Intraportal administration of DPP-IV inhibitor regulates insulin secretion and food intake mediated by the hepatic vagal afferent nerve in rats

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase-IV (DPP-IV) inhibitor extends the half-life of endogenous GLP-1 by preventing its degradation. This study aimed to determine whether DPP-IV inhibitor-induced elevation of portal GLP-1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP-IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP-1 levels, food intake, and plasma insulin and glucose was examined in sham-operated and vagotomized male Sprague-Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP-IV inhibitor significantly increased portal (but not peripheral) GLP-1 levels, increased insulin levels, and decreased glucose levels. The DPP-IV inhibitor suppressed 1- and 12- but not 24-h cumulative food intake. Intraportal infusion of the DPP-IV inhibitor increased hypothalamic neuronal histamine turnover and increased c-fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP-IV inhibitor-induced changes in portal but not systemic GLP-1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP-IV inhibitor.     

An afferent vagal nerve pathway links hepatic PPARalpha activation to glucocorticoid-induced insulin resistance and hypertension

Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvate carboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara(+/+) mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARalpha null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension.     

Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide

The vagus nerve appears to play a role in communicating cytokine signals to the central nervous system, but the exact extent of its involvement in cytokine-to-brain communication remains controversial. Recently, subdiaphragmatic vagotomy was shown to increase bacterial translocation across the gut barrier and thus may cause endotoxin tolerance. The current experiment tested whether or not vagotomized animals have similar systemic responses to endotoxin challenge as do sham-operated animals. Subdiaphragmatically vagotomized and sham-operated animals were injected intraperitoneally with one of three doses (10, 50, 100 microg/kg) of lipopolysaccharide (LPS) or vehicle, and blood samples were taken at 15, 30, 60, 90, and 120 min after the injection. The intraperitoneal injection of LPS increased circulating LPS levels at all time points examined. In addition, all three doses of LPS significantly increased serum interleukin (IL)-1beta, IL-6, and corticosterone in both control and vagotomized rats. In conclusion, vagotomy itself has no marked effect on circulating endotoxin levels or the production of IL-1beta, IL-6, or corticosterone in blood after an intraperitoneal injection of LPS.     

Effect of ozone on breathing in dogs: vagal and nonvagal mechanisms

We exposed two awake dogs with a chronic tracheostomy and the cervical vagus nerves exteriorized in skin loops to 1.0 ppm of ozone (O3) for 2 h at intervals of 4 wk. We measured ventilatory variables before and after O3 exposure during rest and exercise before and after vagal block. We compared the effects of vagal blockade, exercise, and O3 on the primary determinants of breathing pattern (VT/TI, VT/TE, TI, and TE) in each of three conditions: base line (steady state), during hypercapnia, and after inhalation of 1% histamine. Under base-line conditions, O3 increased respiratory rate and decreased tidal volume (VT) by shortening time of expiration (TE) and time of inspiration (TI) without affecting VT/TI, an indicator of the neural drive to breathing. During progressive hypercapnia, O3 shortened TE and TI by effects both on tonic (nonvolume-related) and on phasic (volume-related) vagal inputs, and only the latter were prevented completely by cooling of the vagus nerves. Histamine-induced tachypnea was increased by O3 and was totally blocked by cooling the vagus nerves. We conclude that O3 shortens the timing of respiration without increasing ventilatory drive, shortens TI and TE through vagal and nonvagal pathways, increases tonic nonvagal and phasic vagal inputs, and stimulates more than one vagal fiber type.     

Effects of high-frequency oscillatory ventilation on vagal and phrenic nerve activities

This study was undertaken to define the mechanism for the respiratory inhibition observed during high-frequency oscillatory ventilation (HFOV). The effects of HFOV on the activities of single units in the vagus (Vna) and phrenic nerves (Pna) were examined in pentobarbital-anesthetized dogs. The animals were either ventilated by intermittent positive-pressure ventilation (IPPV) with and without positive end-expiratory pressure (PEEP), or by HFOV at a frequency of 25 Hz and pump displacement volume of 3 ml/kg. In 13 vagal units the Vna was much higher during HFOV than during IPPV or airway occlusion at a matched airway pressure. Ten units in the phrenic nerves were examined, and Pna (expressed as bursts/min) was attenuated by HFOV in all of them. In four of them, the effect of cooling the vagi to 8-10 degrees C on Pna was examined, and it was found that HFOV failed to alter the Pna. We conclude that 1) HFOV stimulates the pulmonary vagal afferent fibers continuously and to a degree greater than that due to static lung inflation and increased airway pressure and 2) the increased vagal activity during HFOV probably causes phrenic nerve activity inhibition.     

Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux

We tested the hypothesis that, due to greater hepatic free fatty acid (FFA) load, portal delivery of FFAs, as in visceral obesity, induces hyperinsulinemia and increases endogenous glucose production to a greater extent than peripheral FFA delivery. For 5 h, 10 microeq.kg(-1).min(-1) portal oleate (n = 6), equidose peripheral oleate (n = 5), or saline (n = 6) were given intravenously to conscious dogs infused with a combination of portal and peripheral insulin to enable calculation of hepatic insulin clearance during a pancreatic euglycemic clamp. Peripheral FFAs were similar with both oleate treatments and were threefold greater than in controls. Portal FFAs were 1.5- to 2-fold greater with portal than with peripheral oleate. Peripheral insulin concentrations were greatest with portal oleate, intermediate with peripheral oleate (P < 0.001 vs. portal oleate or controls), and lowest in controls, consistent with corresponding reductions in plasma insulin clearance and hepatic insulin clearance. Although endogenous glucose production did not differ between the two routes of oleate delivery, total glucose output (endogenous glucose production plus glucose cycling) was greater with portal than with peripheral oleate (P < 0.001) despite the higher insulin levels. In conclusion, during euglycemic clamps in dogs, the main effect of short-term elevation in portal FFA is to generate peripheral hyperinsulinemia. This may, in the long term, contribute to the metabolic and cardiovascular risk of visceral obesity.     

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.     

Effect of electrical stimulation of the vagus on plasma motilin concentration in dog

Ten dogs anesthetized with α-chloralose were prepared with platinum monopolar electrodes in the antrum, duodenum and jejunum to record myoelectrical activity and bipolar stimulating electrodes placed on distal cut end of both cervical vagi to apply electric stimulation. Blood samples were obtained from both portal and femoral veins before and after bilateral vagal stimulation was initiated while the myoelectric activity was recorded continuously. The stimulation parameters used were low frequency (9V, 5 cps, 0.5 ms) and high frequency stimulus (9V, 30 cps, 10 ms) for 10 min. During the stimulation, plasma motilin concentrations increased significantly in both portal and femoral veins with simultaneous increases in the spike activity. The increment in the motilin level of portal venous blood was more marked. In 7 dogs, high frequency stimulation was repeated while the animals received i.v. atropine, 100 μg/kg-hr. Atropinization completely blocked the increase in the motilin concentration in response to high frequency stimulus with a simultaneous inhibition of the spike activity. The study suggests strongly that the vagus nerve plays an important role on endogenous release of motilin through its cholinergic pathway.     

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.     

α7-cholinergic receptor mediates vagal induction of splenic norepinephrine

Classically, sympathetic and parasympathetic systems act in opposition to maintain the physiological homeostasis. In this article, we report that both systems work together to restrain systemic inflammation in life-threatening conditions such as sepsis. This study indicates that vagus nerve and cholinergic agonists activate the sympathetic noradrenergic splenic nerve to control systemic inflammation. Unlike adrenalectomy, splenectomy and splenic neurectomy prevent the anti-inflammatory potential of both the vagus nerve and cholinergic agonists, and abrogate their potential to induce splenic and plasma norepinephrine. Splenic nerve stimulation mimics vagal and cholinergic induction of norepinephrine and re-establishes neuromodulation in α7 nicotinic acetylcholine receptor (α7nAChR)-deficient animals. Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the α7nAChR nicotinic receptors. α7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation.     

Effect of portacaval surgical anastomosis on systemic and splanchnic hemodynamics in portal hypertensive, cirrhotic rats

The effect of surgical end-to-side portacaval anastomosis (PCSA) on systemic and splanchnic circulation has been studied in cirrhotic rats with portal hypertension (CCl4-phenobarbital method) and in control animals. Hemodynamics have been measured using the microsphere technique, with a reference sample for the systemic hemodynamic measurements, and intrasplenic injection for portal systemic shunting rate measurements. Compared with controls, sham-operated (SO) cirrhotic rats showed a hyperdynamic circulation with increased cardiac output (CO) and decreased mean arterial pressure and peripheral resistances. PCSA in control rats induced only a small change in systemic hemodynamics, with parallel decreases in arterial pressure and peripheral resistances, and a small, nonsignificant increase in CO. In cirrhotic rats, PCSA induced a decrease of CO to values similar to those of control rats, with an increase in total peripheral resistances. PCSA induced an increase in hepatic arterial blood flow in control and in cirrhotic rats, portal pressure becoming in this latter group not different from that of control rats. Blood flow to splanchnic organs was higher in SO cirrhotic than in SO control animals. Thus portal venous inflow was also increased in SO cirrhotic rats. PCSA induced an increase in portal venous inflow in control rats, which was only significant in cirrhotic rats when expressed as a percentage of CO. In SO control animals, a significant correlation was observed between total peripheral resistances and splanchnic arteriolar resistances and between CO and splanchnic blood flow. These correlations were not observed in cirrhotic rats. These results do not support the hypothesis that hyperdynamic circulation shown by cirrhotic rats is based on increases in splanchnic blood flow and (or) massive portal systemic shunting.     

Intraportal glucose infusion and pancreatic islet blood flow in anesthetized rats

The aim of the study was to evaluate whether a selective increase in portal vein blood glucose concentration can affect pancreatic islet blood flow. Anesthetized rats were infused (0.1 ml/min for 3 min) directly into the portal vein with saline, glucose, or 3-O-methylglucose. The infused dose of glucose (1 mg. kg body wt(-1). min(-1)) was chosen so that the systemic blood glucose concentration was unaffected. Intraportal infusion of D-glucose increased insulin release and islet blood flow; the osmotic control substance 3-O-methylglucose had no such effect. A bilateral vagotomy performed 20 min before the infusions potentiated the islet blood flow response and also induced an increase in whole pancreatic blood flow, whereas the insulin response was abolished. Administration of atropine to vagotomized animals did not change the blood flow responses to intraportal glucose infusions. When the vagotomy was combined with a denervation of the hepatic artery, there was no stimulation of islet blood flow or insulin release after intraportal glucose infusion. We conclude that a selective increase in portal vein blood glucose concentration may participate in the islet blood flow increase in response to hyperglycemia. This effect is probably mediated via periarterial nerves and not through the vagus nerve. Furthermore, this blood flow increase can be dissociated from changes in insulin release.     

Bronchomotor vagal preganglionic cell bodies in the dog: an anatomic and functional study.

A previous study in our laboratory demonstrated that the stimulation with microinjection of DL-homocysteic acid of cell bodies in the rostral portion of the external formation of the nucleus ambiguus (Aext) increased total lung resistance in dogs. In the present study anatomic experiments were conducted in dogs to determine if the rostral Aext contains vagal preganglionic cell bodies that give rise to axons in the pulmonary branches of the vagus nerve. The application of horseradish peroxidase (HRP) to either the pulmonary branches or the vagus at a point between the pulmonary branches and the cardiac branches resulted in retrograde labeling of cell bodies in both rostral Aext and the dorsal motor nucleus of the vagus (DMN). On the other hand, application of HRP to the vagus at a point below the pulmonary branches did not result in any retrogradely labeled cell bodies in rostral Aext but did result in labeled cell bodies in DMN. In another series of experiments DL-homocysteic acid (2.5 nmol in 25 nl) was microinjected at sites in rostral Aext and DMN. As we previously reported the injection of DL-homocysteic acid in rostral Aext increased total lung resistance. In contrast, in the same animals, the injection of DL-homocysteic acid in DMN did not change total lung resistance. We conclude that bronchomotor vagal preganglionic cell bodies are located in rostral Aext but not in DMN. The functional significance of vagal preganglionic cell bodies in DMN whose axons contribute to the pulmonary branches of the vagus nerve remains to be determined.     

Motilin and the vagus in dogs

The aim of this work was to determine the influence of the vagus on the circulating levels of immunoreactive (IR) motilin. Five mongrel dogs were equipped with chronically implanted electrodes in the small intestine to record the myoelectrical activity. The release of IR motilin during fasting, after a meal, and during an infusion of insulin was studied before and after truncal vagotomy at the diaphragmatic level. When tested at least two weeks after the operation, the motility pattern of the small intestine and the secretion of IR motilin remained unaltered by vagal section. Cyclic increases in IR motilin associated with phase III's of the interdigestive myoelectric complexes were still observed after vagotomy (maximum levels of IR motilin: 250 +/- 37 versus 239 +/- 19 fmol X mL-1, not significant), and they were still abolished by feeding or by insulin. However, an inhibitory influence can probably be mediated by the vagus since, in normal animals, vagal stimulation by a "modified sham feeding" (tease feeding or presentation of food) at the beginning of a period of phase III activity promptly interrupted this part of the complex and decreased significantly the release of IR motilin by about 20%. The release of motilin is not chronically altered by distal vagotomy in dogs.     

Effects of vagus nerve stimulation and vagotomy on systemic and pulmonary inflammation in a two-hit model in rats

Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO(2) (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated.     

Effects of thromboxane on respiration and pulmonary circulation in the cat: role of vagus nerve

Infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat elicits pulmonary hypertension and rapid shallow breathing (J. Appl. Physiol. 62: 2362-2370, 1987), and thromboxane A2 (TxA2), released from platelets, is responsible for these effects (Respir. Physiol. 71: 169-183, 1988). To investigate the involvement of vagal afferent fibers in these responses, we reversibly blocked signal conduction in the vagus of the cat by bilaterally cooling the vagus nerves to 1 degree C and measured the cardiorespiratory parameters in response to neutral acid-base infusion and infusion of the TxA2 mimetic U-46619. Vagal cooling before infusion caused tidal volume (VT) to increase and respiratory frequency (fresp) to decrease, whereby total ventilation (VE) was slightly enhanced, but did not affect right ventricular blood pressure (Prv). Infusion of neutral acid-base after vagal cooling prompted Prv to rise, on average from 35 Torr to a peak of 60 Torr, and a similar rise was elicited by infusion of U-46619. However, vagal cooling abolished any effect on VT or fresp of both acid-base and U-46619 infusion. After rewarming the vagus nerves, infusion of U-46619 caused fresp to increase and VT to decrease (rapid shallow breathing) with a concomitant rise in Prv, similar to what had been observed in the earlier studies. Our data suggest that the effects of TxA2 and of its mimetic U-46619 on respiration are mediated by the stimulation of vagal afferent fibers, whereas pulmonary hypertension is unrelated to vagal activity.     

Elimination of disorders of electric stability of the heart during post-infarct cardiosclerosis using adaptation to short-term stress and the antioxidant ionol

The experiments were carried out on male Wistar rats (300-400 g) subject to open chest surgery under nembutal anesthesia. One group of rats with postinfarction cardiosclerosis (PC) was exposed to short-term immobilization stress for 15 days one month after the occlusion of the descending branch of the left coronary artery. The other group of rats with PC was administered synthetic antioxidant ionol (BHT) (60 mg/kg, per os) 3 days prior to the experiments. The electrical stability of the heart was evaluated by assessing ventricular fibrillation threshold (VFT) determined by stimulation of the right ventricular apex by single premature impulses (10 ms) and by measuring the amount of ectopic beats developing during 30-sec stimulation of the right vagus (2 mA, 20 Hz). VFT in rats with PC was significantly lower, as compared to sham-operated rats (2.9 +/- 0.2 and 6.4 +/- 0.2 mA, respectively), with pronounced extrasystoles appearing during vagal bradycardia. In stress-adapted animals with PC VFT returned to the level of sham-operated rats and the amount of premature beats decreased 3-4-fold, as compared to unadapted rats with PC. Ionol (BHT) was shown to have the same effect.     

Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.

Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.     

Vagal afferent activity and body temperature in 3 to 10-day-old and adult rats

This study examined the possible contribution of vagal stretch receptor activity to the increased power of the Hering-Breuer reflex in hyperthermia in rats during the early postnatal period. Experiments were performed on 10 anesthetized (pentobarbital 40 mg/kg, i.p.) 3 to 10-day-old (body weight of 16 +/- 1 g; SE) and, for comparison, 18 adult Sprague-Dawley rats (body weight of 336 +/- 35 g). Animals were tracheostomized and artificially ventilated with oxygen. The left vagus nerve was cut. In adult animals, single receptor fibers or a bundle of a few fibers were recorded using a bipolar stainless-steel electrode under mineral oil. In the young rats, a suction electrode filled with normal saline was used. Positive pressure of either 5 or 10 cmH2O was applied to the trachea when the respirator was turned off. The vagal activity was amplified and monitored on a storage oscilloscope for calculation of the frequency of vagal afferent activity during a given pressure application at different rectal temperatures (T(R); range 28 to 42 degrees C). In total, 30 and 31 sets of vagal activity in the young and adult rats, respectively, were analyzed. In all cases, an increase in tracheal pressure (P(TR)) from 5 to 10 cmH2O increased the frequency of vagal firing. The increase was greater in the adult versus the young animals; at 36 degrees C the increase was 49 +/- 11% and 16 +/- 3% in the adult and young rats, respectively (P < 0.01). In all animals, vagal receptors showed temperature-sensitivity, but less so in the young than in the adult rats (P < 0.0004 and P < 0.003; for P(TR) of 5 and 10 cmH2O, respectively). In addition, the relationship between temperature-sensitivity and T(R) had significant slopes (P < 0.001 for both inflation pressures) in the adults but not in the young rats, indicating that in the latter the temperature-sensitivity of vagal receptors is independent of TR. These results imply that temperature-sensitivity of vagal receptors could have contributed to the increased power of the Hering-Breuer reflex in rats during the early postnatal period in the warmer environment.     

Disordered central cardiovascular regulation in portal hypertensive and cirrhotic rats

Portal hypertension due to either prehepatic portal hypertension or cirrhosis is associated with cardiovascular derangement. We aimed to delineate regulatory mechanisms in the brain stem cardiovascular nuclei in rat models of prehepatic portal hypertension and cirrhosis. Neuronal activation in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM) were assessed by immunohistochemical staining for the immediate-early gene product Fos. In the same sections, catecholaminergic neurons were counted by tyrosine hydroxylase (TH) staining. Ninety minutes after hypotensive hemorrhage (or no volume challenge), the animals were killed for Fos and TH medullary staining. These protocols were repeated after capsaicin administration. The NTS of unchallenged sham-operated rats had scant Fos-positive cells (3.6 +/- 0.4 cells/section), whereas hemorrhage significantly increased Fos staining (91.8 +/- 14). In contrast, the unchallenged portal hypertensive and cirrhotic groups showed increased Fos staining (14.3 +/- 5.8 and 32.8 +/- 2.8, respectively), which hemorrhage did not alter significantly. The numbers of TH-positive cells were similar in the three unchallenged groups; double labeling revealed that approximately 50% of TH-positive cells were activated by hemorrhage in the sham and cirrhotic rats but not the portal hypertensive rats. Similar patterns of Fos and TH staining were observed in the VLM. Capsaicin treatment not only significantly reduced the Fos-positive neuron numbers in portal hypertensive and cirrhotic rats but also attenuated hemorrhage-induced Fos and double-positive cells in both NTS and VLM. These results suggest that disordered trafficking in capsaicin-sensitive nerves and central dysregulation contribute to blunted cardiovascular responsiveness in cirrhosis and prehepatic portal hypertension.