Bicarbonate Response Research Articles

Pancreatic bicarbonate response to intraduodenal tryptophan in dogs: role of muscarinic M1-receptors and cholecystokinin.

In dogs, 1. Activation of cholecystokinin-receptors is needed for an adequate pancreatic bicarbonate response to secretin; 2. Cholinergic nerve fibers ending on M1-receptors are probably of little or no importance for the bicarbonate response to secretin in the given dose; 3. The bicarbonate response to tryptophan, given with a secretin background, is controlled by cholinergic M1-fibers and by cholecystokinin; 4. M1-fibers mainly mediate the bicarbonate response to low loads of tryptophan, whereas cholecystokinin controls the response to low and high loads of tryptophan; and 5. Both mediators interact in a synergistic manner. In six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol/kg/h), the cholecystokinin-receptor antagonist L-364,718 (0.025-0.1 mg/kg/h), and combinations of both on the pancreatic bicarbonate response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h). Secretin significantly (p < 0.05) stimulated the pancreatic bicarbonate output above basal levels. All doses of L-374,718, but not telenzepine, significantly decreased the bicarbonate response to secretin by up to 64%. Additional administration of telenzepine together with L-364,718 had no further inhibitory effect on the secretin-stimulated bicarbonate output as compared to L-364,718 given alone. All loads of tryptophan significantly increased the bicarbonate output over that seen with secretin alone (= incremental bicarbonate response to tryptophan). Telenzepine significantly decreased the incremental bicarbonate response to the two lower loads (0.37-1.1 mmol/h) of tryptophan (by 82-124%); L-364,718 decreased the incremental bicarbonate response to all loads of tryptophan (by 50-118%). The incremental bicarbonate output, as well as the 180-min integrated bicarbonate response to all loads of tryptophan, were abolished by all combinations of both antagonists.

Retinal pigment epithelial origin of bicarbonate response

The mechanisms of the bicarbonate-induced decrease in the ocular standing potential (bicarbonate response) were investigated in the cat. An intravenous infusion of 1.4% sodium bicarbonate solution caused a decrease in the standing potential. A high-bicarbonate solution decreased or increased the potential across the retinal pigment epithelium-choroid tissue of the excised cat eye when applied basally or apically, respectively, but did not affect the potential across the anterior portion of the excised eye or across the isolated neural retina. A high-bicarbonate solution principally depolarized the apical membrane of the retinal pigment epithelium (RPE) when applied basally, and hyperpolarized it when applied apically. These results suggest that the bicarbonate response in the cat is primarily due to the effects of an increase in bicarbonate concentration on the basal membrane of the RPE.

Differentiation of neovascular maculopathies by nonphotic electrooculogram responses

Four kinds of electrooculographic (EOG) responses for the retinal pigment epithelium (RPE) were studied to assess RPE integrity in neovascular macular diseases. In 20 eyes with age-related macular degeneration (ARMD), 13 fellow eyes of ARMD patients, eight eyes with central exudative chorioretinopathy (CECR), and seven unaffected eyes of CECR patients, we evaluated the light peak/dark trough ratio, and the hyperosmolarity, Diamox, and bicarbonate responses. We found no abnormalities in any ARMD eyes or fellow eyes of ARMD patients. In both the CECR eyes and unaffected eyes of CECR patients, however, the Diamox response was subnormal whereas the other three EOG responses remained normal. There was no significant difference in Diamox response between the CECR eyes and unaffected eyes of CECR patients. The selective deterioration of the Diamox response in CECR, but not in ARMD, can serve as a new index for differentiating between these similar conditions.

Pancreatic Secretory Response to Intrajejunal Tryptophan

In two sets of dogs with gastric, duodenal, and jejunal fistulas, we studied the effect of atropine (14 nmol/ kg/h) on the pancreatic secretory response to intrajejunal tryptophan (0.12-10.0 mmol/h; given against a secretin background) before (n = 7) and after extrinsic denervation of the jejunoileum (orthotopical autotransplantation; n = 6). Plasma levels of cholecystokinin were determined by radioimmunoassay. The incremental bicarbonate response to tryptophan was not significantly different between the two sets of dogs. Atropine had no effect on the incremental bicarbonate response to tryptophan. In both sets of dogs, intrajejunal tryptophan caused a dose-dependent increase in pancreatic protein output, which was reduced by atropine. The tryptophan-stimulated levels of plasma cholecystokinin were not significantly altered by denervation and or atropine. We conclude that in dogs (1) intrajejunal tryptophan stimulates pancreatic bicarbonate and protein secretion via release of hormones, (2) extrinsic denervation of the jejunoileum does not significantly alter the incremental bicarbonate and protein responses to intrajejunal tryptophan, (3) the cholinergic intrinsic nerves of the jejunoileum and the hormone cholecystokinin are probably involved in control of the pancreatic protein response to tryptophan, and (4) the release of cholecystokinin by intrajejunal tryptophan does not depend on the extrinsic and intrinsic cholinergic nerves of the jejunoileum.

Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis.

We have shown elsewhere that acidification is an early event in apoptosis, preceding DNA cleavage. Cells expressing the most common mutation (delF508) of the cystic fibrosis transmembrane regulator (CFTR) exhibit a higher resting intracellular pH and are unable to secrete chloride and bicarbonate in response to cAMP. We hypothesized that defective acidification in cells expressing delF508 CFTR would interfere with the acidification that accompanies apoptosis, which in turn, would prevent endonuclease activation and cleavage of DNA. We therefore determined whether the function of the CFTR would affect the process of apoptosis in mouse mammary epithelial C127 cells stably transfected with the wild-type CFTR (C127/wt) or the delF508 mutation of the CFTR (C127/508). C127 cells possessed an acid endonuclease capable of DNA degradation at low pH. Sixteen hours after treatment with cycloheximide, C127/wt cells underwent cytoplasmic acidification. In contrast, C127/508 cells failed to demonstrate acidification. Furthermore, the C127/508 cells did not show nuclear condensation or DNA fragmentation detected by in situ nick-end labeling after treatment with cycloheximide or etoposide, in contrast to the characteristic features of apoptosis demonstrated by the C127/wt cells. Measurement of cell viability indicated a preservation of cell viability in C127/508 cells but not in C127/wt cells. That this resistance to the induction of apoptosis depended upon the loss of CFTR activity is shown by the finding that inhibition of the CFTR with diphenylamine carboxylate in C127/wt cells conferred similar protection. These findings suggest a role for the CFTR in acidification during the initiation of apoptosis in epithelial cells and imply that a failure to undergo programmed cell death could contribute to the pathogenesis of cystic fibrosis.

The effect of pancreatic denervation and atropine on the cholecystokinin-induced pancreatic exocrine response.

To study the influence of extrapancreatic neural and cholinergic activity on the pancreatic response to cholecystokinin (CCK), six dogs underwent creation of Herrera pancreatic fistulas, placement of Thomas gastric cannulas, and distal pancreatectomies (innervated; INN). Six additional dogs were prepared similarly, with the addition of total extrinsic pancreatic denervation (denervated; DEN). The pancreatic protein and bicarbonate response to graded 12.5 to 200 ng/kg/h CCK doses was determined for INN and DEN animals both alone and with 10 micrograms/kg/h atropine infusion. The influence of extra-pancreatic neural and cholinergic activity on secretin's potentiation of the CCK-induced pancreatic response was then determined by repeating the studies with a 125 ng/kg/h secretin infusion. The latter results were compared to those predicted by summating the responses seen during separate 12.5-200 ng/kg/h CCK dose-response and 125 ng/kg/h secretin studies. Unstimulated protein output was diminished by atropine in INN animals (78 +/- 21 vs. 39 +/- 9 mg/15 min; p < 0.05) but not in DEN animals. Unstimulated bicarbonate outputs, integrated bicarbonate and protein outputs, and bicarbonate and protein dose-response curves were unaffected by denervation or atropine. Potentiation of CCK-induced bicarbonate output by secretin was also unaffected by atropine and denervation. We conclude that cholinergic elements are involved in unstimulated, but not CCK-induced, enzyme secretion. Further, potentiation of CCK-induced bicarbonate output by secretin does not depend on extrinsic neural or cholinergic elements.

Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates exocrine pancreas in conscious preruminating calves

The effects of new hypothalamic peptides, PACAP-27 and PACAP-38, and secretin and VIP on the interdigestive pancreatic secretion and duodenal myoelectric activity during the asecretory phase of the pancreatic interdigestive cycle, compared with the milk ingestion phase, were examined in five calves. Peptides were infused for 5 min into the external jugular vein (0, 3, 10, 30 and 100 pmol/kg body wt during the asecretory phase of the pancreatic interdigestive cycle, and the pancreatic secretory response was compared with that obtained during milk ingestion. Intravenous infusion of PACAP-27 caused dose-related stimulation of pancreatic juice flow and bicarbonate and protein output; this effect was identical to infusion of secretin. The effect of PACAP-38 was less pronounced, and that of VIP was the weakest. Pancreatic juice volume and bicarbonate responses during milk ingestion were similar to responses obtained with the highest doses of hypothalamic peptides and secretin, whereas postprandial protein secretion was much greater than the secretion stimulated with peptides. It was concluded that PACAP from the VIP/secretin family may stimulate pancreatic exocrine secretion in conscious calves and a part of the pancreatic response to food intake can be mediated by PACAP.

Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates exocrine pancreas in conscious preruminating calves

The effects of new hypothalamic peptides, PACAP-27 and PACAP-38, and secretin and VIP on the interdigestive pancreatic secretion and duodenal myoelectric activity during the asecretory phase of the pancreatic interdigestive cycle, compared with the milk ingestion phase, were examined in five calves. Peptides were infused for 5 min into the external jugular vein (0, 3, 10, 30 and 100 pmol/kg body wt during the asecretory phase of the pancreatic interdigestive cycle, and the pancreatic secretory response was compared with that obtained during milk ingestion. Intravenous infusion of PACAP-27 caused dose-related stimulation of pancreatic juice flow and bicarbonate and protein output; this effect was identical to infusion of secretin. The effect of PACAP-38 was less pronounced, and that of VIP was the weakest. Pancreatic juice volume and bicarbonate responses during milk ingestion were similar to responses obtained with the highest doses of hypothalamic peptides and secretin, whereas postprandial protein secretion was much greater than the secretion stimulated with peptides. It was concluded that PACAP from the VIP/secretin family may stimulate pancreatic exocrine secretion in conscious calves and a part of the pancreatic response to food intake can be mediated by PACAP.

Modulation of Pancreatic Secretion by Capsaicin-Sensitive Sensory Neurons in the Rat

The purpose of this work was to study whether stimulation or destruction of sensory afferents can modulate pancreatic secretion. The neurotoxin capsaicin is specific for a subpopulation of small diameter primary afferent neurons. Small doses of capsaicin were administered to anesthetized rats as intraduodenal or intragastric bolus injections to stimulate digestive sensory fibers, and pancreatic secretory response was measured. In addition, several high-dose subcutaneous capsaicin injections were administered 10 days before the experiments began, in order to inactivate sensory fibers. Basal and 2-deoxy-D-glucose (2DG)-stimulated pancreatic secretion was then measured. Intraduodenal capsaicin (96-3,050 micrograms/kg) induced a progressive (peak response 40-60 min after the injection), dose-related and long-lasting (> 180 min) increase in pancreatic output of sodium, bicarbonate, and total protein. The maximal response was obtained with 964 micrograms/kg capsaicin; it amounted to about 15% of the maximal response to exogenous cholecystokinin octapeptide (CCK8). The response was not decreased by atropine, hexamethonium, vagotomy, a mixture of adrenoceptor antagonists (prazosin + idazoxan + propranolol), or by the CCKB receptor antagonist L365,260. In contrast, the CCKA receptor antagonist L364,718 reduced by 30-40% the sodium and bicarbonate response and reduced by 90% the protein response induced by capsaicin, but not the response induced by methacholine or 2DG. However, intraluminal capsaicin did not release CCK in a preparation of isolated perfused duodeno-jejunum. Intragastric capsaicin did not significantly change pancreatic secretion. Capsaicin pretreatment had no effect on basal and 2DG-stimulated secretion, but abolished the response to intraduodenal capsaicin. In conclusion, intraduodenal capsaicin can stimulate external pancreatic secretion in anesthetized rats through capsaicin-sensitive sensory neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of neurotensin stimulation of external pancreatic secretion in the rat.

The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of this study was to analyze the mechanism of the neurotensin effect on external pancreatic secretion in the rat. The pancreatic dose-response curve to 40-min venous infusions of neurotensin 1-13 (0.1-10 micrograms/kg-h = 0.06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 micrograms/kg-h and reached approximately 30% of the maximal response to cholecystokinin (CCK). The ED50 was 0.27 micrograms/kg-h (= 0.16 nmol/kg-h) for bicarbonate and 0.45 micrograms/kg-h (= 0.27 nmol/kg-h) for protein output. Pancreatic secretion in response to each neurotensin dose increased steadily during the infusion and peaked 20-40 min after the end of infusion. Atropine and hexamethonium suppressed the stimulatory effect of neurotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCKA receptor antagonist L364718 decreased by 80% sodium and bicarbonate response (p < 0.01) and suppressed protein response (p < 0.01) to neurotensin. Methadone reduced the response to neurotensin by 85%, vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha 1-, alpha 2-, and beta-adrenoreceptors or of CCKB receptors did not change the neurotensin effect. We conclude that the mechanism of neurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCKA receptors, and, in part, capsaicin-sensitive sensory fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

The Inhibitory Effect of Octreotide on Exocrine Pancreatic Secretion in Conscious Dogs

The effects of somatostatin and its analogue, octreotide (SMS201-995), on pancreatic secretion and gastroduodenal motility in response to secretin and cholecystokinin octapeptide (CCK-8) were studied in five conscious dogs. Intravenous infusions of octreotide or somatostatin (1 nmol kg-1 h-1) inhibited periodic pancreatic secretion and the potentiation of fluid and bicarbonate responses to secretin at 60 ng kg-1 h-1 associated with the interdigestive gastroduodenal motility peaks (migrating motor complex). Pancreatic fluid and bicarbonate responses to secretin (125-1,000 ng kg-1 h-1) were not inhibited by octreotide or somatostatin. Pancreatic protein and enzyme responses to secretin and CCK-8 at 50 and 100, but not at 200 and 400, ng kg-1 h-1 were inhibited by octreotide and somatostatin. These inhibitory effects were similar to those of atropine (25 micrograms kg-1 h-1). The inhibition of protein responses to CCK-8 (100 ng kg-1 h-1) was dependent on octreotide dose. It is concluded that both octreotide and somatostatin, like atropine, inhibit interdigestive pancreatic secretion and the responses to small, but not large, doses of secretin and CCK-8 in conscious dogs.

Evaluation of retinal integrity in eyes with retained intraocular metallic foreign body by ERG and EOG

In three eyes with a retained intraocular metallic foreign body, the neural retina and retinal pigment epithelial (RPE) integrity were evaluated by means of ERG (a-wave, b-wave, oscillatory potentials) and non-photic EOG responses from the RPE (hyperosmolarity response, Diamox response, bicarbonate response). All three cases were judged in an early stage of retinal impairment on the basis of a well-preserved or supernormal b-wave amplitude and showed good postoperative prognosis. Out of three non-photic responses from the RPE, only the bicarbonate response was preoperatively reduced in two out of the three eyes.

Hormonal Control of Pancreatic Secretion by Intrajejunal HCl

To elucidate the role of hormones in the control of pancreatic secretion, we developed, in seven dogs, a model of total extrinsic denervation of the jejunoileum by autotransplanting this segment of bowel. A Thomas-like cannula was placed into the stomach, the duodenum (to collect pure pancreatic juice), and the proximal part of the jejunum. Thus, intestinal stimulants could only stimulate the pancreas via release of humoral (= hormonal) mediators. Seven control dogs received only the three fistulas. After recovery, dose-response curves of pancreatic bicarbonate and protein response to perfusion of the extrinsically denervated or innervated jejunoileum with HCl (1.5 to 48 mmol h-1) were performed with and without atropine (14 nmol kg-1 h-1 i.v.). Plasma levels of secretin were determined by radioimmunoassay. The maximal bicarbonate output occurred in response to 24 mmol h-1 of HCl and was significantly (p less than 0.05) higher in intact as compared to denervated animals. Atropine only significantly depressed the bicarbonate response to HCl in dogs with a denervated jejunoileum. HCl caused a dose-dependent increase in plasma levels of secretin, which was not altered by denervation and/or atropine. Irrespective of the innervation of the small bowel, pancreatic protein output was only significantly stimulated above basal when high loads (12-48 mmol h-1) of HCl were given. Atropine significantly reduced these responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of Cholecystokinin-Stimulated Pancreaticobiliary Output in Man by the Cholecystokinin Receptor Antagonist MK-329

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.

Pancreatic Secretory Responses to Long-Term Infusions of Secretin and Cerulein in Humans

We measured pancreatic enzyme and bicarbonate responses to graded doses of intravenous secretin or cerulein alone or together in healthy human subjects. Bicarbonate responses were steady and well maintained during the last 3.5 h of the 4 h of infusions of secretagogues, giving evidence for a constant pancreatic flow rate. Potentiation (more-than-additive response) was observed between secretin and cerulein for bicarbonate secretion, but not for enzyme secretion. Secretin stimulated pancreatic enzyme secretion. The effect was most pronounced with amylase secretion and less prominent with lipase, trypsin, and chymotrypsin secretion. Changes in the proportion of enzymes were seen over time, with trypsin and chymotrypsin output declining towards the end of cerulein infusion. We conclude that in humans the effects of secretin on pancreatic enzyme secretion are complex and include time-dependent changes in the enzyme mixture, but potentiation between secretin and cerulein does not occur for enzyme output.

Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer

Proximal duodenal mucosal bicarbonate production is impaired in patients with duodenal ulcer disease. Because prostaglandins of the E class increase human proximal duodenal bicarbonate secretion, this study tested the hypothesis that endogenous prostaglandin E2 production is defective in patients with duodenal ulcer. Ten patients, five with active and five with inactive duodenal ulcer disease, were studied along with 10 normal volunteers. The proximal 4 cm of duodenum, the bulb, was isolated and continuously perfused with 154 mmol/L NaCl. Basal bicarbonate secretion was measured for 30 minutes. The test segment was then acidified with a physiological amount of HCl (2 mmol over 5 minutes), and acid-stimulated bicarbonate secretion was measured by pH/PCO2 and back-titration for 55 more minutes. Prostaglandin E2 was measured in the effluents by a radioimmunologic assay validated by gas chromatography-mass spectrometry. Compared with the normal subjects after luminal acidification, the duodenal ulcer patients had significantly greater PGE2 release and decreased total 1-hour bicarbonate output. The peak 5-minute acid-stimulated bicarbonate responses were not significantly different between the duodenal ulcer patients and normal subjects. After luminal acidification, PGE2 output remained elevated in the duodenal ulcer patients but returned promptly to basal in the normal subjects. Furthermore, the ratio of bicarbonate secreted to the amount of PGE2 released was significantly less in the ulcer patients. These findings suggest that patients with duodenal ulcer disease have an impaired mucosal bicarbonate response to endogenous PGE2. The increased acid-stimulated PGE2 response in duodenal ulcer patients suggests a compensatory phenomenon in response to the diminished mucosal bicarbonate production.

Geranyl-Geranyl Acetone

Geranyl-geranyl acetone (GGA), a new acyclic polyisoprenoid, anti-ulcer drug appears to exert its beneficial effect by stimulating bicarbonate secretion from the stomach and pancreas. Its efficacy in stimulating pancreatic bicarbonate is particularly striking, and this study was designed to examine the mechanism for this action. Since it is structurally similar to the side chain of the prostaglandin molecule, its ability to stimulate bicarbonate secretion could be a direct one. On the other hand, the magnitude of pancreatic bicarbonate response (about 50% of maximal response to secretin) suggests it might act by releasing secretin. Two types of experiments were performed in dogs with pancreatic fistulas: first, secretagogue interactions were examined by studying the effect of intraduodenal GGA (8 mg/kg) or its carrier (control) on the dose-response curves to exogenous secretin and cholecystokinin octapeptide (CCK-8); second, the effect of graded doses of intraduodenal GGA on pancreatic bicarbonate and plasma secretin-like immunoreactivity (SLI) responses was tested directly. Pancreatic bicarbonate responses (micromoles per 30 min) were to secretin doses of 32, 125, and 500 ng/kg/h. Without and with GGA, responses were 74 +/- 27, 952 +/- 215, and 2,000 +/- 425 and 599 +/- 110, 1,624 +/- 472, and 2,129 +/- 398 ng/kg/h, respectively. Similarly, the bicarbonate responses to CCK-8 were augmented. Basal plasma SLI was 1.5 +/- 0.6 pM/ml. Peak plasma SLI in response to 2, 4, and 8 mg of GGA intraduodenally were 6.8 +/- 0.7, 8.9 +/- 3.1, and 19.6 +/- 2.7 pM/ml, respectively. It is concluded that GGA is a potent stimulant of pancreatic bicarbonate secretion, and this action appears to be mediated by the release of duodenal secretin.

Stimulation of duodenal bicarbonate secretion in conscious rats by cerebral somatostatin-28: Role of neurohumoral pathways

The central nervous system effects of somatostatin-28 on proximal duodenal bicarbonate secretion were studied in freely moving rats. Cerebroventricular administration of somatostatin-28 (0.2-2.0 nmol) significantly stimulated duodenal bicarbonate secretion in a dose-dependent fashion. Somatostatin-28 was approximately twice as effective as somatostatin-14. Intravenous administration of somatostatin-28 or somatostatin-14 did not significantly alter the bicarbonate response. Ganglionic blockade with chlorisondamine and truncal vagotomy abolished the stimulatory effect of somatostatin-28 while bretylium, naloxone, indomethacin, and adrenalectomy did not. Furthermore, atropine methylnitrate significantly attenuated and the vasoactive intestinal peptide antagonist 4Cl-D-Phe6, Leu17-vasoactive intestinal peptide abolished the bicarbonate response produced by cerebroventricular somatostatin-28. In contrast, hypophysectomy and pretreatment with the vasopressin V1-receptor antagonist [1-deaminopenicillamine, 2-(0-methyl)Tyr, 8-Arg]-vasopressin significantly enhanced the bicarbonate response produced by cerebroventricular somatostatin-28. These findings indicate that somatostatin-28 acts within the central nervous system to stimulate duodenal bicarbonate secretion in freely moving rats via vagal efferents by release of vasoactive intestinal peptide and, in part, by a muscarinic pathway and not by catecholamine, opiate, or prostaglandin release.

TRH-induced vagal stimulation of duodenal HCO-3 mediated by VIP and muscarinic pathways

The central nervous system effects of thyrotropin-releasing hormone (TRH) on proximal duodenal bicarbonate secretion were studied in freely moving rats. Cerebroventricular administration of TRH (0.5-5.0 nmol) significantly stimulated basal duodenal bicarbonate secretion, whereas intravenous administration of TRH did not. Ganglionic blockade with chlorisondamine and truncal vagotomy abolished TRH-induced bicarbonate secretion, whereas atropine significantly attenuated the response. The vasoactive intestinal peptide (VIP) receptor antagonist, (4Cl-D-Phe6, Leu17) VIP given intravenously completely prevented the stimulatory effect of central TRH on duodenal bicarbonate secretion. In contrast, hypophysectomy, adrenalectomy, opiate and noradrenergic blockade, or indomethacin did not affect the TRH-induced bicarbonate response. Intravenous administration of VIP and carbachol significantly stimulated bicarbonate outputs, and these responses were blocked by the VIP antagonist and atropine, respectively. These results indicate that TRH may serve as a central nervous system mediator that stimulates duodenal bicarbonate secretion in rats by increasing vagal outflow. Vagal stimulation induced by TRH increases duodenal bicarbonate secretion by the release of VIP and, in part, by activation of a muscarinic pathway but not by pituitary, adrenal, and noradrenergic pathways or endogenous opiates and prostaglandins. The actions of peripheral VIP and carbachol appear to be mediated by specific VIP and muscarinic receptors, respectively.

Effects of neuropeptides on gastric acid and duodenal bicarbonate secretions in freely moving rats

The central nervous system effects of neuropeptides on gastric acid and duodenal bicarbonate secretions were examined. In freely moving rats, i.c.v. administration of thyrotropin-releasing hormone (TRH), human gastrin-17 (hG-17) and the somatostatin analogue, desAA 1,2,4,5,12,13 [ d-Trp 8]somatostatin (ODT8-SS), significantly increased gastric acid secretion, while vasoactive intestinal peptide (VIP) had no effect. In the order of potency and efficacy, the following peptides decreased acid secretion: bombesin (BOM) > calcitonin gene-related peptide (CGRP) > calcitonin (CT) > corticotropin-releasing factor (CRF) > β-endorphin (β-END) > neurotensin (NT). In anesthetized rats, none of these peptides significantly altered proximal duodenal bicarbonate secretion. In awake, freely moving rats, cerebroventricular administration of CGRP significantly decreased while ODT8-SS, TRH and CRF significantly increased duodenal bicarbonate secretion. β-Endorphin, VIP, CT, BOM, NT and hG-17 given i.c.v. did not significantly alter the bicarbonate response. These results indicate that neuropeptides administered into the central nervous system modulate gastric acid as well as duodenal bicarbonate secretions in awake, freely moving rats in a differentiated fashion. CGRP inhibits both acid and bicarbonate secretions, a somatostatin analogue and TRH both stimulate acid and bicarbonate secretions and CRF inhibits gastric acid but stimulates duodenal bicarbonate secretions.