Vagal esophagomotor nerve function and esophageal motor performance in dogs with congenital idiopathic megaesophagus.

OBJECTIVES: To examine the integrity of the vagal efferent innervation to the esophagus and to assess esophageal motor performance in dogs with congenital idiopathic megaesophagus. DESIGN: An acute experimental protocol performed in control dogs and dogs with naturally acquired congenital idiopathic megaesophagus under pentobarbitone anesthesia. ANIMALS: 4 dogs with congenital idiopathic megaesophagus and 16 control dogs. PROCEDURE: Esophageal motor nerve conduction studies were performed by recording evoked compound motor action potentials from the tunica muscularis of the distal thoracic portion of the esophagus in response to supramaximal stimulation of the cervical portion of the vagus nerve at cranial and caudal sites. Subsequently, esophageal motor performance was measured over a wide range of esophageal muscle lengths by recording intraesophageal pressure responses to supramaximal twitch and tetanic stimulation of the cervical portion of the vagus at varying, stepwise amounts of esophageal distention. RESULTS: In dogs with congenital idiopathic megaesophagus, no electrophysiologic evidence was found for segmental demyelination or axonal degeneration in cervical vagal motor fibers innervating striated muscle of the thoracic esophagus portion. Nor was spontaneous EMG activity, indicative of esophageal muscle denervation or a primary myopathy, observed. In contrast, esophageal motor performance, which was dependent on esophageal dimensions, was reduced in dogs with congenital idiopathic megaesophagus. CONCLUSIONS: In dogs with congenital idiopathic megaesophagus, the vagal efferent innervation to the esophagus is likely to be normal, a primary esophageal myopathy is unlikely to be present, and the observed reduction in esophageal motor performance may arise as a secondary consequence of altered esophageal biomechanical properties rather than from a primary neuromuscular abnormality.

Sympathetic nervous system effects on feline bladder wall compliance throughout continence.

The urinary bladder is a compliant organ, high compliance being essential for useful urine storage. The extent to which the sympathetic nervous system promotes the storage of urine by increasing bladder compliance is unclear. The aim of the present study was to determine the range of bladder volumes over which the sympathetic nervous system increased bladder wall compliance. In supine, anaesthetized cats, the bladder was filled at twice the rate of natural filling, the continence cycle being interrupted at five stages. These stages were when the bladder had become globular, during prodromal contractions, soon after non-micturating contractions had commenced, approximately two-thirds of the way through the continence cycle and just prior to micturition. During each of these interruptions, bladder volume was held constant while pelvic nerve afferent activity and bladder pressure were recorded. Recordings were obtained before and during the intravenous infusion of trimethaphan, the resulting partial ganglion blockade decreasing arterial pressure by a third. Bladder pressure as well as afferent nerve activity increased significantly when the sympathetic drive was transiently blocked, indicating that there had been a prevailing net sympatho-inhibitory effect promoting bladder wall relaxation. This effect was observed during prodromal contractions and continued until the onset of micturition. This net sympatho-inhibitory effect is a potential therapeutic path for the treatment of bladder storage disorders.

Urine storage mechanisms.

The urine storage process depends upon the coordinated control of a storage chamber, the bladder body, and its outlets, the bladder base and urethra. While urine storage disorders are of considerable clinical significance, the mechanisms underlying this process are poorly understood. Many species possess an ability to alter the duration of urine storage in the face of widely varying filling rates. The storage chamber appears largely responsible for this ability to alter capacity and compliance. However, there has been some controversy over the contribution of intrinsic smooth muscle and extrinsic neural systems to the storage process, which is partly related to the various methodologies used in experimental and clinical studies. Thus, the storage phase is greatly influenced by the filling regimes, anaesthesia, non-specific factors and infusates used in these studies. Further, the techniques used to examine and measure urine storage mechanisms often obscure the subtle nature of this process. There is little doubt that, under natural filling conditions, myogenic factors allow the bladder to store increasing volumes at low pressure. More recent studies indicate that, in addition to a quiescent parasympatho-excitatory drive, the extrinsic neural systems contribute to the storage phase with a precisely controlled sympatho-inhibitory drive. However, the sympatho-inhibitory drive does not increase capacity by promoting high compliance. Instead this drive partially reduces the level of bladder wall tension transduced by the bladder wall mechanoreceptors, and thus delays the time at which the micturition tension threshold is reached.

Vagal afferent dysfunction in naturally occurring canine esophageal motility disorder.

Few studies have examined the vagal afferent innervation of the esophagus in naturally occurring esophageal motility disorders. The present study assessed the integrity of distension-sensitive vagal afferents innervating the esophagus in naturally occurring canine megaesophagus. In the dog, esophageal distension induces reflex inhibition of crural diaphragm electromyographic activity that is mediated by vagal afferents innervating esophageal mechanoreceptors. This reflex was measured during stepwise esophageal distension in six dogs with congenital idiopathic megaesophagus, two dogs with megaesophagus secondary to esophageal striated muscle disease, and eight matched controls. In contrast to control dogs, inhibition of crural electromyographic activity was not observed in megaesophagus dogs with esophageal distension within the control volume range. With esophageal distensions far in excess of the control volume range, inhibition of crural electromyographic activity was not observed in five of six dogs with congenital idiopathic megaesophagus, while crural inhibition was observed in the two dogs with secondary megaesophagus. These findings indicate that a defect is present in the vagal afferent innervation to the esophagus in a majority of dogs with congenital idiopathic megaesophagus.

Gender, bladder distension and hypogastric nerve activity in the cat.

In the pentobarbitone anaesthetised cat, postganglionic activity was recorded from the whole hypogastric nerve and from hypogastric filaments destined for the bladder wall during bladder distension. A gender difference was observed in whole hypogastric nerve recordings, cardiac-related activity obscuring other components in females with intact internal reproductive organs. In contrast, nerve activity in the vesical hypogastric filaments was dominated by bladder distension-related activity in both sexes. These observations suggest that bladder distension-related activity, which has a continence promoting action on the bladder detrusor muscle, is destined for the bladder wall, while the cardiac-related activity is largely destined for the uterine and vaginal vasculature.

Oesophageal compliance in naturally occurring canine megaoesophagus.

The passive biomechanical property of oesophageal compliance (OC) was measured in 8 naturally occurring cases of canine megaoesophagus, 8 matched control and 7 vagotomised control dogs. Of the 8 dogs with megaoesophagus, 6 had congenital idiopathic megaoesophagus and 2 had secondary megaoesophagus attributable to generalised skeletal muscle disease. Stepwise distension of the whole oesophagus was employed for measurement of OC at the 4.0 and 8.0 mL/kg injected volume steps within the control volume range (0 to 12.0 mL/kg). At both injected volume steps OC was higher in megaoesophagus dogs than in either matched control or vagotomised control dogs (P < 0.01 in both cases), and no significant difference was observed in OC between matched control and vagotomised control dogs. No correlation was demonstrated between OC and the estimated duration of clinical signs of dogs with megaoesophagus. These findings suggest that in most cases of canine megaoesophagus the viscoelastic properties of the oesophageal wall are significantly altered, that in such cases the disorder is unlikely to be purely dynamic and that processes other than the duration of oesophageal dilatation are responsible for the alteration in oesophageal wall biomechanical properties. The relevance of these findings to current concepts on pathophysiological mechanisms underlying the evolution and resolution of various forms of canine megaoesophagus is discussed.

Role of sympathetic innervation in the feline continence process under natural filling conditions.

1. The effect of the sympathetic innervation on the bladder detrusor muscle was assessed in pentobarbitone-anesthetized cats by measuring the changes in bladder wall tension that occurred during sympathetic ganglion blockade after filling the bladder at a natural rate. 2. At a point 60% of the way through the continence process, systemic sympathetic blockade was produced by intravenous trimethaphan, and selective blockade of postganglionic hypogastric nerve activity was produced by application of trimethaphan to the exposed inferior mesenteric ganglia. The level of blockade was monitored with an in-continuity hypogastric nerve recording. 3. During both systemic and selective ganglion blockade, there was an increase in baseline transmural bladder pressure and a decrease in the amplitude of nonmicturating contractions. 4. Although there was no change in the mean level of transmural bladder pressure during either systemic or selective blockade, there was a significant increase in the mean level of bladder wall mechanoreceptor discharge, suggesting that before the blockade sympathoinhibitory effects were greater than sympathoexcitatory effects. 5. Measurement of bladder wall mechanoreceptor discharge before and during ganglion blockade revealed a net sympathoinhibitory influence on the level of bladder wall tension under natural filling conditions. These results confirm that the detrusor muscle of the feline bladder is under both sympathoinhibitory and sympathoexcitatory influences for a significant portion of the continence process.

The neuropathic oesophagus. A radiographic and manometric study on the evolution of megaoesophagus in dogs with developing axonal neuropathy.

Dogs given the neurotoxin acrylamide develop peripheral neuropathy and megaoesophagus. Sequential radiographic and manometric studies on the oesophagus demonstrated that the initial abnormalities consisted of a progressive decrease in the proportion of swallows that initiated peristalsis and a gradual increase in oesophageal calibre. Regurgitation, peristaltic failure and oesophageal dilatation all appeared within three days. The eating behaviour and gait abnormalities quickly resolved on stopping the neurotoxin, but the oesophagus remained dilated for longer. Previous studies have suggested that the abnormalities present in dogs which are developing a distal axonal neuropathy or in some dogs with idiopathic megaoesophagus may be limited to the proprioceptive elements of the oesophageal innervation. The present study suggests that the progressive inefficiency in the transmission of swallows and changes in oesophageal calibre in dogs with evolving megaoesophagus may be a consequence of damage to these proprioceptive elements.

Baroreceptor dysfunction in acrylamide axonal neuropathy.

Clinical studies suggest that baroreceptor dysfunction may occur in peripheral neuropathies but this abnormality has never been observed directly or characterized. Carotid sinus nerve and depressor nerve activity was recorded in rabbits with a mild axonal neuropathy produced by acrylamide. Arterial pressure was changed by altering intravascular volume. The pattern of baroreceptor discharge in the affected animals was always different, there being a marked reduction of diastolic phase nerve activity at normal arterial pressures. In addition, nerve activity in both baroreceptor nerves was significantly reduced. The thresholds of aortic arch baroreceptors were elevated and aortic arch baroreceptor activity was less than carotid sinus baroreceptor activity at lower arterial pressures. In acrylamide axonal neuropathy, even when mild, there is baroreceptor dysfunction.

Abnormalities of sympathetic vasomotor tone in distal axonal neuropathy.

Microneurographic studies have shown that sympathetic vasomotor nerve activity is observed less frequently in patients with peripheral neuropathy than in controls, but when detected its pattern and the baroreflex latencies appear to be normal. Vasomotor nerve function was examined in chloralose-urethane anaesthetised dogs by comparing the discharge of renal sympathetic nerves in control animals and animals with acrylamide neuropathy. There was a normal pattern of pulse related inhibition of sympathetic nerve activity as well as normal amplitude spontaneous compound nerve action potentials in the animals with neuropathy. When vasomotor tone was altered abruptly by raising pressure in a bilateral isolated carotid sinus preparation, the baroreflex latencies were normal in the affected animals. However, when carotid sinus pressure was kept constant, pulse-related sympathetic inhibition, normally mediated by vagal cardiopulmonary baroreceptors, was absent in animals with neuropathy. It is likely that the vagal nerve fibres to cardiopulmonary baroreceptors as well as the receptors themselves are damaged while shorter carotid sinus nerve fibres are relatively spared in axonal neuropathies. As long as these shorter nerves are intact patients with axonal neuropathy should have relatively normal baroreflexes and normal sympathetic vasomotor tone when measured microneurographically.

Breathing pattern, lung inflation reflex and airway tone in acrylamide neuropathy.

Slowly adapting pulmonary stretch receptors (SARs) participate in numerous respiratory reflexes, including the Hering-Breuer lung inflation reflex (HBR), and reflex control of respiratory rate and depth. In addition, SAR discharge may modulate airway tone. We studied the effect of acrylamide neuropathy, which causes reversible dysfunction of SARs and their myelinated vagal afferents, on the breathing pattern, HBR and airway tone in conscious dogs. As neuropathy evolved, breathing became slow and deep, and both the apnoeic and bronchodilatory responses to lung inflation were markedly reduced, findings consistent with SAR dysfunction. Recovery of clinical neuropathy and respiratory reflexes followed acrylamide withdrawal. Despite the obvious abnormalities of SAR-mediated reflexes in acrylamide-affected dogs, airway tone remained normal and sinus arrhythmia prominent in the presence of neuropathy, suggesting that small diameter vagomotor efferents are relatively resistant to acrylamide. Acrylamide neuropathy provides a useful preparation for the study of vagomotor function in animals in which feedback from myelinated pulmonary afferents is attenuated.

Firing rate may be a determinant of nerve fibre vulnerability in axonopathies.

Analysis of the discharge characteristics and conduction velocities of single vagal nerve fibres innervating slowly adapting mechanoreceptors in the oesophagus and lungs of acrylamide affected dogs has demonstrated that a group of fibres, the fastest conducting fibres to each organ, fail to conduct. The two failed groups have conduction velocities which are grossly different and yet they have a common receptor type, they have a similar fibre length and they have the same central nervous system destination. Amongst the oesophageal fibres, the failed group with conduction velocities in the upper third of the control range had firing rates which were normally higher than those of the surviving slower conducting fibres (P less than 0.01). The same observation applied to the respiratory fibres (P less than 0.05). It is possible that firing rate is also a factor in predicting the vulnerability of axons in axonopathies.

Evoked skin sympathetic nerve responses in man.

Activity in human unmyelinated efferent nerve fibres was recorded from seven upper limb cutaneous nerve fascicles. The activity induced by contralateral nerve trunk stimulation or tone burst was averaged and could be compared providing the stimuli were delivered at random times and in a random sequence. The average evoked sympathetic nerve responses to nerve trunk stimulation and tone burst were identical in latency and duration.

Abnormal pulmonary slowly adapting receptors in canine acrylamide neuropathy.

Slowly adapting lung stretch receptors (SARs) and their vagal afferents are considered to play an important role in the mediation of numerous respiratory reflexes. The understanding of such reflexes has been facilitated by altering the discharge properties of SARs or by preventing the conduction of SAR-generated impulses to the brain stem. In a number of naturally occurring diseases of the peripheral nervous system, the vagus nerve and vagal reflexes are damaged. We have studied the function of SARs in anesthetized dogs with acrylamide neuropathy, a distal axonopathy that has been used as a model of naturally occurring neuropathies. There was a marked increase in threshold and decrease in firing rate of SARs in dogs with moderate neuropathy. Abnormal SAR discharge patterns were observed, and there was a depletion of those units innervated by the fastest conducting vagal afferent fibers in treated animals. Acrylamide induced degeneration of myelinated fibers in bronchial branches of the vagus nerve. These abnormalities were partially reversed upon withdrawal of the neurotoxin. Acrylamide may be a useful agent in the study of vagally mediated respiratory reflexes. SAR function is likely to be abnormal in diseases of the peripheral nervous system.

The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats.

The interrelationship between sorbitol excess and myoinositol deficiency in the peripheral nerve was examined in acutely diabetic rats. Nerve myoinositol concentration was also studied in galactosemic rats. Polyol pathway blockade with Sorbinil (Pfizer, Connecticut) prevented nerve myoinositol reduction in both groups of animals. This conclusion was independent of alteration in the fluid content of the peripheral nerve. It is likely that myoinositol loss from nerves is causally related to the sorbitol and galactitol accumulation.

Abnormalities of oesophageal mechanoreceptors in canine acrylamide neuropathy.

Dogs exposed to acrylamide develop peripheral neuropathy and megaoesophagus. The properties of slowly adapting oesophageal mechanoreceptors were studied in six control and five acrylamide affected greyhounds in which the oesophagus had been surgically isolated under anaesthesia and oesophageal pressure was controlled while monitoring impulses in oesophageal afferent fibres in the cervical vagus. In the acrylamide affected animals oesophageal afferent units had elevated thresholds and significantly reduced firing rates during ramp increases in oesophageal pressure. It is concluded that abnormalities of oesophageal mechanoreceptors may be important in the pathogenesis of certain oesophageal motility disorders in man and animals.

Circulatory control in canine acrylamide neuropathy.

The baroreflex regulation of arterial blood pressure and heart rate was examined in dogs with acrylamide-induced peripheral neuropathy. In anaesthetized animals the carotid sinuses were isolated from the systemic circulation and perfused. The carotid sinus and vagus nerves were kept intact. The maximum baroreflex gain (the ratio of the change in systemic pressure to a change in sinus pressure) was significantly greater in the treated animals. A step increase in carotid sinus pressure produced long periods of asystole and sustained bradycardia in the animals with neuropathy. The alterations in the baroreceptor reflex responses were consistent with dysfunction of baroreceptor fibres in the vagus.

Canine oesophageal mechanoreceptors.

The properties of slowly adapting oesophageal mechanoreceptors were determined in anaesthetized dogs in which the oesophagus had been isolated surgically. Changes in oesophageal pressure resulted in reproducible changes in oesophageal volume. Action potentials were recorded from thirty-three oesophageal afferent nerve fibres in the cervical vagus. All the receptors were located in the thoracic oesophagus. The conduction velocities of the afferent fibres ranged from 9.3 to 27.7 m/s (mean, 17.2; S.D., 4.1). The receptors were of the 'in series' type. In the pressure range of 0-1 mmHg, all units were tonically active with irregular firing rates that ranged from 0.2 to 13.0 Hz. Lung inflation altered the discharge rate in a variable manner depending upon the degree of distension of the oesophagus. The adapted discharge rate of eight units reached a maximum of 23-44 Hz (mean, 35; S.D., 8) at an oesophageal pressure of 8-15 mmHg (mean, 11; S.D., 3). The relationship between pressure and discharge rate was linear over a narrow pressure range. Ramps of similar gradient produced higher discharge rates in units whose afferent fibres had higher conduction velocities. In some units a large increase in firing rate occurred over a narrow pressure range and became more pronounced with ramps of increasing gradient. This increase in firing rate was called a 'burst'. Six out of thirty-three units showed a 'burst' response. The conduction velocities of these six units ranged from 18.7 to 23.5 m/s. Slowly adapting oesophageal mechanoreceptors could be subdivided functionally into two types. Their discharge pattern was dominated by a narrow response range. These properties may be significant in an organ that is normally empty and has a low residual volume.

The effect of aldose reductase inhibition on motor nerve conduction velocity in diabetic rats.

This study examined the effects of an aldose reductase inhibitor (CP 45634, Sorbinil, Pfizer, New York, New York) on the neuropathy of streptozotocin-induced diabetic rats. Sorbinil treatment for 4 wk reduced sciatic nerve sorbitol concentration and improved motor nerve conduction velocity in diabetes of 2-9 mo duration. It remains to be determined whether Sorbinil can prevent chronic diabetic neuropathy.