJP) associated with muscle relaxation. 2. Sodium nitroprusside (SNP, 100 microm) induced hyperpolarization correlated to mechanical relaxation. 3. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-l-arginine (from 0.1 to 100 microm) caused a concentration-dependent reduction of electromechanical response to EFS indicating a role for NO in this response. 4. Apamin (1 microm) reduced both IJP and relaxation to EFS but was without effect on the response to SNP indicating a role for purines, which are also blocked by apamin. 5. Adenosine, AMP, ADP and ATP (all from 1 microm to 1 mm) application caused transient hyperpolarization and muscular relaxation with the following order of potency: adenosine > AMP > ADP > ATP. 6. Inhibitory responses evoked by purines are TTX (1 microm) insensitive but they were inhibited by apamin. This indicates that a purine component for the non-adrenergic non-cholinergic (NANC) response exists but the purine receptor site is not located on the neurone. 7. Overall these results suggest that NANC inhibitory response elicited by EFS presents two different components apamin-sensitive, probably purines-mediated and apamin-insensitive probably NO-mediated as apamin only partially block the response to EFS.

Background: Nitric oxide (NO) and cholecystokinin (CCK) are involved in the modulation of several neurotransmitter systems in the basal ganglia, and a functional interaction between their modulatory effects could be hypothesised. Materials and Methods: We studied the effects exerted by the administration of 7-nitroindazole (7-NI) (50 mg kg-1 i.p.), a selective inhibitor of neuronal NO synthase, on the depth EEG activity of the striatum and of the globus pallidus in both not pre-treated and sulphated CCK octapeptide (CCK- 8S)-treated (100 nM kg-1 i.p.) rats. Striatal and pallidal depth EEG power spectra were examined by means of a Fast Fourier Transform analysis. Results: Striatal depth recordings showed a marked increase of % power of slow standard rhythms after 7-NI systemic treatment. In contrast, pallidal recordings revealed an increase of % power of rapid standard rhythms after i.p. injection of 7-NI. The same modifications were not evidenced in CCK-8S pre-treated rats after 7-NI administration. Conclusion: The results show an influence exerted by peripheral CCK on the nitrergic modulation of the bioelectric activities of the striatum and of the globus pallidus. This effect could be of particular interest in the light of NO and CCK involvement in the neuroprotective mechanisms., peer-reviewed

In the pigeon oesophageal smooth muscle electrical field stimulation (EFS), in the presence of atropine and guanethidine, evoked TTX-sensitive inhibitory effects on both the electrical and mechanical activity. N(omega)-Nitro L-arginine (L-NA) (0.1-100 microM), an inhibitor of nitric oxide synthase, reduced the inhibitory EFS-evoked effects. Sodium nitroprusside (SNP) (10 microM), a NO-donor, mimicked the effects evoked by EFS. Apamin (1 microM) perfusion did not modify the inhibitory effects induced by SNP. Cystamine (10 microM), a guanylate-cyclase inhibitor, reduced the inhibitory effects elicited by EFS. This study shows a possible role for NO in the non-adrenergic non-cholinergic (NANC) inhibitory responses induced by EFS in the pigeon oesophagus.

Pigeon oesophageal smooth muscle in vitro has spontaneous electromechanical activity. In the presence of atropine and guanethidine, electrical field stimulation evokes a transient TTX-sensitive response comprising inhibition of electric bursting activity and muscular relaxation. This NANC inhibitory response was analysed using the K+ channel blockers TEA and apamin, TEA perfusion (0.1-5 mM) induced a concentration-dependent reduction in amplitude of EFS-evoked relaxation. Responses to higher stimulation frequencies were more sensitive to TEA than those to lower ones. The maximum reduction in amplitude (29% of control) was obtained on 30 Hz EFS evoked responses during 5 mM TEA perfusion. In a similar way, apamin (0.01-10 microM) perfusion reduced NANC relaxation, up to 30% of control. These results suggest that in the pigeon oesophagus, NANC intramural neurons are responsible for muscular relaxation. We speculate that an increase in K+ conductance might be the main mechanism involved, although the residual response after K+ channel blockade indicates the existence of an additional ionic mechanism.

The effects of the efferent glossopharyngeal nerve stimulation, on EMG activity of the pigeon cervical oesophagus, were studied. In control animals, stimulation caused a biphasic response characterized by an intra-stimulus excitatory component followed by a post-stimulus inhibitory one. The EMG response to glossopharyngeal stimulation appeared simultaneously throughout the cervical oesophagus. A bell-shaped mechanical wave was detected relating to the electrical excitatory component. Atropine administration antagonized the excitatory component, while the inhibitory one persisted. It occurs intra-stimulus, and its duration is increased, compared to control ones. A reduction in the oesophageal resting pressure was observed relating to the electrical inhibitory component. Hexamethonium caused complete disappearance of any EMG response to glossopharyngeal stimulation, as well as suppression of mechanical responses. The comparison between the EMG responses to swallow and to efferent glossopharyngeal stimulation suggests that in pigeon cervical oesophagus: primary peristalsis is central in origin; a dual system of glossopharyngeal fibres, excitatory and inhibitory, carries the central control for oesophageal motility; these excitatory and inhibitory fibres supply the oesophageal muscle via intramural neurons; the synaptic arrangement of the inhibitory pathway is more complex than the excitatory one.

The influence of vagal afferents on the EMG peristaltic pattern was studied in pigeon oesophagus.Bilateral vagotomy did not abolish the primary peristalsis, but induced significant modifications of the peristaltic pattern parameters.Vagal afferent stimulation induced an inhibitory effect consisting of a temporary break or definitive block of the EMG peristaltic activity already in progress.Vagal afferent stimulation also induced a reduction of the spontaneous EMG activity and this effect was abolished either by glossopharyngeal bilateral section or ganglionic block.Likewise vagal afferent stimulation, the crop distension caused inhibitory effects on EMG peristaltic pattern. This effect was abolished by bilateral vagotomy.These results indicate that vagal afferents, originating from the crop, could influence the central neurons responsible for the peristaltic motor programme.

An investigation was made into the links between electric activity of antral and of duodeno-jejunal musculature in different functional conditions. The function of the gastroduodenal junction in this linking mechanism was analysed. The following observations were made: (a) in the absence of gastric stimulation, the slow electric activities of stomach and duodenum appear to be completely independent; (b) the gastroduodenal junction evidences no electric activity of its own but is affected by that of the two adjacent structures; (c) chemical stimulation of the gastric mucosa causes activation of the electric and mechanical activity of the stomach and analogous activation of duodenal musculature; this effect is mediated by the gastroduodenal junction; (d) very probably, the transmission of gastric activation to the duodenum is myogenic for it ceases after surgical transection but not after cooling or after ligature. The possible functional role of the pyloric junction in the complex gastroduodenal mechanism is discussed.

The role of both peripheral and central mechanism in the control of primary peristalsis was studied in pigeon cervical oesophagus.The results from the transection of oesophageal muscular wall and of extrinsic nerves suggest that :i) primary peristalsis is programmed centrally.ii) extrinsic motor input is carried in glossopharyngeal nerves and distributed separately at each oesophageal level through intramural neurons.iii) intramural neurons do not seem capable of propagating the peristaltic sequence irrespective of the central control.

The effects and the mechanism of action of morphine, methionine-enkephalin and leucine-enkephalin were examined in transverse muscular strips from pigeon oesophagus. All the opiates produced a concentration-dependent excitatory effect on the spontaneous EMG activity, characterized mainly by an increase in the spike burst frequency. The maximal excitatory response to morphine and opioid peptides was fully antagonized by naloxone and tetrodotoxin, significantly reduced by atropine and it was not affected by guanethidine pretreatment. Treatment of pigeons with reserpine abolished the excitatory effects induced by opiates. The above results suggest the existence of specific opioid receptors in pigeon oesophagus. Opiates have no direct action on smooth muscle cells, increasing the EMG activity via excitatory both cholinergic and non-adrenergic non-cholinergic neurons. The hypothesis of a possible involvement of serotonergic interneurons might be advanced.

Swallowing elicits two propagated EMG peristaltic patterns in pigeon cervical oesophagus: i) "simple" peristaltic pattern and ii) "complex" peristaltic pattern. "Simple" peristaltic pattern is characterized by an intense, long-lasting burst of spikes, high in amplitude with an aboral increasing delay in onset. "Complex" peristaltic pattern presents an early short period of reduction in spontaneous electrical activity, followed by an excitatory period similar to that of "simple" pattern. The early inhibitory component has a very short delay in onset increasing aborally. Atropine abolishes the EMG excitatory component of both patterns, while the inhibitory period persists, showing increased duration and reduced propagation speed. "Simple" peristaltic pattern, mediated by cholinergic nerves, acting on muscular muscarinic receptors, is identifiable with an "on response". "Complex" peristaltic pattern shows a cholinergic muscarinic excitatory component and an atropine-resistant inhibitory component. This latter component is not a passive post-inhibitory rebound ("off response").

At rest, the pigeon cervical oesophagus, which is entirely smooth muscle, shows electric activity. This activity consists of bursts of spikes with frequency increasing in the oral-aboral direction. The bursts are un-phase locked, and there are no slow waves (E.C.A.). The surgical transection of the oesophageal muscular wall does not affect the electric activity even in a disconnected segment. After asphyxia electric activity persists, whereas the aboral gradient of frequency disappears. Therefore, the electric activity is thought to be myogenic in origin, and the frequency gradient nervous in origin. Atropine and neostigmine administration suggests that the cholinergic system modulates the electric activity, but it is not involved in the control of the frequency gradient. On the contrary, hexamethonium administration, by abolishing this gradient, lends support to the idea of a postganglionic atropine-resistant neuronal system responsible for the gradient.