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Chung Owyang

Publications and source records attributed to Chung Owyang.

At least 19 recordsLinked to original sources
PubMed2006

Modulation of intestinal gas dynamics in healthy human volunteers by the 5-HT receptor agonist tegaserod.

OBJECTIVES: Bloating in irritable bowel syndrome (IBS) may result from impaired intestinal gas transit and is reduced by the 5-HT4 agonist tegaserod. Abnormal serotonergic function underlies many IBS symptoms, but the role of 5-HT4 pathways in regulating gas dynamics under healthy conditions is unexplored. We hypothesized that 5-HT4 activation by tegaserod stimulates gas transit in healthy individuals. METHODS: Sixteen normal volunteers underwent jejunal perfusion of gas mixtures (88% N2, 5.5% O2, 6.5% CO2) at 11.2 mL/min x 3 h under control conditions and 3 h after oral tegaserod 6 mg on separate days. Gas collected from an intrarectal catheter was quantified using a barostat. RESULTS: Under control conditions, gas evacuation after a lag period (1,959 +/- 428 s) was predominantly pulsatile with expulsion of 1,984 +/- 90 mL. A mean of 29 +/- 2 boluses with volumes of 72 +/- 5 mL were expelled. In 10 subjects with physiologic degrees of gas retention in control studies (248 +/- 73 mL), tegaserod increased expulsion from 1,768 +/- 73 to 1,973 +/- 37 mL and decreased retention to 43 +/- 37 mL (p < 0.05). Total volumes expelled as boluses were greater after tegaserod (1,708 +/- 73 vs 1,846 +/- 59 mL, p < 0.05) from increased bolus numbers in four subjects and increased bolus volumes in seven. Nonpulsatile continuous flow tended to increase with tegaserod (43 +/- 7 vs 126 +/- 43 mL, p= 0.10). Tegaserod did not increase evacuation in individuals without physiologic gas retention. CONCLUSIONS: The 5-HT4 agonist tegaserod promotes evacuation of jejunally perfused gas mixtures in healthy humans. These findings provide the foundation for future investigations into use of 5-HT4 agonists in conditions of pathologic gas retention.

Administration, Oral↗
PubMed2006

Ghrelin acts on the dorsal vagal complex to stimulate pancreatic protein secretion.

Ghrelin receptors are present in the central nervous system. We hypothesized that ghrelin released from the stomach acts as an endocrine substance and stimulates brain stem vagovagal circuitry to evoke pancreatic secretion. In an in vivo anesthetized rat model, an intravenous infusion of ghrelin at doses of 5, 10, and 25 nmol increased pancreatic protein secretion from a basal level of 125 +/- 6 to 186 +/- 8, 295 +/- 12, and 356 +/- 11 mg/h, respectively. Pretreatment with atropine or hexamethonium or an acute vagotomy, but not a perivagal application of capsaicin, completely abolished pancreatic protein secretion responses to ghrelin. In conscious rats, an intravenous infusion of ghrelin at a dose of 10 nmol resulted in a 2.2-fold increase in pancreatic protein secretion over basal volume. Selective ablation of the area postrema abolished pancreatic protein secretion stimulated by intravenous infusion of ghrelin but did not alter the increase in pancreatic protein secretion evoked by diversion of bile-pancreatic juice. Immunohistochemical staining showed a marked increase in the number of c-Fos-expressing neurons in the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus after an intravenous infusion of ghrelin in sham-lesioned rats; selective ablation of the area postrema eliminated this increase. In conclusion, ghrelin stimulates pancreatic secretion via a vagal cholinergic efferent pathway. Circulating ghrelin gains access to the brain stem vagovagal circuitry via the area postrema, which represents the primary target on which peripheral ghrelin may act as an endocrine substance to stimulate pancreatic secretion.

Animals↗
PubMed2006

Nutrient modulation of intestinal gas dynamics in healthy humans: dependence on caloric content and meal consistency.

The actions of nutrients on gut transit of liquids and solids have been extensively studied, but the effects of meal ingestion on intestinal gas flow are unexplored. We hypothesized that meals of varying caloric content and consistency modulate gas transit to different degrees. Nine healthy volunteers underwent jejunal perfusion of physiological gas mixtures at 12 ml.min(-1).3 h, with ingestion of nothing (control), water (240 ml), 240-kcal liquid meals, and 240-kcal solid meals at the end of the second hour in separate studies. Gas was quantified from an intrarectal catheter. After an initial lag phase, gas evacuation approached steady state by the end of the fasting period. Solid and liquid caloric meals increased total gas volumes evacuated from 5-40 min after ingestion vs. control studies (P < 0.05). These increases resulted from increased numbers of bolus gas evacuations (P < 0.05), whereas bolus volumes, pressures, and flow rates were similar for all test conditions. Solid and liquid caloric meals elicited similar effects on bolus gas dynamic parameters, whereas water did not affect these measures vs. control (NS, not significant). Both caloric meals and the noncaloric liquid meal increased continuous gas flow, which represented <2% of total gas expulsion. In conclusion, caloric meals promote bolus gas transit in healthy humans, whereas noncaloric liquids have no effect. Solids stimulate early postprandial gas dynamics to the same extent as liquid meals of similar caloric content. Thus modulatory effects of meals on intestinal gas transit depend on their caloric content but not their consistency.

Adaptation, Physiological↗
PubMed2005

Enhanced responses of the anterior cingulate cortex neurones to colonic distension in viscerally hypersensitive rats.

The anterior cingulate cortex (ACC) is critically involved in processing the affective component of pain sensation. Visceral hypersensitivity is a characteristic of irritable bowel syndrome. Electrophysiological activity of the ACC with regard to visceral sensitization has not been characterized. Single ACC neuronal activities in response to colorectal distension (CRD) were recorded in control, sham-treated rats and viscerally hypersensitive (EA) rats (induced by chicken egg albumin injection, i.p). The ACC neurones of controls failed to respond to 10 or 30 mmHg CRD; only 22% were activated by 50 mmHg CRD. Among the latter, 16.4% exhibited an excitatory response to CRD and were labelled 'CRD-excited' neurones. In contrast, CRD (10, 30 and 50 mmHg) markedly increased ACC neuronal responses of EA rats (10%, 28% and 47%, respectively). CRD produced greater pressure-dependent increases in ACC spike firing rates in EA rats compared with controls. Splanchnicectomy combined with pelvic nerve section abolished ACC responses to CRD in EA rats. Spontaneous activity in CRD-excited ACC neurones was significantly higher in EA rats than in controls. CRD-excited ACC neurones in control and EA rats (7 of 16 (42%) and 8 of 20 (40%), respectively) were activated by transcutaneous electrical and thermal stimuli. However, ACC neuronal activity evoked by noxious cutaneous stimuli did not change significantly in EA rats. This study identifies CRD-responsive neurones in the ACC and establishes for the first time that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization, characterized by increased spontaneous activity of CRD-excited neurones, decreased CRD pressure threshold, and increased response magnitude. Enhanced ACC nociceptive transmission in viscerally hypersensitive rats is restricted to visceral afferent input.

Albumins↗
PubMed2005

Secretin activates vagal primary afferent neurons in the rat: evidence from electrophysiological and immunohistochemical studies.

In this study, we evaluated the vagal afferent response to secretin at physiological concentrations and localized the site of secretin's action on vagal afferent pathways in the rat. The discharge of sensory neurons supplying the gastrointestinal tract was recorded from nodose ganglia. Of 91 neurons activated by electrical vagal stimulation, 19 neurons showed an increase in firing rate in response to intestinal perfusion of 5-HT (from 1.5 +/- 0.2 to 25 +/- 4 impulses/20 s) but no response to intestinal distension. A close intra-arterial injection of secretin (2.5 and 5.0 pmol) elicited responses in 15 of these 19 neurons (from 1.5 +/- 0.2 impulses/20 s at basal to 21 +/- 4 and 43 +/- 5 impulses/20 s, respectively). Subdiaphragmatic vagotomy and perivagal application of capsaicin, but not supranodose vagotomy, completely abolished the secretin-elicited vagal nodose neuronal response. In a separate study, 9 tension receptor afferents among 91 neurons responded positively to intestinal distension but failed to respond to luminal 5-HT. These nine neurons also showed no response to administration of secretin. As expected, immunohistochemical studies showed that secretin administration significantly increased the number of Fos-positive neurons in vagal nodose ganglia. In conclusion, we demonstrated for the first time that vagal sensory neurons are activated by secretin at physiological concentrations. A subpopulation of secretin-sensitive vagal afferent fibers is located in the intestinal mucosa, many of which are responsive to luminal 5-HT.

Animals↗
PubMed2005

A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice.

BACKGROUND & AIMS: Cystic fibrosis transmembrane regulator (CFTR) gene mutations are associated with pancreatic insufficiency and pancreatitis. Chronic pancreatitis, including cystic fibrosis-related disease, may exist as a continuum between acute and chronic disease and may manifest as recurrent pain. We hypothesized that cftr(m1UNC) (-/-) mice, which have no evidence of chronic pancreatitis, are susceptible to developing acute pancreatitis. METHODS: We used a cerulein hyperstimulation model of acute pancreatitis and measured histological changes, tissue edema, neutrophil infiltration, inflammatory mediators' mRNA expression, apoptosis markers, and pancreatic trypsin and serum lipase activities. Additionally, we quantitated in vivo pancreatic secretion and pancreatic digestive enzymes. RESULTS: Multiple proinflammatory cytokine genes were constitutively overexpressed in cftr (-/-) pancreas compared with wild-type mice. During acute pancreatitis, cftr (-/-) mice developed more severe acute pancreatitis than wild-type, as indicated by greater pancreatic edema, neutrophil infiltration, mRNA expression of multiple inflammatory mediators, and less apoptotic cell death. In contrast to wild-type mice, cftr (-/-) mice had blunted increases in pancreatic trypsin and serum lipase activities, but similar percentages of pancreatic trypsinogen activation. Finally, cftr (-/-) mice had less in vivo pancreatic secretion in response to cholecystokinin octapeptide and reduced pancreatic digestive enzyme protein and mRNA levels, thus suggesting mild pancreatic insufficiency. CONCLUSIONS: A baseline proinflammatory state and an antiapoptotic phenotype may sensitize cftr (-/-) mice to developing more severe acute pancreatitis with an exuberant pancreatic inflammatory response. Cftr (-/-) mice have mild pancreatic insufficiency, which partially explains the blunted increase of pancreatic and serum digestive enzymes during acute pancreatitis. These findings may explain the susceptibility to acute pancreatitis in persons with classic and nonclassic cystic fibrosis.

Acute Disease↗
PubMed2004

Selective reversal of hyperglycemia-evoked gastric myoelectric dysrhythmias by nitrergic stimulation in healthy humans.

Acute hyperglycemia disrupts gastric myoelectric rhythm in healthy humans. Defective nitrergic function is a factor in animal models of diabetic gastropathy. We tested participation of nitrergic pathways in hyperglycemia-evoked myoelectric dysrhythmias and compared their role in preventing dysrhythmic actions of experimental motion sickness. Twelve healthy volunteers underwent electrogastrography (EGG) with and without intravenous 20% dextrose to produce plasma glucoses of 250 mg/dl. EGG continued for 2 h after oral nitroglycerin (9 mg) or the cyclic GMP-specific phosphodiesterase inhibitor sildenafil (100 mg). In separate studies, 12 volunteers underwent circular vection (60 degrees /s) without and 90 min after nitroglycerin (9 mg) or sildenafil (100 mg) with concurrent EGG. Hyperglycemia decreased recording time in normal rhythm, increased tachygastria more than 3-fold, and decreased power of the dominant frequency (P < 0.05). Nitroglycerin and sildenafil reversed effects of hyperglycemia, improving normal rhythm, decreasing tachygastria (both P < 0.05), and blunting power decreases. Neither agent affected EGG rhythm during euglycemia. Vection decreased time in normal rhythm and increased tachygastria (P < 0.05). However, nitroglycerin and sildenafil did not reverse dysrhythmic effects of vection (P = N.S.). In conclusion, administration of a nitric oxide (NO) donor or an inhibitor of cyclic GMP-selective phosphodiesterase reverses the dysrhythmic effects of hyperglycemia on gastric myoelectric activity in healthy humans. These agents have no effect on dysrhythmias during motion sickness. These findings are consistent with selective impairment of nitrergic function in this model of diabetic gastropathy and suggest that NO donors and other agents that increase NO activity may be useful for treating diabetic dysrhythmias.

Adult↗
PubMed2004

Prolactin-releasing peptide affects gastric motor function in rat by modulating synaptic transmission in the dorsal vagal complex.

Prolactin-releasing peptide (PrRP) is a recently discovered neuropeptide implicated in the central control of feeding behaviour and autonomic homeostasis. PrRP-containing neurones and PrRP receptor mRNA are found in abundance in the caudal portion of the nucleus tractus solitarius (NTS), an area which together with the dorsal motor nucleus of the vagus (DMV) comprises an integrated structure, the dorsal vagal complex (DVC) that processes visceral afferent signals from and provides parasympathetic motor innervation to the gastrointestinal tract. In this study, microinjection experiments were conducted in vivo in combination with whole-cell recording from neurones in rat medullary slices to test the hypothesis that PrRP plays a role in the central control of gastric motor function, acting within the DVC to modulate the activity of preganglionic vagal motor neurones that supply the stomach. Microinjection of PrRP (0.2 pmol (20 nl)(-1)) into the DMV at the level of the area postrema (+0.2 to +0.6 mm from the calamus scriptorius, CS) markedly stimulated gastric contractions and increased intragastric pressure (IGP). Conversely, administration of peptide into the DMV at sites caudal to the obex (0.0 to -0.3 mm from the CS) decreased IGP and reduced phasic contractions. These effects occurred without change in mean arterial pressure and were abolished by ipsilateral vagotomy, indicating mediation via a vagal-dependent mechanism(s). The pattern of gastric motor responses evoked by PrRP mimicked that produced by administration of L-glutamate at the same sites, and both the effects of L-glutamate and PrRP were abolished following local administration of NMDA and non-NMDA-type glutamate receptor antagonists. On the other hand, microinjection of PrRP into the medial or comissural nucleus of the solitary tract (mNTS and comNTS, respectively) resulted in less robust changes in IGP in a smaller percentage of animals, accompanied by marked alterations in arterial pressure. Superfusion of brain slices with PrRP (100-300 nm) produced a small depolarization and increased spontaneous firing in 10 of 30 retrogradely labelled gastric-projecting DMV neurones. The excitatory effects were blocked by administration of TTX (2 mum) or specific glutamate receptor antagonists, indicating that they resulted from interactions of PrRP at a presynaptic site. Congruent with this, PrRP increased the amplitude of excitatory postsynaptic currents (EPSCs, 154 +/- 33%, 12 of 25 neurones) evoked by electrical stimulation in mNTS or comNTS. In addition, administration of PrRP decreased the paired-pulse ratio of EPSCs evoked by two identical stimuli delivered 100 ms apart (from 0.95 +/- 0.08 to 0.71 +/- 0.11, P < 0.05), whereas it did not affect the amplitude of inward currents evoked by exogenous application of L-glutamate to the slice. The frequency, but not amplitude of spontaneous EPSCs and action potential-independent miniature EPSCs was also increased by administration of PrRP, suggesting that the peptide was acting at least in part at receptors on presynaptic nerve terminals to enhance glutamatergic transmission. In recordings obtained from a separate group of slices, we did not observe any direct effects of PrRP on spontaneous discharge or postsynaptic excitability in either mNTS or comNTS neurones (n = 31). These data indicate that PrRP may act within the DVC to regulate gastric motor function by modulating the efficacy of conventional excitatory synaptic inputs from the NTS onto gastric-projecting vagal motor neurones.

Animals↗
PubMed2004

Structure-activity function for binding and signaling in CHO-K1 and COS-7 cells expressing the cholecystokinin A receptor.

Key amino acids of the cholecystokinin (CCK) peptide for receptor binding are sulfated Y27, W30, D32, and F33-NH(2). Three-dimensional modeling showed that the CCK-A receptor (CCK-AR) antagonist devazepide penetrated into the transmembrane (TM) domains, whereas CCK was placed on the surface of the CCK-AR. Four types of rat CCK-AR cDNAs were transfected into CHO-K1 and COS-7 cells: normal CCK-AR cDNA transfected cells (wild type, WT); K120 substituted with V; K130V; and R352V. Binding of [3H]CCK-8 was observed in WT and K130V, but not in K120V and R352V. CCK caused Ca(2+) spiking in WT and K130V, whereas K120V and R352V had no effect. Three chimeras including the CCK-AR/3ibeta2 adrenergic receptor (beta2AR), 3Nibeta2AR, and 3Cibeta2AR were constructed. Two groups of point mutations in the CCK-AR3i were also made: Y252V, S274V, S281V, and S289V (non-phospho-acceptor Y or S); S260V, S264V, S271V, and S275V (phospho-acceptor S). WT and CCK-AR/3Cibeta2AR increased [Ca(2+)](i) in response to CCK; 3Nibeta2AR was vice versa. CCK failed to increase [IP(3)] in phospho-acceptor S to V without affecting binding. Non-phospho-acceptor S or Y to V showed normal response. Thus, Lys120 outside the TM2 and Arg352 outside the TM6 of the CCK-AR are amino acids interacting with Tyr[SO(3)H]27 and Asp32 of the CCK peptide for binding. Phospho-acceptor Ser groups in the CCK-AR 3Ni are amino acids for initiating cell signaling.

Amino Acid Sequence↗
PubMed2004

Endothelial nitric oxide synthase is protective in the initiation of caerulein-induced acute pancreatitis in mice.

The effect of inhibiting nitric oxide (NO) synthase (NOS) or enhancing NO on the course of acute pancreatitis (AP) is controversial, in part because three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). We investigated whether inhibition or selective gene deletion of NOS isoforms modified the initiation phase of caerulein-induced AP in mice and explored whether this affected pancreatic microvascular blood flow (PMBF). We investigated the effects of nonspecific NOS inhibition with N(omega)-nitro-l-arginine (l-NNA; 10 mg/kg ip) or targeted deletion of eNOS, nNOS, or iNOS genes on the initiation phase of caerulein-induced AP in mice using in vivo and in vitro models. Western blot analysis was performed to assess eNOS phosphorylation status, an indicator of enzyme activity, and microsphere studies were used to measure PMBF. l-NNA and eNOS deletion, but not nNOS or iNOS deletion, increased pancreatic trypsin activity and serum lipase during the initiation phase of in vivo caerulein-induced AP. l-NNA and eNOS did not affect trypsin activity in caerulein-hyperstimulated isolated acini, suggesting that nonacinar events mediate the effect of NOS blockade in vivo. The initiation phase of AP in wild-type mice was associated with eNOS Thr(495) residue dephosphorylation, which accompanies eNOS activation, and a 178% increase in PMBF; these effects were absent in eNOS-deleted mice. Thus eNOS is the main isoform influencing the initiation of caerulein-induced AP. eNOS-derived NO exerts a protective effect through actions on nonacinar cell types, most likely endothelial cells, to produce greater PMBF.

Acute Disease↗
PubMed2004

New insights into neurohormonal regulation of pancreatic secretion.

The existence of high- and low-affinity cholecystokinin (CCK)-A receptors on rodent pancreatic acini is well established. Until recently, CCK was believed to act directly on pancreatic acini to stimulate pancreatic secretion in both rodents and humans. However, conclusive evidence that human pancreatic acini lack functional CCK-A receptors has been presented. Despite substantial differences in rodent and human pancreatic physiology, CCK appears to act via vagal cholinergic pathways to mediate pancreatic secretion in both species. Structural and functional evidence suggests that CCK acts on vagal afferent fibers, which may explain how CCK doses that produce physiologic plasma CCK levels act via vagal cholinergic pathways to stimulate pancreatic secretion. Although most knowledge of vagal CCK-A receptors comes from research on rodents, physiologic studies suggest that this information is applicable to humans. In contrast to its effect on satiety, which is mediated by low-affinity vagal CCK-A receptors, CCK acts through high-affinity CCK-A receptors to evoke pancreatic secretion, suggesting that different affinity states of the vagal CCK receptors mediate different digestive functions. Vagal afferent pathways also transmit sensory information about the mechanical and physiochemical state of the digestive tract, mediated in part by serotonin, which, in turn, influences pancreatic secretion. A synergistic interaction between CCK and serotonin at the level of the nodose ganglia may explain the robust postprandial pancreatic secretion despite a modest postprandial increase in plasma CCK. Important physiologically, these findings not only explain discrepancies in previous in vivo vs. in vitro studies, but they revolutionize our current concept of the mechanism of CCK on pancreatic exocrine secretion.

Animals↗
PubMed2003

Hypothalamus-brain stem circuitry responsible for vagal efferent signaling to the pancreas evoked by hypoglycemia in rat.

Circulating glucose levels significantly affect vagal neural activity, which is important in the regulation of pancreatic functions. Little is known about the mechanisms involved. This study investigates the neural pathways responsible for hypoglycemia-induced vagal efferent signaling to the pancreas and identifies the neurotransmitters involved. Vagal pancreatic efferent nerve activities were recorded in anesthetized rats. Insulin-induced hypoglycemia, a decrease of blood glucose levels from 114 +/- 5 to 74 +/- 6 mg dl(-1), stimulated an increase in pancreatic efferent nerve firing from a basal rate of 1.1 +/- 0.3 to 19 +/- 3 impulses 30 s(-1). In contrast, vagal primary afferent neuronal discharges recorded in the nodose ganglia were unaltered by systemic hypoglycemia. Vagal afferent rootlet section plus splanchnicotomy had no effect on hypoglycemia-induced vagal efferent firing, suggesting a central site of action. Decerebration reduced the increase in nerve firing stimulated by hypoglycemia from 21 +/- 4 to 9.6 +/- 2 impulses 30 s(-1). Chemical ablation of the lateral hypothalamic area, but not the arcuate nucleus, inhibited pancreatic nerve firing evoked by hypoglycemia. Microinjection of the orexin-A receptor antagonist SB-334867 into the dorsal motor nucleus of the vagus (DMV) inhibited pancreatic nerve firing evoked by insulin-induced hypoglycemia by 56%. In contrast, injection of orexin-A (20 pmol) into the DMV elicited a 30-fold increase in pancreatic nerve firing. We concluded that systemic hypoglycemia stimulates pancreatic efferent nerve firing through a central mechanism. Full expression of pancreatic nerve activities during hypoglycemia requires both the forebrain and the brain stem. In addition to activating neurons in the brain stem, central neuroglucopenia activates subpopulations of neurons in the lateral hypothalamic area that contain orexin. The released orexin acts on DMV neurons to stimulate pancreatic efferent nerve activities and thus regulate pancreatic functions.

Action Potentials↗
PubMed2003

Cholecystokinin synthesizes and secretes leptin in isolated canine gastric chief cells.

It is well recognized that a product of obese (ob) locus and body weight control hormone, leptin, acts on both short-term satiety for meal-induced termination of food intake (gastric phase) and long-term satiety for energy expenditure via the hypothalamus. The considerable sources of leptin are chief cells for gastric phase and adipocytes for the long-term satiety. The objective of this study was to demonstrate if CCK enhances leptin synthesis and secretion in isolated canine gastric chief cells. Confocal immunofluorescence studies showed that the CCK-A receptor and leptin were colocalized in the endoplasm. Western blotting demonstrated that canine chief cells expressed the leptin peptide and its protein level was enhanced by CCK treatment. An ELISA further showed that CCK dose-dependently secreted leptin from isolated canine chief cells. This was reproduced by the high-affinity CCK-A receptor agonist, CCK-OPE. These results indicate that canine chief cells synthesize and secrete leptin in response to CCK via the high-affinity state of the CCK-A receptor.

Adipocytes↗
PubMed2003

Hypothalamic regulation of pancreatic secretion is mediated by central cholinergic pathways in the rat.

The vago-vagal reflex plays an important role in mediating pancreatic secretion evoked by cholecystokinin and non-cholecystokinin-dependent luminal factors. We hypothesize that the vago-vagal reflex mediating pancreatic secretion in the rat is under central control and regulated by cholinergic pathways in the hypothalamus. To test this hypothesis, we demonstrated that chronic decerebration decreased basal pancreatic enzyme secretion from 318 +/- 12 to 233 +/- 9 mg h-1 and reduced the net increase in pancreatic secretion stimulated by intraduodenal infusion of 5 % peptone and hypertonic NaCl by 54 % and 45 %, respectively. Intracerebroventricular administration of methscopolamine (MSCP, 50 nmol (5 mul)-1), a blood-brain barrier-impermeant cholinergic muscarinic receptor antagonist, evoked results similar to those achieved by chronic decerebration. To localize the sites of action, we demonstrated that microinjection of MSCP (20 nmol) into the lateral hypothalamic nucleus or the paraventricular nucleus resulted in inhibition of both basal pancreatic protein secretion and luminally stimulated pancreatic secretion by 48 % and 52 %, respectively. Intracerebroventricular injection of hemicholinium-3 at doses known to deplete the endogenous ACh store produced similar inhibitory results. In addition, microinjection of ACh (5 pmol) or the muscarinic M1 receptor agonist McN-A-343 (30 ng) into the lateral hypothalamic nucleus increased pancreatic secretion over basal levels by 46 % and 40 %, respectively. Selective lesions of lateral septal cholinergic neurons decreased basal pancreatic secretion and inhibited peptone-induced pancreatic secretion by 30 %. Destruction of the lateral parabrachial nucleus produced a 44 % inhibition of peptone-induced pancreatic section. Finally, microinjection of glutamate into the lateral septum or the lateral parabrachial nucleus stimulated vagal pancreatic efferent nerve firings from a basal level of 0 +/- 0.5 impulses (30 s)-1 to 4.5 +/- 0.5 and 14 +/- 2 impulses (30 s)-1, respectively, and pancreatic protein output increased 50 % and 84 % over basal levels. Administration of MSCP to the paraventricular nucleus eliminated these effects. These observations suggest that cholinergic neurons of the lateral septum and lateral parabrachial nucleus regulate pancreatic secretion. Further, cholinergic input from the lateral parabrachial nucleus to the hypothalamus plays a major role in the modulation of vagal pancreatic efferent nerve activity and pancreatic secretion evoked by the vago-vagal reflex.

Animals↗
PubMed2003

Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice.

Nitric oxide (NO) and NO synthase (NOS) play controversial roles in pancreatic secretion. NOS inhibition reduces CCK-stimulated in vivo pancreatic secretion, but it is unclear which NOS isoform is responsible, because NOS inhibitors lack specificity and three NOS isoforms exist: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Mice having individual NOS gene deletions were used to clarify the NOS species and cellular interactions influencing pancreatic secretion. In vivo secretion was performed in anesthetized mice by collecting extraduodenal pancreatic duct juice and measuring protein output. Nonselective NOS blockade was induced with N(omega)-nitro-L-arginine (L-NNA; 10 mg/kg). In vivo pancreatic secretion was maximal at 160 pmol.kg(-1).h(-1) CCK octapeptide (CCK-8) and was reduced by NOS blockade (45%) and eNOS deletion (44%). Secretion was unaffected by iNOS deletion but was increased by nNOS deletion (91%). To determine whether the influence of NOS on secretion involved nonacinar events, in vitro CCK-8-stimulated secretion of amylase from isolated acini was studied and found to be unaltered by NOS blockade and eNOS deletion. Influence of NOS on in vivo secretion was further examined with carbachol. Protein secretion, which was maximal at 100 nmol.kg(-1).h(-1) carbachol, was reduced by NOS blockade and eNOS deletion but unaffected by nNOS deletion. NOS blockade by L-NNA had no effect on carbachol-stimulated amylase secretion in vitro. Thus constitutive NOS isoforms can exert opposite effects on in vivo pancreatic secretion. eNOS likely plays a dominant role, because eNOS deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion, whereas nNOS deletion augments CCK-8 but not carbachol-stimulated secretion.

Amylases↗
PubMed2003

Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins.

Acute hyperglycemia evokes gastric slow wave dysrhythmias via endogenous prostaglandin generation. Ginger exhibits slow wave antiarrhythmic effects in other models, but its actions on hyperglycemia-evoked gastric dysrhythmias are unexplored. We hypothesized that ginger prevents disruption of slow wave rhythm by acute hyperglycemia via inhibition of prostaglandin production but not its actions. Twenty-two healthy humans underwent fasting electrogastrography during hyperglycemic clamping to 250 to 290 mg/dl after double-blind placebo or ginger root (1 g). Responses were compared with the prostaglandin E1 analog misoprostol (400 microg). Dominant frequencies (DF) and the percentage of recording times in the bradygastric [0.5-2 cycles/min (cpm)], normal (2-4 cpm), and tachygastric (4-9 cpm) frequency ranges were analyzed. After placebo, hyperglycemia reduced normal 2 to 4 cpm activity from 94.4 +/- 2.6 to 66.0 +/- 10.4%, increased the DF from 2.96 +/- 0.04 to 4.09 +/- 0.45 cpm, and increased tachygastria from 2.0 +/- 1.4 to 29.3 +/- 10.7% (P < 0.05). Hyperglycemia effects on normal activity (77.3 +/- 8.3%), DF (3.46 +/- 0.37 cpm), and tachygastria (15.6 +/- 8.6%) were significantly reduced by ginger (P < 0.05). Misoprostol evoked decreases in normal activity from 95.4 +/- 2.0 to 81.7 +/- 3.0% and increases in tachygastria from 3.1 +/- 1.6 to 11.2 +/- 2.4% (P < 0.05). However, ginger did not correct these abnormalities versus placebo (P = N.S.). In conclusion, acute hyperglycemia evokes gastric slow wave dysrhythmias that are prevented by ginger root. Conversely, the compound has no effect on dysrhythmias elicited by a prostaglandin E(1) analog, indicating that ginger likely acts to blunt production of prostaglandins rather than inhibiting their action. These findings suggest novel mechanisms for the traditional Chinese herbal remedy ginger.

Adult↗
PubMed2003

Musings on the wanderer: what's new in our understanding of vago-vagal reflexes? V. Remodeling of vagus and enteric neural circuitry after vagal injury.

The vago-vagal reflexes mediate a wide range of digestive functions such as motility, secretion, and feeding behavior. Previous articles in this series have discussed the organization and functions of this important neural pathway. The focus of this review will be on some of the events responsible for the adaptive changes of the vagus and the enteric neutral circuitry that occur after vagal injury. The extraordinary plasticity of the neural systems to regain functions when challenged with neural injury will be discussed. In general, neuropeptides and transmitter-related enzymes in the vagal sensory neurons are downregulated after vagal injury to protect against further injury. Conversely, molecules previously absent or present at low levels begin to appear or are upregulated and are available to participate in the survival-regeneration process. Neurotrophins and other related proteins made at the site of the lesion and then retrogradely transported to the soma may play an important role in the regulation of neuropeptide phenotype expression and axonal growth. Vagal injury also triggers adaptive changes within the enteric nervous system to minimize the loss of gastrointestinal functions resulting from the interruption of the vago-vagal pathways. These may include rearrangement of the enteric neural circuitry, changes in the electrophysiological properties of sensory receptors in the intramural neural networks, an increase in receptor numbers, and changes in the affinity states of receptors on enteric neurons.

Animals↗