acute hyperglycemia impairs vagus activity and inhibits antro-pyloric coordination resulting in...

1
(SC 52). c-Fos activity was measured by counting positive nuclei. RESULTS: A significant increase in c-Fos expression was observed at the area of the parabrachial nuclei (PBN) in CRD-treated rats (56.5+19.6 vs 126.3_+9.8, control vs experimental, p=O.017, by t-test at unequal variances). A trend towards an increase in expression was found in the thalamic paraventricular nucleus (86.1 _+16.2vs 137.2_+24.8,p = 0.1) and the central nucleus of amyg- dale (98.8_+18.9 vs 142.9_+12.8, p=0.1). Similar activation was seen in both control and experimental rats in the nucleus of the solitary tract, area postrema, supranptic nucleus, piriform cortex, cortical amygdaloid area, insular cortex, hypothalamic paraventricuiar nucleus, habenula, and the thalamic mediodorsal nucleus. No activation was seen in the cingulate, infralimbic, or prelimbic cortices. CONCLUSION:Colorectal distention activates PBN neurons in anesthetized rats. The differences in findings in the anesthetized rat and reported human studies using fMRI or PET, or studies in non-anesthetized rats, may result from the use of anesthesia. Comparing findings in anesthetized and non-anesthetized animals may help to differentiate between the pathways involved in the perception of pain and the neural afferent pathway per se. Supported by grants from Glaxo-Wellcomeand NIH (DC00240and MH00653). 3856 Acupuncture-InducedGactdc Relaxation Is Mediated Via SomatmqfmpatheflcReflex In Rats. Hitoshi Tada, Mikio Fujita, Toku Takahashi, Duke Univ Medical Ctr, Durham, NC Background; Acupuncture has been used to treat gastrointestinal (GI) symptoms in China for more than 3,000 years. However, the mechanism of beneficial effects of acupuncture still remains mysterious. On the other hand, recent studies demonstrated that the stimulation of somatic afferent nerves of the abdominal skin modifies GI function. This study was designed to clarify the neural pathway of acupuncture-induced gastric motility. Methods; Under thiobuta- barbial (Inactin; 100 mg/kg)-anesthesia, strain gage transducers were implanted on the serosal surface of various GI tract to record circular muscle contractions in rats. Acupuncture needle with a diameter of 300/~m was inserted into the skin and underlying muscles of the right lower abdomen. The needle was twisted right and left once every second for 60 seconds. Results; Acupuncture caused a transient relaxation in the gastric body, antrum and pylorus, but had no effects on the proximal or distal colon. In contrast, bethanecbol (a muscarinic receptor agonist) caused significant contractions in every G I tract. Acupuncture-induced gastric relaxationswere reproducible more than 5 times when applied every 30 rainand were observed more than 80% of 108 rats tested. Acupuncture-induced gastric relaxations ware significantly reduced by guanethidine, propranolol and hexamethonium to 9_+4%, 12-+5 and 2_+1% of control, respectively (n=6). Splanchnic ganglenectomy and spinal cord transection at C7 significantly reduced acupuncture-induced gastric relaxations to 14-+7% and 4+_3 %, respec- tively (n = 6). In contrast, L-NNA, phentolamine and truncal vagotomy had no effects. These results suggest that acupuncture-induced gastric relaxations were mediated via nicotinic receptors, beta adrenoceptors and sympathetic nerve. Furthermore, acupuncture-induced gastric relaxations were significantly reduced by spieD-medullary transection to 13+_5% (n = 4), but not by suprapontine transection, suggesting that the reflex center of acupuncture- induced gastric relaxations is the brain stem. Conclusions; Acupuncture stimulates somatic afferent nerves of the skin and muscle of the alxlomen. The sensory neural inputs are transferred to the brain stem through the spinal cord. Efferent limb involves gastric sympathetic neurons and releasedcatecholamine stimulates beta adrenoceptor of the smooth muscle cells, resulting in gastric relaxations. We believe that this neural pathway may help to understand the mysterious mechanism of acupuncture-induced gastric motility. 3857 Repetitive Body Rotation Alters Subjective And Objective Nausea Sensitivity Joachim Klose, Dept of Internal Medicine, LMU, Munich Germany; Sandra Hausmann, Institute of Medical Psychology, HH-University, Duesseldorf Germany; Baerbel Otto, Dept of Internal Medicine, LMU, Munich Germany; Ursula Stockhorst, Institute of Medical Psychology, HH-University, Duesseldorf Germany; Paul Enck, Dept of Gen Surg, Univ of Tuebingen, Tuebingen Germany; Sibylle Klosterhalten, institute of Medical Psychology, HH- University, Duesseldorf Germany It is said that repetitive exposure to a stressful stimulus, e.g. a nauseogenic body rotation will result in altered responsiveness in the peiphery and/or at a central level but the exact mechanisms of both and their relationship are incompletely understood. Methods: On 4 consecutive days, and always at the same time of the day, 8 healthy subjects (29.3 _+ 1.5 yrs, 4:4 males:females) were seated in a rotation chair, and rotated along the vertical axis for 5xl minute maximum. Rotation tolerance (sec) was noted. Prior to, immediately afterwards and post 15 min, symptom ratings were taken (in arbitrary units), and blood samples were drawn for ACTH measure (pg/ml) (at post 30 rain). All subjects also rated their susceptibility towards rotation and gave their nausea profile (NP) (Muth et al. 1996) on two standardized and validated tests. Effects were tested using repeated measure ANOVAs (x -+ SEM). Results: 1) Rotation time decreasedonly minimal cross the trial (from 129.4 _+ 32.8 at day 1 to 119.1 _+ 33.3 sec at day 4, n.s.), 2) Baseline ACTH, peak ACTH response after rotation, and post 30 min levels decreased from 34 _+ 8.4 to 21 _ 4.5 (p=.123), 68 _+ 13.5 to 26 _+ 4.8 (p = .026), and 54 _+ 14.3 to 22 _+ 3.9 pg (p = .005), resp.; 3) Nausearating remained virtually identical (29.1 _+ 4.9 to 27.1 _+ 0.4; n.s.). 4) The somatic scale of the NP did not change (44.7 -+ 8.0 to 42.6 _+ 9.3 %, n.s.), but the GI subscale decreased (56.7 -+ 8.6 to 46.4 + 7.6 %, p = .04), as did the emotional subscale (17.6 + 4.6 to 9.7 ± 4.1%, p = .11). 5) Motion sickness susceptibility was not associated with any of the measures except with the baseline ACTH level at day 1 (r= .64, p<.05). 6) Individual ACTH levels showed adaptation in 6/8 cases, but sensitization in one case. The NP decreased in only 4/8 cases, with the GI subscale being the most and the emotional subscale the least sensitive. Rotation time was indicative of habituation in one case only, but showed dishabltuation in 3 cases. 6) Clustering of the individual responses revealed almost as many clusters (4) as subjects (8) in the trial. Conclusion: Habituation and sensitization to nauseogenicstimuli seem to be individual patterns which may vary independently between subjects with respect to symptoms, behaviors, and physiologic measures (Supported by grants from DLR Germany, DFG Germany and the Wellcome Trust, UK). 3858 Acute Hyperglycemia Impairs Vagus Activity And Inhibits Antro-Pyloric Coordination, Resulting In Delayed Gastric Emptying In ConsciousRats. Tadesbi Ishiguchi, Hidekazu ltoh, Wakayama Medical Coil Kihoku Hosp, Wakayama Japan; Hitoshi Tada, Toku Takaheshi, Duke Univ Medical Ctr, Durham, NC Background; Delayed gastric emptying is a common complication of diabetes. Although it has been proposed that hyperglycemia, not only autonomic neuropathy, contribute to the pathogenesis of delayed gastric emptying, the inhibitory mechanism of hyperglycemia on gastric emptying remains unclear. We studied the effects of acute hyperglycemia on solid gastric emptying and postprandial gastric motility in conscious rats. Methods: After 24 hr- fasting, rats were given preweighed pellets (1.5 g) for 10 rain. Food intake was measured by weighing the uneaten pellets. Rats were sacrificed 90 min after the feeding and the gastric content was recoveredfrom the stomach. Calculatedgastric emptying was compared between rats received intravenous (i.v.)-infusion of saline (euglycemia) and D-glucose (hyperglycemia). To study postprandial antro-pyloric motility, two strain gage transducers were implanted on the antrum and pylorus. To investigate whether the inhibitory effect of hyperglycemia on gastric motility is mediated via a vagal pathway, sham feeding-induced gastric motility was compared between euglycemia and hyperglycemia. Results; i.v.-infusion of D-glucose (50%) for 30 rain increased the blood glucose level from 5.4_+0.5 mM to 13.0_+1.3 mM (n=7). Acute hyperglycemia significantly delayed solid gastric emptying to 5_+3% compared to that in euglycemia (62_+4%, n = 7, P<O.01). In euglycemia, contractions with low frequency (< 3 cycles/min) and high amplitude (>15 g) were frequently observed in the antrum 40 rain after the feeding. The peak contraction of the antrum occurred most often 2-4 sec before the peak contraction of the pylorus. Antro-pyloric coordination was defined as a single contraction that observed at the antrum propagated aborally into the pylorus within 10 sec and was followed by quiescenceat least 20 sec. Acute hyperglycemia significantly reduced postprandial antral contractions. The number of episode of antro-pyloric coordination was significantly reduced from 8.5_+3.1 in euglycemia to 0.3-+0.2 in hyperglycemia at 40-60 rain after the feeding (n=5, P<O.05). Sham feeding-induced antral contractions were also significantly reduced by hyperglycemia. Conclusion; It is suggested that acute hyperglycemia inhibits antral contractions and antro-pyloric coordination, resulting in delayedgastric emptying in conscious rats. The inhibitory effects of acute hyperglycemia on gastric emptying is, at least in part, due to impaired vagal actMty. 3850 The lefluuce Of Different Neonatal Maternal Deprivation Patterns On The Development Of Visceral Hypersensitivity In Rats Andras Rosztoczy, Jean Floramonti, INRA, Toulouse France; Janos Lonovics, Tibor Wntmann, Univ of Szeged, Szeged Hungary; Lionel Bueno, INRA, Toulouse France Stressful events in the early postnatal period of life, such as painful stimuli or maternal deprivation, has been shown to modify the development of the nociceptive neuronal circuits resulting visceral and/or somatic hyperaigesia. The aim of the present study was to establish the effect of different pettems of maternal deprivation on the development of visceral hyperaigesia. Methods: Newborn male Wistar rat pups were submitted to different patterns of maternal deprivation or left undisturbed with their dam. Maternal deprivation was applied for 2 hours daily, between postnatal days 1-14. In 'lype M" deprivation all the pups were removed from the dam, while in "type P" deprivation only the half of the counterparts were separated. Pups of "untouched" families and the "non-deprived" counterparts of the "type P" families served as controls. Visceral sensitivity was tested in the young adult rats (200-250g). Progressive rectal distension was carried out by intrarectal balloon inflation (0.4-0.8-1.2 ml volumes) and abdominal contractions (AC) were recorded and counted according to our previously published protocol. Results: The figure shows, that compared to the respective controls the numbers of AC at 0.4 ml were increased in "type P" deprivation (p<O.01), while data were similar at the higher volumes. In the contrary, "type M" deprivation significantly increasedthe numbers of AC at all volumes (p<O.Ot). Differenceswere significant compared to the 'lype P" separated subjects as well (p<O.01). Values of the two types of controls appeared identical. Conclusion: Both patterns of maternal deprivation induce visceral hypersensitivity in male Wistar rats. The differences between the two patterns may reflect that maternal factors are also involved in this process. ' .o. ¢onUcls (n=19) j ...-.--t ~" ../ -.-~,., i~=,~ 1o' ~"" ." *" p<OOl(toco~aol=) I 3860 The Effect of Liquid Carbohydrateand Protein Meals on Gastric Tachyardiythmia and Susceptibility to Vection-luduced Motion Sickness Max E. Levine, Manda J. Williamscn, Penn State Univ, University Park, PA; Eric R. Muth, Clemson Univ, Clemson, SC; Robert M. Stem, Penn State Univ, University Park, PA Background: The ingestion of a meal often reduces susceptibility to the development of gastric tachyarrhythmia, the abnormal activity of the stomach that frequently accompanies nausea. The purpose of this study was to determine what types of meals are most effective for preventing the development of gastric tachyarrhythmia and the symptoms of motion sickness provoked by a rotating optokinetic drum. Method: A repeated measures, counterbalanced A-716

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Page 1: Acute hyperglycemia impairs vagus activity and inhibits antro-pyloric coordination resulting in delayed gastric emptying in conscious rats

(SC 52). c-Fos activity was measured by counting positive nuclei. RESULTS: A significant increase in c-Fos expression was observed at the area of the parabrachial nuclei (PBN) in CRD-treated rats (56.5+19.6 vs 126.3_+9.8, control vs experimental, p=O.017, by t-test at unequal variances). A trend towards an increase in expression was found in the thalamic paraventricular nucleus (86.1 _+16.2 vs 137.2_+24.8, p = 0.1) and the central nucleus of amyg- dale (98.8_+18.9 vs 142.9_+12.8, p=0.1). Similar activation was seen in both control and experimental rats in the nucleus of the solitary tract, area postrema, supranptic nucleus, piriform cortex, cortical amygdaloid area, insular cortex, hypothalamic paraventricuiar nucleus, habenula, and the thalamic mediodorsal nucleus. No activation was seen in the cingulate, infralimbic, or prelimbic cortices. CONCLUSION: Colorectal distention activates PBN neurons in anesthetized rats. The differences in findings in the anesthetized rat and reported human studies using fMRI or PET, or studies in non-anesthetized rats, may result from the use of anesthesia. Comparing findings in anesthetized and non-anesthetized animals may help to differentiate between the pathways involved in the perception of pain and the neural afferent pathway per se. Supported by grants from Glaxo-Wellcome and NIH (DC00240 and MH00653).

3856

Acupuncture-Induced Gactdc Relaxation Is Mediated Via Somatmqfmpatheflc Reflex In Rats. Hitoshi Tada, Mikio Fujita, Toku Takahashi, Duke Univ Medical Ctr, Durham, NC

Background; Acupuncture has been used to treat gastrointestinal (GI) symptoms in China for more than 3,000 years. However, the mechanism of beneficial effects of acupuncture still remains mysterious. On the other hand, recent studies demonstrated that the stimulation of somatic afferent nerves of the abdominal skin modifies GI function. This study was designed to clarify the neural pathway of acupuncture-induced gastric motility. Methods; Under thiobuta- barbial (Inactin; 100 mg/kg)-anesthesia, strain gage transducers were implanted on the serosal surface of various GI tract to record circular muscle contractions in rats. Acupuncture needle with a diameter of 300/~m was inserted into the skin and underlying muscles of the right lower abdomen. The needle was twisted right and left once every second for 60 seconds. Results; Acupuncture caused a transient relaxation in the gastric body, antrum and pylorus, but had no effects on the proximal or distal colon. In contrast, bethanecbol (a muscarinic receptor agonist) caused significant contractions in every G I tract. Acupuncture-induced gastric relaxations were reproducible more than 5 times when applied every 30 rain and were observed more than 80% of 108 rats tested. Acupuncture-induced gastric relaxations ware significantly reduced by guanethidine, propranolol and hexamethonium to 9_+4%, 12-+5 and 2_+1% of control, respectively (n=6). Splanchnic ganglenectomy and spinal cord transection at C7 significantly reduced acupuncture-induced gastric relaxations to 14-+7% and 4+_3 %, respec- tively (n = 6). In contrast, L-NNA, phentolamine and truncal vagotomy had no effects. These results suggest that acupuncture-induced gastric relaxations were mediated via nicotinic receptors, beta adrenoceptors and sympathetic nerve. Furthermore, acupuncture-induced gastric relaxations were significantly reduced by spieD-medullary transection to 13+_5% (n = 4), but not by suprapontine transection, suggesting that the reflex center of acupuncture- induced gastric relaxations is the brain stem. Conclusions; Acupuncture stimulates somatic afferent nerves of the skin and muscle of the alxlomen. The sensory neural inputs are transferred to the brain stem through the spinal cord. Efferent limb involves gastric sympathetic neurons and released catecholamine stimulates beta adrenoceptor of the smooth muscle cells, resulting in gastric relaxations. We believe that this neural pathway may help to understand the mysterious mechanism of acupuncture-induced gastric motility.

3857

Repetitive Body Rotation Alters Subjective And Objective Nausea Sensitivity Joachim Klose, Dept of Internal Medicine, LMU, Munich Germany; Sandra Hausmann, Institute of Medical Psychology, HH-University, Duesseldorf Germany; Baerbel Otto, Dept of Internal Medicine, LMU, Munich Germany; Ursula Stockhorst, Institute of Medical Psychology, HH-University, Duesseldorf Germany; Paul Enck, Dept of Gen Surg, Univ of Tuebingen, Tuebingen Germany; Sibylle Klosterhalten, institute of Medical Psychology, HH- University, Duesseldorf Germany

It is said that repetitive exposure to a stressful stimulus, e.g. a nauseogenic body rotation will result in altered responsiveness in the peiphery and/or at a central level but the exact mechanisms of both and their relationship are incompletely understood. Methods: On 4 consecutive days, and always at the same time of the day, 8 healthy subjects (29.3 _+ 1.5 yrs, 4:4 males:females) were seated in a rotation chair, and rotated along the vertical axis for 5xl minute maximum. Rotation tolerance (sec) was noted. Prior to, immediately afterwards and post 15 min, symptom ratings were taken (in arbitrary units), and blood samples were drawn for ACTH measure (pg/ml) (at post 30 rain). All subjects also rated their susceptibility towards rotation and gave their nausea profile (NP) (Muth et al. 1996) on two standardized and validated tests. Effects were tested using repeated measure ANOVAs (x -+ SEM). Results: 1) Rotation time decreased only minimal cross the trial (from 129.4 _+ 32.8 at day 1 to 119.1 _+ 33.3 sec at day 4, n.s.), 2) Baseline ACTH, peak ACTH response after rotation, and post 30 min levels decreased from 34 _+ 8.4 to 21 _ 4.5 (p=.123), 68 _+ 13.5 to 26 _+ 4.8 (p = .026), and 54 _+ 14.3 to 22 _+ 3.9 pg (p = .005), resp.; 3) Nausea rating remained virtually identical (29.1 _+ 4.9 to 27.1 _+ 0.4; n.s.). 4) The somatic scale of the NP did not change (44.7 -+ 8.0 to 42.6 _+ 9.3 %, n.s.), but the GI subscale decreased (56.7 -+ 8.6 to 46.4 + 7.6 %, p = .04), as did the emotional subscale (17.6 + 4.6 to 9.7 ± 4.1%, p = .11). 5) Motion sickness susceptibility was not associated with any of the measures except with the baseline ACTH level at day 1 (r= .64, p<.05). 6) Individual ACTH levels showed adaptation in 6/8 cases, but sensitization in one case. The NP decreased in only 4/8 cases, with the GI subscale being the most and the emotional subscale the least sensitive. Rotation time was indicative of habituation in one case only, but showed dishabltuation in 3 cases. 6) Clustering of the individual responses revealed almost as many clusters (4) as subjects (8) in the trial. Conclusion: Habituation and sensitization to nauseogenic stimuli seem to be individual patterns which may vary independently between subjects with respect to symptoms, behaviors, and physiologic measures (Supported by grants from DLR Germany, DFG Germany and the Wellcome Trust, UK).

3858

Acute Hyperglycemia Impairs Vagus Activity And Inhibits Antro-Pyloric Coordination, Resulting In Delayed Gastric Emptying In Conscious Rats. Tadesbi Ishiguchi, Hidekazu ltoh, Wakayama Medical Coil Kihoku Hosp, Wakayama Japan; Hitoshi Tada, Toku Takaheshi, Duke Univ Medical Ctr, Durham, NC

Background; Delayed gastric emptying is a common complication of diabetes. Although it has been proposed that hyperglycemia, not only autonomic neuropathy, contribute to the pathogenesis of delayed gastric emptying, the inhibitory mechanism of hyperglycemia on gastric emptying remains unclear. We studied the effects of acute hyperglycemia on solid gastric emptying and postprandial gastric motility in conscious rats. Methods: After 24 hr- fasting, rats were given preweighed pellets (1.5 g) for 10 rain. Food intake was measured by weighing the uneaten pellets. Rats were sacrificed 90 min after the feeding and the gastric content was recovered from the stomach. Calculated gastric emptying was compared between rats received intravenous (i.v.)-infusion of saline (euglycemia) and D-glucose (hyperglycemia). To study postprandial antro-pyloric motility, two strain gage transducers were implanted on the antrum and pylorus. To investigate whether the inhibitory effect of hyperglycemia on gastric motility is mediated via a vagal pathway, sham feeding-induced gastric motility was compared between euglycemia and hyperglycemia. Results; i.v.-infusion of D-glucose (50%) for 30 rain increased the blood glucose level from 5.4_+0.5 mM to 13.0_+1.3 mM (n=7). Acute hyperglycemia significantly delayed solid gastric emptying to 5_+3% compared to that in euglycemia (62_+4%, n = 7, P<O.01). In euglycemia, contractions with low frequency (< 3 cycles/min) and high amplitude (>15 g) were frequently observed in the antrum 40 rain after the feeding. The peak contraction of the antrum occurred most often 2-4 sec before the peak contraction of the pylorus. Antro-pyloric coordination was defined as a single contraction that observed at the antrum propagated aborally into the pylorus within 10 sec and was followed by quiescence at least 20 sec. Acute hyperglycemia significantly reduced postprandial antral contractions. The number of episode of antro-pyloric coordination was significantly reduced from 8.5_+3.1 in euglycemia to 0.3-+0.2 in hyperglycemia at 40-60 rain after the feeding (n=5, P<O.05). Sham feeding-induced antral contractions were also significantly reduced by hyperglycemia. Conclusion; It is suggested that acute hyperglycemia inhibits antral contractions and antro-pyloric coordination, resulting in delayed gastric emptying in conscious rats. The inhibitory effects of acute hyperglycemia on gastric emptying is, at least in part, due to impaired vagal actMty.

3850

The lefluuce Of Different Neonatal Maternal Deprivation Patterns On The Development Of Visceral Hypersensitivity In Rats Andras Rosztoczy, Jean Floramonti, INRA, Toulouse France; Janos Lonovics, Tibor Wntmann, Univ of Szeged, Szeged Hungary; Lionel Bueno, INRA, Toulouse France

Stressful events in the early postnatal period of life, such as painful stimuli or maternal deprivation, has been shown to modify the development of the nociceptive neuronal circuits resulting visceral and/or somatic hyperaigesia. The aim of the present study was to establish the effect of different pettems of maternal deprivation on the development of visceral hyperaigesia. Methods: Newborn male Wistar rat pups were submitted to different patterns of maternal deprivation or left undisturbed with their dam. Maternal deprivation was applied for 2 hours daily, between postnatal days 1-14. In 'lype M" deprivation all the pups were removed from the dam, while in "type P" deprivation only the half of the counterparts were separated. Pups of "untouched" families and the "non-deprived" counterparts of the "type P" families served as controls. Visceral sensitivity was tested in the young adult rats (200-250g). Progressive rectal distension was carried out by intrarectal balloon inflation (0.4-0.8-1.2 ml volumes) and abdominal contractions (AC) were recorded and counted according to our previously published protocol. Results: The figure shows, that compared to the respective controls the numbers of AC at 0.4 ml were increased in "type P" deprivation (p<O.01), while data were similar at the higher volumes. In the contrary, "type M" deprivation significantly increased the numbers of AC at all volumes (p<O.Ot). Differences were significant compared to the 'lype P" separated subjects as well (p<O.01). Values of the two types of controls appeared identical. Conclusion: Both patterns of maternal deprivation induce visceral hypersensitivity in male Wistar rats. The differences between the two patterns may reflect that maternal factors are also involved in this process.

' . o . ¢onUcls (n=19)

j ...-.--t ~" ../ - . -~ , . , i~=,~ 1o' ~ " " . " *" p < O O l ( t o c o ~ a o l = ) I

3860

The Effect of Liquid Carbohydrate and Protein Meals on Gastric Tachyardiythmia and Susceptibility to Vection-luduced Motion Sickness Max E. Levine, Manda J. Williamscn, Penn State Univ, University Park, PA; Eric R. Muth, Clemson Univ, Clemson, SC; Robert M. Stem, Penn State Univ, University Park, PA

Background: The ingestion of a meal often reduces susceptibility to the development of gastric tachyarrhythmia, the abnormal activity of the stomach that frequently accompanies nausea. The purpose of this study was to determine what types of meals are most effective for preventing the development of gastric tachyarrhythmia and the symptoms of motion sickness provoked by a rotating optokinetic drum. Method: A repeated measures, counterbalanced

A-716