Firing patterns and functional roles of different classes of spinal afferents in rectal nerves during colonic migrating motor complexes in mouse colon

The functional role of the different classes of visceral afferents that innervate the large intestine is poorly understood. Recent evidence suggests that low-threshold, wide-dynamic-range rectal afferents play an important role in the detection and transmission of visceral pain induced by noxious colorectal distension in mice. However, it is not clear which classes of spinal afferents are activated during naturally occurring colonic motor patterns or during intense contractions of the gut smooth muscle. We developed an in vitro colorectum preparation to test how the major classes of rectal afferents are activated during spontaneous colonic migrating motor complex (CMMC) or pharmacologically induced contraction. During CMMCs, circular muscle contractions increased firing in low-threshold, wide-dynamic-range muscular afferents and muscular-mucosal afferents, which generated a mean firing rate of 1.53 ± 0.23 Hz (n = 8) under isotonic conditions and 2.52 ± 0.36 Hz (n = 17) under isometric conditions. These low-threshold rectal afferents were reliably activated by low levels of circumferential stretch induced by increases in length (1-2 mm) or load (1-3 g). In a small proportion of cases (5 of 34 units), some low-threshold muscular and muscular-mucosal afferents decreased their firing rate during the peak of the CMMC contractions. High-threshold afferents were never activated during spontaneous CMMC contractions or tonic contractions induced by bethanechol (100 μM). High-threshold rectal afferents were only activated by intense levels of circumferential stretch (10-20 g). These results show that, in the rectal nerves of mice, low-threshold, wide-dynamic-range muscular and muscular-mucosal afferents are excited during contraction of the circular muscle that occurs during spontaneous CMMCs. No activation of high-threshold rectal afferents was detected during CMMCs or intense contractile activity in na?ve mouse colorectum.     

Mechanosensory properties in the human gastric antrum evaluated using B-mode ultrasonography during volume-controlled antral distension

The aims of this study were to evaluate gastric antral mechanical behavior and distension-induced sensorimotor responses in the human gastric antrum using transabdominal ultrasound scanning. Ten healthy volunteers underwent volume-controlled ramp inflation of a bag located in the antrum with volumes up to 125 ml. The active and passive circumferential tensions and stresses were calculated from measurements of pressure, diameter, and wall thickness before and during the administration of the anticholinergic drug butylscopolamine. The bag distensions elicited contractions in the antrum and sensory responses below the pain threshold. Butylscopolamine abolished the contractions and significantly reduced the sensory response. The length-tension diagram known from in vitro studies of smooth muscle strips could be reproduced as tension-volume diagrams in the human gastric antrum. The number of induced contractions and the contraction pressure amplitude (afterload) showed a parabolic behavior as function of the distension volume (preload), with maximum approximately at 70 ml. At the sensation threshold, the luminal circumference showed the lowest variation coefficient (13-25%), whereas the variation coefficient was more than 100% for the pressure, tensions, and stresses. We conclude that the muscle length-tension diagram and typical preload-afterload curves ad modem the Frank-Starling cardiac law can be obtained in the human gastric antrum. The sensory responses were most closely associated with the luminal circumference, indicating that the sensation during antral distension depends on deformation rather than on tension.     

CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents

Capsaicin treatment destroys vagal afferent C fibers and markedly attenuates reduction of food intake and induction of hindbrain Fos expression by CCK. However, both anatomical and electrophysiological data indicate that some gastric vagal afferents are not destroyed by capsaicin. Because CCK enhances behavioral and electrophysiological responses to gastric distension in rats and people, we hypothesized that CCK might enhance the vagal afferent response to gastric distension via an action on capsaicin-insensitive vagal afferents. To test this hypothesis, we quantified expression of Fos-like immunoreactivity (Fos) in the dorsal vagal complex (DVC) of capsaicin-treated (Cap) and control rats (Veh), following gastric balloon distension alone and in combination with CCK injection. In Veh rats, intraperitoneal CCK significantly increased DVC Fos, especially in nucleus of the solitary tract (NTS), whereas in Cap rats, CCK did not significantly increase DVC Fos. In contrast to CCK, gastric distension did significantly increase Fos expression in the NTS of both Veh and Cap rats, although distension-induced Fos was attenuated in Cap rats. When CCK was administered during gastric distension, it significantly enhanced NTS Fos expression in response to distension in Cap rats. Furthermore, CCK's enhancement of distension-induced Fos in Cap rats was reversed by the selective CCK-A receptor antagonist lorglumide. We conclude that CCK directly activates capsaicin-sensitive C-type vagal afferents. However, in capsaicin-resistant A-type afferents, CCK's principal action may be facilitation of responses to gastric distension.     

Ia-afferent input to motoneurons during shortening and lengthening muscle contractions in humans.

The central nervous system employs different strategies to execute specific motor tasks. Because afferent feedback during shortening and lengthening muscle contractions differs, the neural strategy underlying these tasks may be quite distinct. Cortical drive may be adjusted or afferent input regulated. The exact mechanisms are not clear. Here, we examine the control of synaptic transmission across the Ia synapse during shortening and lengthening muscle contractions. Subjects were instructed to maintain isolated activity in a single tibialis anterior (TA) motor unit while muscle length was varied from flexion to extension and back. At a fixed interval after a firing of the active motor unit, a single electrical stimulus was applied to the common peroneal nerve to activate Ia afferents from the TA muscle. We investigated the stimulus-induced change in firing probability of 19 individual low-threshold TA motor units during shortening and lengthening contractions. Any change in firing probability depends on both pre- and postsynaptic mechanisms. In this experiment, motoneuron firing rate was similar during both contraction types. There was no difference in the firing probability between shortening and lengthening contractions (0.23 +/- 0.03 and 0.20 +/- 0.02, respectively). We suggest that there is no contraction type-specific control of Ia input to the motoneurons during shortening and lengthening muscle contractions. Cortical adjustments may have occurred.     

Role of vagus nerve in postprandial antropyloric coordination in conscious dogs

It is generally believed that gastric emptying of solids is regulated by a coordinated motor pattern between the antrum and pylorus. We studied the role of the vagus nerve in mediating postprandial coordination between the antrum and pylorus. Force transducers were implanted on the serosal surface of the body, antrum, pylorus, and duodenum in seven dogs. Dogs were given either a solid or a liquid meal, and gastroduodenal motility was recorded over 10 h. Gastric emptying was evaluated with radiopaque markers mixed with a solid meal. Dogs were treated with hexamethonium, N(G)-nitro-l-arginine methyl ester (l-NAME), or transient vagal nerve blockade by cooling. A postprandial motility pattern showed three distinct phases: early, intermediate, and late. In the late phase, profound pyloric relaxations predominantly synchronized with giant antral contractions that were defined as postprandial antropyloric coordination. A gastric emptying study revealed that the time at which gastric contents entered into the duodenum occurred concomitantly with antropyloric coordination. Treatment by vagal blockade or hexamethonium significantly reduced postprandial antral contractions and pyloric relaxations of the late phase. l-NAME changed pyloric motor patterns from relaxation dominant to contraction dominant. Solid gastric emptying was significantly attenuated by treatment with hexamethonium, l-NAME, and vagal blockade. Postprandial antropyloric coordination was not seen after feeding a liquid meal. It is concluded that postprandial antropyloric coordination plays an important role to regulate gastric emptying of a solid food. Postprandial antropyloric coordination is regulated by the vagus nerve and nitrergic neurons in conscious dogs.     

Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.     

Motions of Alexis St. Martin's stomach

In addition to studies on the action of gastric juice, William Beaumont studied the motility of Alexis St. Martin's stomach. He documented the nature of fundal and antral motility and how antral contractions might convert an admixture of solid food and gastric juice into a uniform homogenous semifluid. Beaumont described forcible contractions of the antrum, closure of the pylorus during antral contraction, and the discriminatory nature of the pylorus. Beaumont may also have made the first observations of the gastric motor component of the interdigestive migrating motor complex.     

A stomach road or "Magenstrasse" for gastric emptying

Gastric muscle contractions grind and mix solid/liquid meal within the stomach, and move it into the bowels at a controlled rate. Contractions are of two types: slow volume-reducing contractions of the proximal stomach (the fundus), and peristaltic contraction waves in the distal stomach (the antrum). Fundic squeeze maintains gastro-duodenal pressure difference to drive gastric emptying. Emptying is generally assumed to proceed from the antrum to the fundus, so that ingested drugs can take hours to enter the small intestines and activate. Antral contraction waves (ACW), in contrast, generate fluid motions that break down and mix gastric content. Using a computer model of the human stomach, we discover a new function of these contraction waves apart from grinding and mixing. In coordination with fundic contraction, antral contraction waves move liquid content from the fundus along a very narrow path to the duodenum through the center of the antrum. Using physiological data, we show that this gastric emptying "Magenstrasse" (stomach road) can funnel liquid gastric content from the farthest reaches of the fundus directly to the intestines within 10 min. Consequently, whereas drugs (tablets, capsules, liquid) released off the Magenstrasse may require hours to enter the duodenum, at low concentration, when released on the Magenstrasse the drug can enter the duodenum and activate within 10 min-at high concentration. This discovery might explain observed high variability in drug initiation time, and may have important implications to both drug delivery and digestion, as well as to other wall-driven emptying of elastic containers.     

Restraint stress augments postprandial gastric contractions but impairs antropyloric coordination in conscious rats

Central corticotropin-releasing factor (CRF) plays an important role in mediating restraint stress-induced delayed gastric emptying. However, it is unclear how restraint stress modulates gastric motility to delay gastric emptying. Inasmuch as solid gastric emptying is regulated via antropyloric coordination, we hypothesized that restraint stress impairs antropyloric coordination, resulting in delayed solid gastric emptying in conscious rats. Two strain gauge transducers were sutured onto the serosal surface of the antrum and pylorus, and postprandial gastric motility was monitored before, during, and after restraint stress. Antropyloric coordination, defined as a propagated single contraction from the antrum to the pylorus within 10 s, was followed by > or = 20 s of quiescence. Restraint stress enhanced postprandial gastric motility in the antrum and pylorus to 140 +/- 9% and 134 +/- 9% of basal, respectively (n = 6). The number of episodes of antropyloric coordination before restraint stress, 2.4 +/- 0.4/10 min, was significantly reduced to 0.6 +/- 0.3/10 min by restraint stress. Intracisternal injection of the CRF type 2 receptor antagonist astressin 2B (60 microg) or guanethidine partially restored restraint stress-induced impairment of antropyloric coordination (1.6 +/- 0.3/10 min, n = 6). The restraint stress-induced augmentation of antral and pyloric contractions was increased by astressin 2B and guanethidine but abolished by atropine, hexamethonium, and vagotomy. Restraint stress enhanced postprandial gastric motility via a vagal cholinergic pathway. Restraint stress-induced delay of solid gastric emptying is due to impairment of antropyloric coordination. Restraint stress-induced impairment of antropyloric coordination might be mediated via a central CRF pathway.     

Impaired gastrocolonic response and peristaltic reflex in slow-transit constipation: role of 5-HT(3) pathways

Colonic motility is modulated by the 5-hydroxytryptamine (5-HT)(3)-dependent gastrocolonic response and 5-HT(3)-independent peristaltic reflex. We compared descending colon tone responses to antral distension, duodenal lipid perfusion, and colonic distension after double-blind placebo or granisetron in 13 healthy volunteers and nine slow-transit constipated patients. Antral distension (100-300 ml) and duodenal lipids (3 kcal/min) evoked increases in colon tone in volunteers, which were blunted in constipated patients (P < 0.05). Granisetron (10 microg/kg) reduced responses to antral distension and lipids in volunteers and to lipids in constipated patients (P < 0.05). The ascending contraction of the peristaltic reflex was blunted in constipated patients (P < 0.05), whereas descending responses were similar. Granisetron did not modify the peristaltic reflex. Colonic responses to bethanechol were similar in patients and volunteers. In conclusion, antral distension- and duodenal lipid-activated gastrocolonic responses and ascending contractions of the peristaltic reflex are impaired with slow-transit constipation with loss of both 5-HT(3)-dependent and -independent function. Thus abnormalities of neural reflex modulation of colonic motor function may play pathophysiological roles in slow-transit constipation.     

Pressure-geometry relationship in the antroduodenal region in humans

Understanding of the control mechanisms underlying gastric motor function is still limited. The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin. In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry. After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin. Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%). Eighty-two percent (51/62) of contraction waves were detected manometrically. Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event. Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026). After erythromycin, episodes of strong antroduodenal contractions were observed. In conclusion, antral contractions alone do not reliably predict gastric emptying. Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying. Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.     

Vagal innervation of the rat pylorus: an anterograde tracing study using carbocyanine dyes and laser scanning confocal microscopy

In an attempt to identify the distribution and structure of vagal fibers and terminals in the gastroduodenal junction, vagal efferents were labeled in vivo by multiple injections of the fluorescent carbocyanine dye DiA into the dorsal motor nucleus (dmnX), and vagal afferents were anterogradely labeled by injections of DiI into the nodose ganglia of the same or separate rats. Thick frontal cryostat sections were analysed either with conventional or laser scanning confocal microscopy, using appropriate filter combinations and/or different wavelength laser excitation to distinguish the fluorescent tracers. Vagal efferent terminal-like structures were present in small ganglia within the circular sphincter muscle, which, in the absence of a well-developed, true myenteric plexus at this level, represent the myenteric ganglia. Furthermore, vagal efferent terminals were also present in submucosal ganglia, but were absent from mucosa, Brunner's glands and circular muscle fibers. Vagal afferent fibers and terminal-like structures were more abundant than efferents. The most prominent afferent terminals were profusely branching, large net-like aggregates of varicose fibers running within the connective tissue matrix predominantly parallel to the circular sphincter muscle bundles. Profusely arborizing, highly varicose endings were also present in large myenteric ganglia of the antrum and duodenum, in the modified intramuscular ganglia, and in submucosal ganglia. Additionally, afferent fibers and terminals were present throughout the mucosal lining of the gastroduodenal junction. The branching patterns of some vagal afferents suggested that individual axons produced multiple collaterals in different compartments. NADPH-diaphorase positive, possibly nitroxergic neurons were present in myenteric ganglia of the immediately adjacent antrum and duodenum, and fine varicose fibers entered the sphincter muscle from both sides, delineating the potential vagal inhibitory postganglionic innervation. These morphological results support the view of a rich and differentiated extrinsic neural control of this important gut region as suggested by functional studies.     

Modulatory influences on antegrade and retrograde tonic reflexes in the colon and rectum

Tonic reflexes in the colon and rectum are likely to be important in health and in disorders of gastrointestinal function. The aim of this study was to evaluate the fasting and postprandial "colorectal" and "rectocolic" reflexes in response to 2-min isobaric distensions of the colon and rectum, accounting for enteric sensation, compliance, and distending balloon volume. In 14 healthy fasting subjects, a dual barostat assembly was positioned (descending colon and rectum). A 2-min phasic distension was performed in the colon and rectum in random order while the opposing balloon volume was recorded. Sensation (phasic distension) and compliance (ramp distension) were also determined. The experiment was repeated postprandially. Colonic distension resulted in significant rectal tonic contraction in the fasting (rectal volume change: -35.4 +/- 8.4 ml, P < 0.01) and postprandial (-22.2 +/- 8.4 ml, P < 0.01) states. After adjustment for colonic sensitivity, for compliance, and for distending balloon volume, the rectal volume change remained significant; the extent of the tonic response, however, correlated significantly with increasing pain score (P < 0.01). In contrast, rectal distension did not produce a significant tonic response in the colon (fasting: -6.5 +/- 7.3 ml; postprandial: 2.7 +/- 7.3 ml), either unadjusted or adjusted for rectal sensitivity, compliance, and distending balloon volume. In conclusion, the colorectal reflex, but not the rectocolic reflex, can be readily demonstrated both before and after a meal in response to a 2-min isobaric distension in the colon and rectum, respectively. Although the presence of the colorectal reflex does not depend on colonic sensitivity or the volume of the distending colonic balloon, these factors modulate the reflex, especially in the fasting state.     

Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice

Using a recently developed in vitro preparation of vagal afferent pathways, we examined the role of TRPV1 and ASIC3 on the mechano- and chemosensitive properties of gastroesophageal sensory neurons. Esophagus, stomach, and the intact vagus nerves up to the central terminations were carefully dissected from TRPV1 and ASIC3 knockout mice and wild-type controls. The organ preparation was placed in a superfusion chamber to obtain intracellular recordings from the soma of nodose neurons during luminal stimulation of esophagus and stomach. The proximal esophagus and distal stomach were separately intubated to allow perfusion and graded luminal distension. In wild-type mice, mechanosensitive neurons were activated by low distension pressures and encoded stimulus intensity over the entire range tested. Luminal acidification significantly transiently increased the resting frequency but did not alter responses to subsequent mechanical stimulation. ASIC3 and TRPV1 knockout significantly blunted responses to distension compared with wild-type controls, with deletion of TRPV1 having a more significant effect than ASIC3 deletion. Luminal acidification did not activate mechanosensory neurons in ASIC3 and TRPV1 knockout mice. Our data demonstrate a role of TRPV1 in chemo- and mechanosensation of gastroesophageal afferents. ASIC3 may contribute to acid sensation but plays a more subtle role in responses to distending stimuli. Considering the importance of acid in dyspeptic symptoms and gastroesophageal reflux, TRPV1 or ASIC3 may be an attractive target for treatment strategies in patients who do not respond to acid suppressive therapy.     

Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats

It has been shown that centrally administered neuropeptide Y (NPY) delays gastric emptying. To determine the receptor subtypes of NPY mediating the inhibitory effects on gastric emptying, effects of intracerebroventricular injection of NPY, [Leu31,Pro34]NPY (a Y1 agonist) and NPY-(3-36) (a Y2 agonist) on solid gastric emptying and postprandial antropyloric motility were studied in conscious rats. Intracerebroventricular injection of NPY and NPY-(3-36), but not [Leu31,Pro34] NPY, delayed solid gastric emptying in a dose-dependent manner (0.03-3 nmol). After the feeding (40 min), contractions with low frequency and high amplitude of the antrum were frequently observed, and the peak contraction of the antrum occurred most often 3-6 s before the peak contraction of the pylorus. Intracerebroventricular injection of NPY and NPY-(3-36) (3 nmol), but not [Leu31,Pro34]NPY, significantly reduced antral contractions and the number of antropyloric coordination events. It is suggested that centrally administered NPY impairs postprandial antral contractions and antropyloric coordination via Y2 receptors, resulting in delayed gastric emptying.     

Systemic lipopolysaccharide influences rectal sensitivity in rats: role of mast cells, cytokines, and vagus nerve

Intraperitoneal lipopolysaccharide (LPS) produces somatic hyperalgesia, releases interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha), and activates vagal afferents. The aim of this study was to evaluate the effect of peripheral LPS on rectal sensitivity and to specify the mechanisms involved. Abdominal muscle contractions were recorded in conscious rats equipped with intramuscular electrodes. Rectal distension (RD) was performed at various times after LPS or experimental treatments. In controls, RD significantly increased the number of abdominal contractions from a threshold volume of distension of 0.8 ml. At the lowest volume (0.4 ml), this number was increased after administration of LPS (3, 9, and 12 h later), recombinant human IL-1beta (from 3 to 9 h), recombinant bovine TNF-alpha (from 6 to 9 h), and BrX-537A (from 6 to 12 h), a mast cell degranulator. The effect of LPS was reduced by doxantrazole, Lys-D-Pro-Thr, and soluble recombinant TNF receptor. Vagotomy selectively amplified the response to LPS. We conclude that, in vivo, intraperitoneal LPS lowers visceral pain threshold (allodynia) through a mechanism involving mast cell degranulation and IL-1beta and TNF-alpha release and that the vagus nerve may exert a tonic protective role against LPS-induced rectal allodynia.     

Modification of efferent vagal effects on the isolated atrium by increased extracellular K+ concentrations

Isolated vagal-innervated rabbit atria are electrically driven. Alterations of action potential, contraction, and electrotropic and inotropic vagal effects are investigated during variations of the external potassium concentration. Action potential area and contraction amplitude decrease by increasing external potassium concentration. If the potassium concentration is higher than 11 mM, the action potential disappears. At 24 mM potassium concentration the contraction amplitude of the driven atrium is reduced to 2%. Adrenaline (2.10(-5) g/ml) causes a restitution of the action potential and the contraction. With increasing potassium concentration the inotropic and the electrotropic vagal effectivity increases also. The vagal effects at the adrenaline restituted action potentials and contractions (15 mM potassium, 2.10(-5) g/ml adrenaline) are also higher than in normal solutions. The relations of electromechanical coupling are altered by potassium variation at the same coupling curve. With increasing potassium concentration the reproducibility of the vagal effects decreases.     

Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.     

Changes in afferent and efferent phrenic activities with electrically induced diaphragmatic fatigue.

In anesthetized artificially ventilated cats, diaphragmatic fatigue was produced by direct muscle stimulation with trains of pulses for 30 min. Failure of contraction was assessed from decrease in the maximal relaxation rate of transdiaphragmatic pressure twitches. Motor activities (electromyogram and motor phrenic neurogram) were processed by fast-Fourier transform analysis, which provided the power spectrum density function (PSDF). The discharge frequency of diaphragmatic afferents was also measured. In control conditions (before fatigue), intra-arterial bolus injection of lactic acid enhanced tonically active diaphragmatic afferents, whereas it reduced the firing rate of afferent fibers activated in phase with diaphragmatic contraction or relaxation. The same sensory response pattern was observed with the development of diaphragmatic fatigue. Leftward shift in PSDFs of motor phrenic neurogram also occurred, but it preceded the failure of diaphragmatic contraction as well as the changes in the electromyogram's PSDF and afferent paths, which were closely associated with lengthening of both inspiratory and total breath durations. After section of the phrenic nerves, the motor phrenic response disappeared during the fatigue trial. This demonstrates the existence of complex reflex-induced changes in the ventilatory control during diaphragmatic fatigue. They seem to involve the participation of several types of phrenic afferents.