Release of nitric oxide in the central nervous system mediates tonic and phasic contraction of the cat lower oesophageal sphincter.

Nitric oxide (NO) in the brainstem is implicated in the control of swallowing and oesophageal peristalsis. This study examines the role of brainstem NO in the maintenance of lower oesophageal sphincter (LOS) tone, relaxation and contraction. In urethane-anaesthetized cats, oesophageal peristalsis and sphincter pressures were continuously monitored. Drugs were administered into the fourth ventricle. Oesophageal peristalsis and sphincter relaxation and contraction were induced by superior laryngeal nerve stimulation or intra-oesophageal balloon distention. Basal sphincter pressure was significantly reduced after the i.c.v. administration of the nitric oxide synthase (NOS) inhibitor, l-Ng-monomethyl arginine. The inhibitor's d-isomer had no significant effect on basal sphincter pressure, while l-arginine partially reversed the effect. The NOS inhibitor had no effect on sphincter relaxation, whereas the contraction of the sphincter following relaxation was significantly inhibited. Central nitric oxide synthase inhibition reduces basal LOS tone and contraction amplitude but has no effect on swallow or balloon distention induced sphincter relaxation. Therefore, central release of NO acts in the pathway to stimulate dorsal motor nucleus of the vagus neurones projecting to excitatory neurones in the sphincter. Inhibition of nitric oxide synthase in the CNS does not prevent relaxation of the LOS, suggesting that other pathways that do not utilize NO are important in the induction of LOS relaxation.

Central nervous system nitric oxide induces oropharyngeal swallowing and esophageal peristalsis in the cat.

BACKGROUND & AIMS: The functional role of brainstem nitric oxide (NO) in swallowing and esophageal peristalsis remains unknown. We examined the effects of blockade of central nervous system (CNS) NO synthase (NOS) on swallowing and on primary and secondary peristalsis. METHODS: (1) The effect of intravenous (IV) NOS inhibitor N(G)-nitro-L-arginine (L-NNA) on swallowing and swallowing-induced peristalsis was examined. (2) An NOS inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]) was administered into the fourth ventricle intracerebroventricularly (ICV), and its effects on swallowing and primary and secondary peristalsis were examined. RESULTS: (1) IV L-NNA significantly reduced the number of oropharyngeal swallows and the induction of primary peristalsis in the smooth muscle portion of the esophageal body; the change was not significant within the striated muscle portion. (2) L-NMMA given ICV significantly reduced the number of oropharyngeal swallows and the incidence of primary peristalsis in both smooth and striated muscle, but the reduction in amplitude was significant only for the smooth muscle contraction. There was a significant reduction in both the amplitude and incidence of secondary peristalsis, only in the smooth muscle portion. CONCLUSIONS: CNS NO is an important neurotransmitter in the induction of oropharyngeal swallowing and esophageal peristalsis. The neural substrates mediating striated and smooth muscle peristalsis may be both anatomically and neurochemically distinct.

Superior laryngeal nerve stimulation in the cat: effect on oropharyngeal swallowing, oesophageal motility and lower oesophageal sphincter activity.

Superior laryngeal nerve (SLN) stimulation can activate the brainstem swallowing mechanism to produce a complete swallowing sequence consisting of oropharyngeal, oesophageal and lower oesophageal sphincter (LOS) components. However, little is known of the effect of SLN stimulation (peripheral-sensory input from the pharynx) on the characteristics of oesophageal motor activity, especially in the smooth muscle portion. The present study examined the effect of varying stimulus train length and frequency on each of the three components of the reflex. Acute studies were performed in urethane anaesthetized cats. Oesophageal motility was monitored using conventional manometric techniques, and oropharyngeal swallowing by the mylohyoid electromyogram. SLN stimulus train length (1-10 sec) and frequency (5-30 Hz) were varied independently. Increased train length or frequency resulted in (1) an increase in oropharyngeal swallowing and incidence of the complete swallowing response, (2) an increase in latency to onset of the oesophageal peristaltic wave, (3) reduction of the amplitude of the evoked peristaltic contraction in the smooth muscle portion, without altering its velocity, (4) increased LOS relaxation, and increased LOS after-contraction. The LOS contraction was abolished by atropine (100 micrograms kg-1). Therefore, increased SLN stimulation not only results in excitation of the central swallowing program and the oropharyngeal stage of swallowing, but has major effects on the oesophageal and LOS stages of swallowing. Afferent SLN stimuli can impact on the control mechanisms for each stage, to inhibit or excite the stages in different ways.

Effects of nitric oxide synthase blockade on esophageal peristalsis and the lower esophageal sphincter in the cat.

The present study explores the role of nitric oxide (NO) in control of esophageal peristalsis and lower esophageal sphincter (LES) function in the cat. Studies were performed on 20 ketamine-anesthetized cats with manometric recording at the LES, 0, 2, 4, and 6 cm above the LES (smooth muscle section), and 12 and (or) 14 cm above the LES (striated muscle section). L-Ng-Nitro-arginine (L-NNA, 10(-6)-10(-4) mol/kg) was given intravenously, and the effects on swallow-induced esophageal peristalsis were assessed. (i) L-NNA increased the velocity of swallow-induced peristalsis in the smooth muscle esophagus; the effect was dose dependent, more prominent distally, and completely reversed by L-arginine (10(-3) mol/kg). (ii) L-NNA decreased the amplitude of peristaltic contraction in the very distal esophagus; the decrease also was dose dependent but not returned to normal by L-arginine. (iii) L-NNA inhibited LES relaxation (reversed by L-arginine) and decreased the LES "after-contraction" amplitude (unaffected by L-arginine). (iv) L-NNA was associated with the appearance of repetitive contractions. Basal LES tone was unaffected by L-NNA. In conclusion, NO is an important mediator for the timing of peristalsis in the distal smooth muscle esophagus and for LES relaxation in the cat, a species whose contraction amplitude is largely determined by cholinergic excitation. The role of NO in controlling esophageal body and LES contraction amplitude, and in preventing repetitive contractions, requires further study.

Electrical slow wave activity of the cat stomach: its frequency gradient and the effect of indomethacin.

The present study was performed to establish the intrinsic frequency of the slow waves in different regions of the cat stomach, to define the propagation velocity of the slow wave along the stomach, and to determine whether endogenous prostaglandins can affect the slow wave frequency. In 20 cats, electrical activity was recorded from the anterior wall of the intact stomach in vivo and in vitro, and in vitro after cutting the stomach into 16 pieces to isolate each pair of electrodes. In vivo, slow waves (4.1 +/- 0.5 cpm) were seen only from mid corpus to pylorus, the apparent propagation velocity decreasing towards the antrum. In vitro: (a) after cutting, the slow wave frequency increased, to a maximum in 1 h (12 +/- 1.8 cpm; range 10.2-17.3), with the highest frequency always in the mid or orad corpus, usually on the greater curvature (GC), (b) with indomethacin (10(-5) M) the increase in slow wave frequency was prevented or reversed, and there was a frequency gradient with the highest frequency (4.4 +/- 1.2 cpm) uniformly located in the most proximal active site on the GC, and (c) slow waves on the GC were more stable, regular and continuous than on the lesser curvature (LC), the difference being most evident in the corpus. The results suggest that the cat stomach behaves as a system of electrically coupled oscillators of different frequencies. The dominant oscillator of highest frequency is situated in the proximal corpus of the GC, with the remainder of the distal stomach entrained at this frequency. All gastric slow wave oscillators can be driven to higher frequencies by endogenous prostaglandins. The decreasing velocity of slow wave propagation distally suggests that oscillator properties and/or coupling among oscillators differs in the cat.

The central vagal efferent supply to the esophagus and lower esophageal sphincter of the cat.

BACKGROUND: Little is known of the central efferent neurons innervating the smooth muscle esophagus. The aim of this study was to define the location of the efferent neural pathways of the brain stem swallowing mechanism in the cat, particularly those supplying the esophageal body smooth muscle. METHODS: Fluorescent, retrogradely transported tracers were injected into the cervical striated muscle and thoracic smooth muscle segments of the esophagus and also the lower esophageal sphincter. RESULTS: Striated muscle efferents were found in the rostral nucleus ambiguus, but approximately 8% were located in the dorsal motor vagal nucleus. Smooth muscle efferents were present in the dorsal motor vagal nucleus in two groups, one rostral and one caudal to the obex. An additional group was found in nucleus retroambiguus. Approximately 8% of the total smooth muscle efferents were present in rostral nucleus ambiguus and were lateral to the striated muscle efferents. The lower esophageal sphincter efferents had a similar distribution to the smooth muscle efferents, but the rostral concentration of cells in the dorsal motor vagal nucleus was shifted caudally. CONCLUSIONS: Esophageal body smooth muscle motoneurons are arranged with a similar distribution to those innervating the lower esophageal sphincter but with some topographic variation.

The distribution of spinal and vagal sensory neurons that innervate the esophagus of the cat.

The distribution of spinal and vagal neurons that convey sensory information from the distal smooth muscle esophagus is poorly documented. Therefore, sensory cell bodies were retrogradely labeled by injecting fast blue into the striated and smooth muscle of the esophageal body and into the lower esophageal sphincter of the cat. The maximum distribution of spinal sensory neuron labeling was found in the following dorsal root ganglia: C1-T8 (striated muscle); C5-L2 (smooth muscle), and T1-L3 (lower esophageal sphincter). Vagal sensory neurons in the nodose ganglion were found to have a crude topographic layout. The total number of vagal sensory neurons labeled by injection into the three esophageal areas was greater than the number of spinal neurons labeled (809.7 +/- 166.1 vs. 328.9 +/- 53.4; mean +/- SEM; n = 12; P less than 0.005). It is concluded that spinal sensory neurons of the esophagus are segmentally arranged. Accordingly, each level of the esophagus has a distinct but overlapping sensory projection to the spinal cord, and afferents from all parts of the esophagus overlap the known spinal distribution of cardiac afferents.

Evidence for a non-cholinergic excitatory innervation in the control of colonic motility.

The colon of the ferret anesthetized with urethane exhibits two distinct types of motility patterns. These were abolished or considerably reduced by blocking nervous conduction in the vagus nerves by cooling to below 4 degrees C. Atropine transiently abolished motility which on its return was also found to be sensitive to vagal integrity. Electrical stimulation of either the cut central or peripheral end of a branch of the abdominal vagus caused large amplitude contractions of the colon which were not blocked by atropine or by atropine and a combination of alpha- and beta-adrenoceptor blocking agents. These results are consistent with either two separate motor pathways to the colon in the vagus nerve, one cholinergic, the other non-adrenergic, non-cholinergic, or a single pathway with the effects mediated by a primary and a co-transmitter. They also demonstrate that "spontaneous activity" is driven in part by both cholinergic and non-cholinergic mechanisms.

Vago-vagal reflexes to the colon of the anaesthetized ferret.

Electrical stimulation of the central end of the vagal communicating branch in the thorax at frequencies between 2 and 20 Hz elicited, after a latency of 7.2 +/- 0.8 s, large-amplitude colonic contractions. 5 Hz stimulation gave near maximal contractions and, because vomiting was more likely to occur at higher stimulus frequencies, was used as the standard stimulus for subsequent experiments. At this frequency the peak colonic contraction was 6.5 +/- 0.9 kPa. Following atropine the characteristics of the response to central vagal stimulation differed from that seen before atropinization. The latency was longer (45.7 +/- 8.2 s) and the amplitude greatly attenuated (0.7 +/- 0.2 kPa). Cooling the vagus nerves to 2 degrees C at a level either above or below the site of stimulation completely abolished both the cholinergic and the atropine-resistant colonic responses to central vagal stimulation. These results are consistent with the vagus containing two motor pathways to the colon which are reflexly stimulated by a vagal afferent input. The functional significance of these reflexes is discussed.

Vagal control of colonic motility in the anaesthetized ferret: evidence for a non-cholinergic excitatory innervation.

Spontaneous colonic motility in the urethane-anaesthetized ferret consists of two distinct types of contraction which correspond to the patterns recorded myoelectrically in conscious animals. This motility was abolished or greatly reduced when nervous conduction was prevented in the cervical vagi by cooling to below 4 degrees C. On rewarming the nerves the colonic motility returned, after a short latency, to the pre-cool level. Atropine transiently abolished colonic motility. On its return the motility was significantly reduced but still sensitive to vagal integrity. Thus the atropine-resistant colonic motility was also abolished or markedly reduced by cooling the cervical vagi to below 4 degrees C. On rewarming there was a longer latency for the return of motility compared to that before atropinization. Electrical vagal stimulation produced, after a short latency, large-amplitude colonic contractions. Following atropine, the short-latency response to electrical vagal stimulation was replaced in the majority of animals by a long-latency response whose characteristics were quite different from those of the cholinergic response. These results are consistent with the vagus containing two functional motor pathways to the colon, one to cholinergic post-ganglionic neurones and the other operating via a non-cholinergic mechanism.

Vagal influences on the jejunal 'minute rhythm' in the anaesthetized ferret.

Spontaneous jejunal motility in the urethane-anaesthetized ferret shows a cyclical pattern of contraction bursts alternating with quiescent periods described as 'minute rhythm' in conscious animals. Cooling the cervical vagi to below 4 degrees C or acute vagotomy abolished this pattern of motility. On re-warming the vagi there was a return to cyclical motility after a latency which depended upon the contractile state at the time vagal conduction was restored. Electrical vagal stimulation produced bursts of contractions at the same frequency as the spontaneous motility. Longer periods of stimulation gave rise to bursts of contractions interrupted by periods of relative quiescence, mimicking the spontaneous motility, despite the continuous stimulation. Following atropinization all spontaneous motility was abolished, but electrical stimulation of the vagi revealed a non-cholinergic, non-adrenergic response whose characteristics differed from that of the cholinergic response. It is concluded that the vagus plays a permissive role in regulating the jejunal 'minute rhythm' via a cholinergic pathway and that there is a second excitatory vagal pathway which innervates non-cholinergic post-ganglionic neurones whose functional significance and transmitter mechanism is unknown.