Cigarette smoke in lungs evokes reflex increase in tracheal submucosal gland secretion in dogs.

Stimulation of pulmonary C-fibers (PCs) by capsaicin and of rapidly adapting receptors (RARs) by reduced lung compliance reflexly increases airway submucosal gland secretion in dogs. Because both PCs and RARs are stimulated by cigarette smoke (nicotine being the primary stimulus), we performed experiments in anesthetized open-chest artificially ventilated dogs (with aortic nerves cut) to determine whether cigarette smoke reflexly stimulates airway secretion. We measured submucosal gland secretion by counting the hillocks in a 1.2-cm2 field of tracheal epithelium coated with tantalum dust. Secretion was stimulated by delivery of 40-320 ml smoke from high-nicotine cigarettes to the lower trachea, secretion rate increasing from 7.4 +/- 1.3 to 48.1 +/- 5.1 hillocks.cm-2.min-1. Results of cutting the pulmonary vagal branches or carotid sinus nerves or both indicated that the secretory response was initiated by stimulation of lower respiratory vagal afferents and augmented several seconds later by stimulation of carotid chemoreceptors. Results of cooling the cervical vagus nerves to 7 and 0 degrees C indicated that most of the vagally mediated increase in secretion was due to stimulation of afferent lung C-fibers.     

Activation of lung vagal sensory receptors by circulatory endotoxin in rats

Although endotoxin is known to induce various pulmonary responses that are linked to the function of lung vagal sensory receptors, its effects on these pulmonary receptors are still not clear. This study investigated the effects of circulatory endotoxin on the afferent activity of lung vagal sensory receptors in rats. We recorded afferent activity arising from vagal pulmonary C fibers (CFs), rapidly adapting receptors (RARs), tonic pulmonary stretch receptors (T-PSRs), and phasic pulmonary stretch receptors (P-PSRs) in 64 anesthetized, paralyzed, and artificially ventilated rats. Intravenous injection of endotoxin (50 mg/kg; lipopolysaccharide) stimulated 7 of the 8 CFs, 8 of the 8 RARs, and 4 of the 8 T-PSRs studied, while having no effect on the 8 P-PSRs tested. The stimulation started 3-16 min after endotoxin injection and lasted until the end of the 90-min observation period. The evoked discharge of either CFs or RARs was not in phase with the ventilatory cycle, whereas that of T-PSRs showed a respiratory modulation. Injection of a saline vehicle caused no significant change in the discharge of these receptors. Additionally, endotoxin significantly produced an increase in total lung resistance, and decreases in dynamic lung compliance and arterial blood pressure. Our results demonstrate that a majority of lung vagal sensory receptors are activated following intravenous injection of endotoxin, and support the notion that these pulmonary receptors may function as an important afferent system during endotoxemia.     

Phenyldiguanide activates cardiac receptors to produce responses by involving three different efferent pathways in anaesthetized rats

The present study was undertaken to determine the afferent and efferent pathways involved in the phenyldiguanide (PDG)-induced reflex response in rats. Intravenous (iv) injection of PDG (10 microg/kg), produced hypotension, bradycardia and apnea over a period of time. Bilateral vagotomy abolished the PDG-induced reflex changes. Atropine (2 mg/kg; iv) blocked only the bradycardiac response produced by PDG, while prazosin (0.5 mg/kg; iv) blocked the hypotensive response, and bilateral vagotomy in these animals abolished the apneic response. In separate series of experiments, intrapericardial injection of lignocaine abolished the hypotensive and bradycardiac responses evoked by PDG in artificially ventilated rats. The results reveal that the PDG-induced reflex is mediated through vagal afferents originating from the heart and efferents involve three different pathways. The bradycardiac response was through the muscarinic receptors, the hypotension is mediated through alpha1 adrenoceptors and the apnea presumably through the spinal motoneurones supplying the respiratory muscles.     

Acute hypoxia prolongs the apnea induced by right atrial injection of capsaicin.

Inspiratory central drive is augmented by acute hypoxia that leads to a hyperventilation, but it is inhibited by capsaicin (Cap)-induced stimulation of pulmonary C fibers (PCFs) that produces an expiratory apnea. We hypothesized that acute hypoxia should shorten or eliminate the Cap-induced apnea. The ventilatory responses to bolus injection of Cap (0.2-0.5 microg) into the right atrium before and during acute hypoxia (10% O(2) for approximately 1 min; Hypoxia+Cap) were compared in anesthetized and spontaneously breathing rats. We found that Cap injection during acute hypoxia produced an extremely long-lasting apnea (69.67 +/- 11.97 s) that was 16-fold longer than the apnea induced by Cap alone (expiratory duration = 4.37 +/- 0.53 s; P < 0.01). A similar prolonged apnea was also observed during hypoxia in anesthetized guinea pigs. Bilateral vagotomy abolished apneic responses to Cap both before and during hypoxia. Subsequent recording of single-fiber activity of PCFs (PCF(A)) showed that acute hypoxia did not significantly affect baseline PCF(A) but that it doubled PCF(A) responses to Cap via increasing both the firing rate (3.34 +/- 0.76 to 7.65 +/- 1.32 impulses/s; P < 0.05) and burst duration (1.12 +/- 0.18 to 2.32 +/- 0.31 s; P < 0.05). These results suggest that acute hypoxia augments PCF-mediated inspiratory inhibition and thereby leads to an extremely long-lasting apnea. This interaction is partially due to hypoxic sensitization of PCF response to Cap.     

Two subgroups of lung vagal C-fibers with different vulnerabilities to blockades by perivagal capsaicin and vagal cooling in dogs

Perivagal capsaicin treatment and vagal cooling are two techniques that have been widely used to study the respiratory reflexes mediated by lung vagal C-fibers because they can block the neural conduction of unmyelinated fibers. We hypothesized that there are two subgroups of lung vagal C-fibers which have different vulnerabilities to blockades by these two techniques. To test this hypothesis, afferent activity arising from lung vagal C-fibers was recorded in 29 anesthetized, paralyzed, and artificially ventilated dogs. Afferent C-fiber activity was recorded before and after various concentrations of perivagal capsaicin treatment or before and during various temperatures of vagal cooling. Of the 89 lung vagal C-fibers studied, 73 fibers were classified as the group of "low resistance" to capsaicin, while the other 16 were classified as the group of "high resistance". The former group differed from the latter due to their afferent activity being blocked at relatively low concentrations of perivagal capsaicin and at relatively low temperatures of vagal cooling. Our results suggest that lung vagal C-fibers can be categorized into two subgroups, based upon their different blocking thresholds for perivagal capsaicin and vagal cooling. Our data may provide information for researchers to further differentiate the respiratory reflexes originating from these two subgroups of lung vagal C-fibers.     

BCTC和辣椒辣素对卵清蛋白致敏大鼠气管平滑肌张力的影响

目的：评价BCTC和辣椒辣素对气道高反应性大鼠气管平滑肌张力的影响。方法：健康成年SD大鼠32只,每只大鼠第1天和第8天腹腔加皮下注射卵清蛋白致敏,第15天连续雾化吸入卵清蛋白（OVA）三天,激发建立哮喘模型。分离气管平滑肌,随机分为四组,0组（Ovalbumin）卵清蛋白组,OC组（Ovalbumin＋capsaicin）卵清蛋白＋辣椒辣素组,0B组（Ovalbumin＋BCTC）,DSMO组（DSMO＋Ovalbumin）溶剂组。分别在4组溶液的刺激下测定离体气管平滑肌张力的变化。结果：离体气管平滑肌的张力OC组较0组为高;O组气管平滑肌张力比0B组高。结论：辣椒辣素增加致敏离体气管平滑肌张力,BCTC能够降低致敏大鼠气管平滑肌张力,对致敏离体平滑肌有松弛作用。     

Oxidative stress impairs cardiac chemoreflexes in diabetic rats

We investigated the effects of diabetes mellitus and antioxidant treatment on the sensory and reflex function of cardiac chemosensory nerves in rats. Diabetes was induced by streptozotocin (STZ; 85 mg/kg ip). Subgroups of sham- and STZ-treated rats were chronically treated with an antioxidant, vitamin E (60 mg/kg per os daily, started 2 days before STZ). Animals were studied 6-8 wk after STZ injection. We measured renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MABP), and cardiac vagal and sympathetic afferent activities in response to stimulation of chemosensitive sensory nerves in the heart by epicardial application of capsaicin (Caps) and bradykinin (BK). In cardiac sympathetic-denervated rats, Caps and BK (1-10.0 microg) evoked a vagal afferent mediated reflex depression of RSNA and MABP, which was significantly blunted in STZ-treated rats (P < 0.05). In vagal-denervated rats, Caps and BK (1-10.0 microg) evoked a sympathetic afferent-mediated reflex elevation of RSNA and MABP, which also was significantly blunted in STZ-treated rats (P < 0.05). Chronic vitamin E treatment effectively prevented these cardiac chemoreflex defects in STZ-treated rats without altering resting blood glucose or hemodynamics. STZ-treated rats with insulin replacement did not exhibit impaired cardiac chemoreflexes. In afferent studies, Caps and BK (0.1 g-10.0 microg) increased cardiac vagal and sympathetic afferent nerve activity in a dose-dependent manner in sham-treated rats. These responses were significantly blunted in STZ-treated rats. Vitamin E prevented the impairment of afferent discharge to chemical stimulation in STZ rats. The following were concluded: STZ-induced, insulin-dependent diabetes in rats extensively impairs the sensory and reflex properties of cardiac chemosensitive nerve endings, and these disturbances can be prevented by chronic treatment with vitamin E. These results suggest that oxidative stress plays an important role in the neuropathy of this autonomic reflex in diabetes.     

Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.     

Capsaicin administration inhibits the abducent branch but excites the thyroarytenoid branch of the recurrent laryngeal nerves in the rat.

Our recent study showed that both inspiratory and expiratory activities of the recurrent laryngeal nerve (RLN) were enhanced by capsaicin administration in the rat (Lu IJ, Ku LC, Lin JT, Lee KZ, and Hwang JC. Chin J Physiol 45: 143-154, 2002). There are two intralaryngeal branches of the RLN: one innervates the thyroarytenoid (TA) muscle and the other innervates the abductor (Abd) muscles. To examine whether these two intralaryngeal branches respond similarly to capsaicin administration, their discharges as well as activities of the phrenic nerve (PNA) and the superior laryngeal nerve (SLNA) were monitored in anesthetized and ventilated rats at normocapnia in hyperoxia. The low dose of capsaicin (0.625 microg/kg) produced a cardiopulmonary chemoreflex, showing apnea, a decrease in PNA, hypotension, and bradycardia, and significant decreases in SLNA and the activity of the Abd branch. Concurrently, there was an increase in the intralaryngeal TA activity during both apnea and the recovery from apnea. The high dose of capsaicin (1.25 microg/kg) evoked larger chemoreflexive responses and laryngeal nerve activities. In addition, both doses of capsaicin initiated a similar delay in the onset of Abd activity and SLNA but an earlier onset for the TA branch to commence during inspiration. A bilateral vagotomy abolished the laryngeal responses to capsaicin administration. However, PNA and blood pressure were enhanced with capsaicin administration after the vagotomy. These results suggest that laryngeal adduction in response to capsaicin administration is vagal afferent dependent and that it may also represent reflexive protection for the airway and lungs.     

Stimulation of rapidly adapting receptors in canine lungs by a single breath of cigarette smoke

Inhalation of smoke generated from high-nicotine cigarettes frequently evoked an immediate augmented inspiration in conscious dogs (J. Appl. Physiol. 54: 562-570, 1983); this reflex response was believed to result from a stimulation of rapidly adapting receptors in the lungs. To test this hypothesis, we recorded the vagal afferent activity arising from the rapidly adapting receptors in the lungs and delivered 120 ml of high- and low-nicotine cigarette smoke separately in a single ventilatory cycle in 20 anesthetized open-chest and artificially ventilated dogs. These receptors were stimulated on the first breath of delivery of smoke generated by high-nicotine cigarettes; activity increased from a base line of 0.9 +/- 0.2 to a peak of 9.9 +/- 1.2 (SE) impulses/breath (n = 58). After three to six breaths when the receptors' discharge returned toward base-line activity, a delayed increase of activity emerged (peak activity = 3.4 +/- 0.6 impulses/breath, n = 58) in 32 of the 58 receptors studied and lasted for three to seven breaths. By contrast, only a mild stimulatory effect of low-nicotine cigarette smoke was found, either immediately or after a delay, in 15 of the 54 receptors studied. We conclude that rapidly adapting receptors are stimulated by a single breath of cigarette smoke and that nicotine is the primary stimulant agent.     

Postnatal development of right atrial injection of capsaicin-induced apneic response in rats.

Apnea and respiratory failure often occur in infants with pulmonary disease. Bronchopulmonary C-fiber (PCF)-mediated apnea is an important component of respiratory dysfunction. This study was undertaken to define the postnatal development of PCF-mediated apnea. The experiments were conducted in five groups of anesthetized, tracheotomized, and spontaneously breathing rats with ages at postnatal days P1-3, P7-9, P14-16, P21-23, and P56-58. Right atrial bolus injection of three doses of capsaicin (Cap), equivalent to 2, 4, and 8 microg/kg used previously in 450-g rats, was applied to stimulate PCFs. We found that 1) Cap-induced apneic response [percent change from the baseline expiratory duration (Te) values (deltaTe%)] and the sensitivity of this response (deltaTe%.microg(-1)) were significantly greater in the rats P10; 2) the Cap-induced apneas were vagally dependent in all rats tested; and 3) bivagotomy-induced prolongation of Te was much greater in the rats P10. From these findings we concluded that, compared with the older rats (>P10), the newborn rats have a stronger PCF-mediated respiratory inhibition that may contribute to infants' vulnerability to respiratory failure.     

Role of vagal afferents in the control of abdominal expiratory muscle activity in the dog.

We examined the contribution of afferent vagal A- and C-fibers on abdominal expiratory muscle activity (EMA). In seven spontaneously breathing supine dogs anesthetized with alpha-chloralose we recorded the electromyogram of the external oblique muscle at various vagal temperatures before and after the induction of a pneumothorax. When myelinated fibers were blocked selectively by cooling the vagus nerves to 7 degrees C, EMA decreased to 40% of control (EMA at 39 degrees C). With further cooling to 0 degrees C, removing afferent vagal C-fiber activity, EMA returned to 72% of control. On rewarming the vagus nerves to 39 degrees C, we then induced a pneumothorax (27 ml/kg) that eliminated the EMA in all the dogs studied. Cooling the vagus nerves to 7 degrees C, during the pneumothorax, produced a slight though not significant increase in EMA. However, further cooling of the vagus nerves to 0 degrees C caused the EMA to return vigorously to 116% of control. In three dogs, intravenous infusion of a constant incrementally increasing dose of capsaicin, a C-fiber stimulant, decreased EMA in proportion to the dose delivered. These results suggest that EMA is modulated by a balance between excitatory vagal A-fiber activity, most likely from slowly adapting pulmonary stretch receptors, and inhibitory C-fiber activity, most likely from lung C-fibers.     

Selective potentiating effect of RS14203 on a serotoninergic pathway in anesthetized rats

The usefulness of selective inhibitors of type 4 phosphodiesterase (PDE4) in the treatment of inflammation and pulmonary diseases is limited by their side effects: nausea and vomiting. We studied the effect of three structurally diverse PDE4 inhibitors on the vagal nerve afferent and efferent fibers in anesthetized rats. The effects of RS14203, (R)-rolipram, and CT-2450 were evaluated on the von Bezold-Jarisch reflex (vagal afferent fibers) and in a model of vagal electrical stimulation (vagal efferent fibers). All three PDE4 inhibitors were administered at 1, 10, or 100 microg/kg (iv) 15 min prior to the induction of bradycardia by an iv injection of 2-methyl-5-HT (von Bezold-Jarisch reflex) or by vagal electrical stimulation. At 100 microg/kg, RS14203 significantly potentiated the 2-methyl-5-HT response. No statistically significant effects were observed with (R)-rolipram or CT-2450 at the doses studied. RS14203, (R)-rolipram, or CT-2450 (1-100 microg/kg iv) did not affect the bradycardia induced by vagal electrical stimulation. Consequently, our results show that RS14203 selectively facilitates serotoninergic neurotransmission in vagal afferent fibers. The emetic action of RS14203 may be mediated by this mechanism.     

2-aminoethoxydiphenyl borate stimulates pulmonary C neurons via the activation of TRPV channels

This study was carried out to determine the effect of 2-aminoethoxydiphenyl borate (2-APB), a common activator of transient receptor potential vanilloid (TRPV) type 1, 2, and 3 channels, on cardiorespiratory reflexes, pulmonary C fiber afferents, and isolated pulmonary capsaicin-sensitive neurons. In anesthetized, spontaneously breathing rats, intravenous bolus injection of 2-APB elicited the pulmonary chemoreflex responses, characterized by apnea, bradycardia, and hypotension. After perineural treatment of both cervical vagi with capsaicin to block the conduction of C fibers, 2-APB no longer evoked any of these reflex responses. In open-chest and artificially ventilated rats, 2-APB evoked an abrupt and intense discharge in vagal pulmonary C fibers in a dose-dependent manner. The stimulation of C fibers by 2-APB was attenuated but not abolished by capsazepine, a selective antagonist of the TRPV1, which completely blocked the response to capsaicin in these C fiber afferents. In isolated pulmonary capsaicin-sensitive neurons, 2-APB concentration dependently evoked an inward current that was partially inhibited by capsazepine but almost completely abolished by ruthenium red, an effective blocker of all TRPV channels. In conclusion, 2-APB evokes a consistent and distinct stimulatory effect on pulmonary C fibers in vivo and on isolated pulmonary capsaicin-sensitive neurons in vitro. These results establish the functional evidence demonstrating that TRPV1, V2, and V3 channels are expressed on these sensory neurons and their terminals.     

Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.     

Capsaicin-sensitive vagal afferents contribute to gastric acid and vascular responses to intracisternal TRH analog

Central injection of TRH or its stable analog, RX77368, produces a vagal cholinergic stimulation of gastric acid secretion, mucosal blood flow and motor function. In the present study, we have investigated the contribution of capsaicin-sensitive vagal afferent fibers to the gastric responses to intracisternal injection of RX77368. Gastric acid secretion, measured in acute gastric fistula rats anesthetized with urethane, in response to intracisternal injection of RX77368 (3-30 ng) was reduced by 21-65% by perineural pretreatment of the vagus nerves with capsaicin 10-20 days before experiments. The increase in gastric mucosal blood flow measured by hydrogen gas clearance induced by intracisternal injection of RX77368 (30 ng) was also reduced by 65% in capsaicin-pretreated rats. In contrast, increases in gastric motor function measured manometrically or release of gastric luminal serotonin in response to intracisternal injection of RX77368 (3-30 ng) were unaltered by capsaicin pretreatment. The mechanism by which vagal afferent fibers contribute to the secretory and blood flow responses to the stable TRH analog is unclear at present, but it is possible that the decrease in gastric mucosal blood flow by lesion of capsaicin-sensitive vagal afferents limits the secretory response.     

Apolipoprotein A-IV stimulates duodenal vagal afferent activity to inhibit gastric motility via a CCK1 pathway

Apolipoprotein A-IV (apo A-IV), a peptide expressed by enterocytes in the mammalian small intestine and released in response to long-chain triglyceride absorption, may be involved in the regulation of gastric acid secretion and gastric motility. The specific aim of the present study was to determine the pathway involved in mediating inhibition of gastric motility produced by apo A-IV. Gastric motility was measured manometrically in response to injections of either recombinant purified apo A-IV (200 microg) or apo A-I, the structurally similar intestinal apolipoprotein not regulated by triglyceride absorption, close to the upper gastrointestinal tract in urethane-anesthetized rats. Injection of apo A-IV significantly inhibited gastric motility compared with apo A-I or vehicle injections. The response to exogenous apo A-IV injections was significantly reduced by 77 and 55%, respectively, in rats treated with the CCK(1) receptor blocker devazepide or after functional vagal deafferentation by perineural capsaicin treatment. In electrophysiological experiments, isolated proximal duodenal vagal afferent fibers were recorded in vitro in response to close-arterial injection of vehicle, apo A-IV (200 microg), or CCK (10 pmol). Apo A-IV stimulated the discharge of duodenal vagal afferent fibers, significantly increasing the discharge in 4/7 CCK-responsive units, and the response was abolished by CCK(1) receptor blockade with devazepide. These data suggest that apo A-IV released from the intestinal mucosa during lipid absorption stimulates the release of endogenous CCK that activates CCK(1) receptors on vagal afferent nerve terminals initiating feedback inhibition of gastric motility.     

Bradykinin stimulates respiratory drive by activating pulmonary sympathetic afferents in the rabbit.

We recently identified a vagally mediated excitatory lung reflex by injecting hypertonic saline into the lung parenchyma (Yu J, Zhang JF, and Fletcher EC. J Appl Physiol 85: 1485-1492, 1998). This reflex increased amplitude and burst rate of phrenic (inspiratory) nerve activity and suppressed external oblique abdominal (expiratory) muscle activity. In the present study, we tested the hypothesis that bradykinin may activate extravagal pathways to stimulate breathing by assessing its reflex effects on respiratory drive. Bradykinin (1 microg/kg in 0.1 ml) was injected into the lung parenchyma of anesthetized, open-chest and artificially ventilated rabbits. In most cases, bradykinin increased phrenic amplitude, phrenic burst rate, and expiratory muscle activity. However, a variety of breathing patterns resulted, ranging from hyperpnea and tachypnea to rapid shallow breathing and apnea. Bradykinin acts like hypertonic saline in producing hyperpnea and tachypnea, yet the two agents clearly differ. Bradykinin produced a higher ratio of phrenic amplitude to inspiratory time and had longer latency than hypertonic saline. Although attenuated, bradykinin-induced respiratory responses persisted after vagotomy. We conclude that bradykinin activates multiple afferent pathways in the lung; portions of its respiratory reflexes are extravagal and arise from sympathetic afferents.     

Vagal modulation of intestinal afferent sensitivity to systemic LPS in the rat

The central nervous system modulates inflammation in the gastrointestinal tract via efferent vagal pathways. We hypothesized that these vagal efferents receive synaptic input from vagal afferents, representing an autonomic feedback mechanism. The consequence of this vagovagal reflex for afferent signal generation in response to LPS was examined in the present study. Different modifications of the vagal innervation or sham procedures were performed in anesthetized rats. Extracellular mesenteric afferent nerve discharge and systemic blood pressure were recorded in vivo before and after systemic administration of LPS (6 mg/kg iv). Mesenteric afferent nerve discharge increased dramatically following LPS, which was unchanged when vagal efferent traffic was eliminated by acute vagotomy. In chronically vagotomized animals, to eliminate both vagal afferent and efferent traffic, the increase in afferent firing 3.5 min after LPS was reduced to 3.2 +/- 2.5 impulses/s above baseline compared with 42.2 +/- 2.0 impulses/s in controls (P < 0.001). A similar effect was observed following perivagal capsaicin, which was used to eliminate vagal afferent traffic only. LPS also caused a transient hypotension (<10 min), a partial recovery, and then persistent hypertension that was exacerbated by all three procedures. Mechanosensitivity was increased 15 min following LPS but had recovered at 30 min in all subgroups except for the chronic vagotomy group. In conclusion, discharge in capsaicin-sensitive mesenteric vagal afferents is augmented following systemic LPS. This activity, through a vagovagal pathway, helps to attenuate the effects of septic shock. The persistent hypersensitivity to mechanical stimulation after chronic vagal denervation suggests that the vagus exerts a regulatory influence on spinal afferent sensitization following LPS.     

Low frequency-dependent mechanism of the M2 receptor function on vagally mediated bronchoconstriction in rabbits in vivo.

The present study was carried out to investigate whether there is the difference between low and high frequencies of vagal stimulation on the functional appearance of M2 receptors in the rabbit. The animals were anesthetized, artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose-dependent. Although administration of methoctramine (50 and 300 microg/kg), a selective M2 receptor antagonist, had no significant effect on ACh-induced bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn responses to vagal stimulation at 5-15 Hz but did not potentiate bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D-Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5-15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz. Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results suggest that M2 receptors function as the inhibitory receptors in the bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15 Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at a higher frequency (30 Hz) results in the release of SP from the lungs.