Biomedical subjects

J D Kaunitz

Publications and source records attributed to J D Kaunitz.

At least 19 recordsLinked to original sources

PubMed2006

Review article: duodenal bicarbonate - mucosal protection, luminal chemosensing and acid-base balance.

The duodenum serves as a buffer zone between the stomach and the jejunum. Over a length of only 25 cm, large volumes of strong acid secreted by the stomach must be converted to the neutral-alkaline chyme of the hindgut lumen, generating large volumes of CO(2). The duodenal mucosa consists of epithelial cells connected by low-resistance tight junctions, forming a leaky epithelial barrier. Despite this permeability, the epithelial cells, under intense stress from luminal mineral acid and highly elevated Pco(2), maintain normal functioning. Bicarbonate ion uniquely protects the duodenal epithelial cells from acid-related injury. The specific protective mechanisms likely involve luminal bicarbonate secretion, intracellular pH buffering and interstitial buffering. Furthermore, the duodenum plays an active role in foregut acid-base homeostasis, absorbing large amounts of H(+) and CO(2). We have studied mucosal protection and acid-base balance using live-animal fluorescence ratio microimaging and by performing H(+) and CO(2) balance studies on duodenal perfusates. On the basis of these data, we have formulated novel hypotheses with regard to mucosal protection.

Acid-Base Equilibrium↗

PubMed2003

Direct measurement of acid permeation into rat oesophagus.

BACKGROUND AND AIMS: The early responses of the oesophageal mucosa to acid perfusion may predict subsequent pathology. Mucosal responses to luminal acid may result either from acid permeating through the mucosa or from other unknown transduction mechanisms. In order to better understand the dynamics of acid permeation into the oesophageal mucosa, we measured interstitial pH (pH(int)) of the oesophageal basal epithelial layer, pre-epithelial layer thickness, and blood flow in rats in vivo during luminal acid challenge. A novel confocal microscopic technique was used in vitro to measure pH(int) from defined cellular sites in response to luminal and basolateral acidification. METHODS: 5-(and-6)-Carboxyfluorescein (CF) and carboxy-seminapthorhodofluor-1 (SNARF-1) fluorescence was used to measure pH(int) by conventional and confocal microscopy, respectively, in urethane anaesthetised rats. Pre-epithelial layer thickness was measured optically with carbon particles as markers. Blood flow was measured with laser Doppler flowmetry. RESULTS: Luminal acidification failed to alter pH(int) in vivo and in vitro, but pH(int) was lowered by modest serosal acidification. Pre-epithelial layer thickness and blood flow increased significantly during luminal surface acid perfusion. Indomethacin had no effect on any acid related response. CONCLUSION: In this first dynamic measurement of oesophageal acid permeation and pre-epithelial layer thickness, pH(int) was preserved in spite of high luminal acidity by two complementary techniques. Despite the apparent permeability barrier to acid permeation, oesophageal blood flow and thickness responded to luminal acid perfusion.

Acids↗

PubMed2003

Acid-sensing protective mechanisms of duodenum.

The proximal duodenal mucosa, exposed to frequent pulses of gastric acid, is functionally "leaky", increasing the importance of defense mechanisms such as the mucus gel layer, cellular acid/base transporters, bicarbonate secretion, and mucosal blood flow. Our laboratory has used a unique in vitro perfused microscopic system to measure thickness of the adherent mucus gel (MGT), intracellular pH (pHi), bicarbonate secretion, and mucosal blood flow in anesthetized rats. Exposure to pulses of luminal acid, mimicking the rapid physiologic shifts of luminal pH, increases MGT and blood flow, and induces cellular bicarbonate loading, the latter followed by augmented bicarbonate secretion. The mechanism by which the epithelium senses luminal acid includes capsazepine-inhibitable vanilloid receptors, presumably similar to the vanilloid receptor TPVR-1. CFTR, the cAMP-regulated anion channel mutated in the disease cystic fibrosis, plays an essential role in duodenal bicarbonate secretion. Our data are consistent with the hypothesis that cellular bicarbonate loading is an important means of preserving epithelial pHi during luminal acid challenge. Increased MGT may damp rapid shifts of luminal pH. Enhanced mucosal blood flow plays a significant role in the removal of back-diffusing acid. These neurally coordinated systems act coherently to defend the vulnerable duodenal epithelial cells from concentrated gastric acid.

Animals↗

PubMed2002

Regional differences of H+, HCO3-, and CO2 diffusion through native porcine gastroduodenal mucus.

Gastroduodenal mucus may play a critical role in defending the epithelium from luminal acid and in the creation of a microenvironment suitable for H. pylori. We measured transmucus permeation of H+, HCO3-, and CO2 with an in vitro perfusion chamber through freshly harvested or partially purified porcine gastric mucin. pH and CO2 concentrations were measured with selective ion electrodes; HCO3- and CO2 concentrations were derived. Viscosity was measured by rotational microviscometry. Mucin viscosity was directly related to concentration. There was a large variation in viscosity among native mucus from antrum, corpus, and duodenum. The highest viscosity was found in the antral mucus; duodenal mucus had the lowest. Diffusion coefficients of duodenal mucus for H+ and HCO3- were significantly lower than those from corpus and antrum. CO2 diffusion coefficients were invariant. In conclusion, despite large variations in viscosity, antral and corpus gastric mucus were similar in terms of ion diffusion. Surprisingly, the low viscosity duodenal mucus was a more potent barrier to ion diffusion than was gastric mucus. Consequently, duodenal mucus may play a more important role in inhibiting ion diffusion than its gastric counterpart.

Animals↗

PubMed2001

Integrated duodenal protective response to acid.

The proximal duodenum is unique in that it is the only leaky epithelium regularly exposed to concentrated gastric acid. To prevent injury from occurring, numerous duodenal defense mechanisms have evolved. The most studied is bicarbonate secretion, which is presumed to neutralize luminal acid. Less well studied in their protective roles are the mucus gel layer and blood flow. Measuring duodenal epithelial intracellular pH [pHi], blood flow and mucus gel thickness (MGT), we studied duodenal defense mechanisms in vivo so as to more fully understand the mucosal response to luminal acid. Exposure of the mucosa to physiologic acid solutions promptly lowered pHi, followed by recovery after acid was removed, indicating that acid at physiologic concentrations readily diffuses into, but does not damage duodenal epithelial cells. Cellular acid then exits the cell via an amiloride-inhibitable process, presumably sodium-proton exchange (NHE). MGT and blood flow increase promptly during acid perfusion; both decrease after acid challenge and are inhibited by vanilloid receptor antagonists or by sensory afferent denervation. Bicarbonate secretion is not affected by acid superfusion but increases after challenge. Inhibition of cellular base loading lowers pHi, whereas inhibition of apical base extrusion alkalinizes pHi. These observations support the following hypothesis: luminal acid diffuses into the epithelial cells, lowering pHi. Acidic pHi increases the activity of a basolateral NHE, acidifying the submucosal space and increasing cellular base loading. The acidic submucosal space activates capsaicin receptors on afferent nerves, increasing MGT and blood flow. With concontinued acid exposure, a new steady state with thickened mucus gel, increased blood flow, and a higher cellular buffering power protects against acid injury. After acid challenge, mucus secretion decreases, blood flow slows, and pHi returns to normal, the latter occurring via apical bicarbonate extrusion, increasing bicarbonate secretion. Through these integrated mechanisms, the epithelial cells are protected from damage due to repeated pulses of concentrated gastric acid.

Animals↗

PubMed2001

Sensory pathways and cyclooxygenase regulate mucus gel thickness in rat duodenum.

We previously showed that the duodenal hyperemic response to acid occurs through activation of capsaicin-sensitive afferent nerves with subsequent release of vasodilatory substances such as calcitonin gene-related peptide (CGRP) and nitric oxide. We then tested the hypothesis that similar factors regulate duodenal mucus gel thickness. Gel thickness was optically measured using in vivo microscopy in anesthetized rats. Duodenal mucosae were superfused with pH 7.0 buffer with vanilloid receptor agonist capsaicin, bradykinin, or PGE(2) injection or were challenged with pH 2.2 solution, with or without the vanilloid antagonist capsazepine, human CGRP-(8-37), N(G)-nitro-L-arginine methyl ester, and indomethacin. Other rats underwent sensory ablation with high-dose capsaicin pretreatment. Acid, bradykinin, capsaicin, and PGE(2) all quickly thickened the gel. Antagonism of vanilloid and CGRP receptors, inhibition of nitric oxide synthase, and sensory deafferentation delayed gel thickening, suggesting that the capsaicin pathway mediated the initial burst of mucus secretion that thickened the gel. Indomethacin abolished gel thickening due to acid, bradykinin, and capsaicin. Inhibition of gel thickening by indomethacin in response to multiple agonists suggests that cyclooxygenase activity is essential for duodenal gel thickness regulation. Duodenal afferent neural pathways play an important role in the modulation of cyclooxygenase-mediated physiological control of gel thickness.

Animals↗

PubMed2001

Acute adaptive cellular base uptake in rat duodenal epithelium.

We studied the role of duodenal cellular ion transport in epithelial defense mechanisms in response to rapid shifts of luminal pH. We used in vivo microscopy to measure duodenal epithelial cell intracellular pH (pH(i)), mucus gel thickness, blood flow, and HCO secretion in anesthetized rats with or without the Na(+)/H(+) exchange inhibitor 5-(N,N-dimethyl)-amiloride (DMA) or the anion transport inhibitor DIDS. During acid perfusion pH(i) decreased, whereas mucus gel thickness and blood flow increased, with pH(i) increasing to over baseline (overshoot) and blood flow and gel thickness returning to basal levels during subsequent neutral solution perfusion. During a second brief acid challenge, pH(i) decrease was lessened (adaptation). These are best explained by augmented cellular HCO uptake in response to perfused acid. DIDS, but not DMA, abolished the overshoot and pH(i) adaptation and decreased acid-enhanced HCO secretion. In perfused duodenum, effluent total CO(2) output was not increased by acid perfusion, despite a massive increase of titratable alkalinity, consistent with substantial acid back diffusion and modest CO(2) back diffusion during acid perfusions. Rapid shifts of luminal pH increased duodenal epithelial buffering power, which protected the cells from perfused acid, presumably by activation of Na(+)-HCO cotransport. This adaptation may be a novel, important, and early duodenal protective mechanism against rapid physiological shifts of luminal acidity.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2001

Cellular bicarbonate protects rat duodenal mucosa from acid-induced injury.

Secretion of bicarbonate from epithelial cells is considered to be the primary mechanism by which the duodenal mucosa is protected from acid-related injury. Against this view is the finding that patients with cystic fibrosis, who have impaired duodenal bicarbonate secretion, are paradoxically protected from developing duodenal ulcers. Therefore, we hypothesized that epithelial cell intracellular pH regulation, rather than secreted extracellular bicarbonate, was the principal means by which duodenal epithelial cells are protected from acidification and injury. Using a novel in vivo microscopic method, we have measured bicarbonate secretion and epithelial cell intracellular pH (pH(i)), and we have followed cell injury in the presence of the anion transport inhibitor DIDS and the Cl(-) channel inhibitor, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). DIDS and NPPB abolished the increase of duodenal bicarbonate secretion following luminal acid perfusion. DIDS decreased basal pH(i), whereas NPPB increased pH(i); DIDS further decreased pH(i) during acid challenge and abolished the pH(i) overshoot over baseline observed after acid challenge, whereas NPPB attenuated the fall of pH(i) and exaggerated the overshoot. Finally, acid-induced epithelial injury was enhanced by DIDS and decreased by NPPB. The results support the role of intracellular bicarbonate in the protection of duodenal epithelial cells from luminal gastric acid.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2001

Duodenal intracellular bicarbonate and the 'CF paradox'.

HCO(3)(-) secretion, which is believed to neutralize acid within the mucus gel, is the most studied duodenal defense mechanism. In general, HCO(3)(-) secretion rate and mucosal injury susceptibility correlate closely. Recent studies suggest that luminal acid can lower intracellular pH (pH(i)) of duodenal epithelial cells and that HCO(3)(-) secretion is unchanged during acid stress. Furthermore, peptic ulcers are rare in cystic fibrosis (CF), although, with impaired HCO(3)(-) secretion, increased ulcer prevalence is predicted, giving rise to the 'CF Paradox'. We thus tested the hypothesis that duodenal epithelial cell protection occurs as the result of pH(i) regulation rather than by neutralization of acid by HCO(3)(-) in the pre-epithelial mucus. Cellular acidification during luminal acid perfusion, and unchanged HCO(3)(-) secretion during acid stress are inconsistent with pre-epithelial acid neutralization by secreted HCO(3)(-). Furthermore, inhibition of HCO(3)(-) secretion by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) despite preservation of pH(i) and protection from acid-induced injury further question the pre-epithelial acid neutralization hypothesis. This decoupling of HCO(3)(-) secretion and injury susceptibility by NPPB (and possibly by CF) further suggest that cellular buffering, rather than HCO(3)(-) exit into the mucus, is of primary importance for duodenal mucosal protection, and may account for the lack of peptic ulceration in CF patients.

Animals↗

PubMed2000

Dynamic regulation of mucus gel thickness in rat duodenum.

We examined the dynamic regulation of mucus gel thickness (MGT) in vivo in rat duodenum in response to luminal acid, cyclooxygenase (COX) inhibition, and exogenous PGE(2). An in vivo microscopic technique was used to measure MGT with fluorescent microspheres in urethan-anesthetized rats. Duodenal mucosa was topically superfused with pH 7.0 or pH 2.2 solutions with or without PGE(2) and indomethacin treatments. Glycoprotein concentration of duodenal loop perfusates was measured with periodic acid/Schiff (PAS) or Alcian blue (AB) staining. MGT and perfusate glycoprotein concentration were stable during a 35-min perfusion with pH 7.0 solution. Acid exposure increased MGT and PAS- and AB-positive perfusate glycoprotein concentrations. Indomethacin pretreatment increased both PAS- and AB-positive perfusate glycoprotein at baseline; subsequent acid superfusion decreased perfusate glycoproteins and gel thickness. PGE(2) (1 mg/kg iv) simultaneously increased MGT and PAS-positive perfusate glycoprotein concentrations followed by a transient increase in AB-positive glycoprotein concentration, suggesting contributions from goblet cells and Brunner's glands. Parallel changes in MGT and perfusate glycoprotein concentration in response to luminal acid and PGE(2) suggest that rapid MGT variations reflect alterations in the balance between mucus secretion and exudation, which in turn are regulated by a COX-related pathway. Luminal acid and PGE(2) augment mucus secretion from goblet cells and Brunner's glands.

Acids↗

PubMed1999

Regulation of intracellular pH and blood flow in rat duodenal epithelium in vivo.

Duodenal mucosal defense was assessed by measuring blood flow and epithelial intracellular pH (pHi) of rat proximal duodenum in vivo. Fluorescence microscopy was used to measure epithelial pHi using the trapped, pHi-indicating dye 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-AM. Blood flow was measured with laser-Doppler flowmetry. The mucosa was briefly superfused with NH4Cl, pH 2.2 buffer, the potent Na+/H+ exchange inhibitor 5-(N,N-dimethyl)-amiloride (DMA), or the anion exchange and Na+-HCO-3 cotransport inhibitor DIDS. Cryostat sections localized dye fluorescence to the villus tip. Steady-state pHi was 7. 02 +/- 0.01, which remained stable for 60 min. Interventions that load the cells with protons without affecting superfusate pH (NH4Cl prepulse, nigericin with low superfusate K+ concentration, DMA, and DIDS) all decreased pHi, supporting our contention that the dye was faithfully measuring pHi. An acid pulse decreased pHi, followed by a DIDS-inhibitable overshoot over baseline. Intracellular acidification increased duodenal blood flow independent of superfusate pH, which was inhibited by DMA, but not by DIDS. We conclude that we have established a novel in vivo microscopy system enabling simultaneous measurements of pHi and blood flow of duodenal epithelium. Na+/H+ exchange and Na+-HCO-3 cotransport regulate baseline duodenal epithelial pHi. Intracellular acidification enhances duodenal blood flow by a unique, amiloride-inhibitable, superfusate pH-independent mechanism.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1999

Acid-sensing pathways of rat duodenum.

We tested the hypothesis that the duodenal hyperemic response to acid occurs through activation of capsaicin-sensitive afferent nerves with subsequent release of vasodilatory substances such as calcitonin gene-related peptide (CGRP) and nitric oxide (NO). Laser-Doppler flowmetry was used to measure duodenal blood flow in urethan-anesthetized rats. Duodenal mucosa was superfused with pH 7. 0 buffer with capsaicin or bradykinin or was acid challenged with pH 2.2 solution, with or without vanilloid receptor antagonists, a CGRP receptor antagonist, an NO synthase (NOS) inhibitor, or a cyclooxygenase inhibitor. The selective vanilloid receptor antagonist capsazepine (CPZ) dose dependently inhibited the hyperemic response to acid and capsaicin but did not affect bradykinin-induced hyperemia. Ruthenium red was less inhibitory than capsazepine. Selective ablation of capsaicin-sensitive nerves, CGRP-(8-37), and N(G)-nitro-L-arginine methyl ester inhibited acid-induced hyperemia, but indomethacin did not. We conclude that luminal acid, but not bradykinin, stimulates CPZ-sensitive receptors on capsaicin-sensitive afferent nerves of rat duodenum. Activation of these receptors produces vasodilation via the CGRP-NO pathway but not via the cyclooxygenase pathway. Acid appears to be the endogenous ligand for duodenal vanilloid receptors.

Acids↗

PubMed1999

Dynamic regulation of gastric surface pH by luminal pH.

In vivo confocal imaging of the mucosal surface of rat stomach was used to measure pH noninvasively under the mucus gel layer while simultaneously imaging mucus gel thickness and tissue architecture. When tissue was superfused at pH 3, the 25 microm adjacent to the epithelial surface was relatively alkaline (pH 4.1 +/- 0.1), and surface alkalinity was enhanced by topical dimethyl prostaglandin E2 (pH 4.8 +/- 0.2). Luminal pH was changed from pH 3 to pH 5 to mimic the fasted-to-fed transition in intragastric pH in rats. Under pH 5 superfusion, surface pH was relatively acidic (pH 4.2 +/- 0.2). This surface acidity was enhanced by pentagastrin (pH 3.5 +/- 0.2) and eliminated by omeprazole, implicating parietal cell H,K-ATPase as the dominant regulator of surface pH under pH 5 superfusion. With either pH 5 or pH 3 superfusion (a) gastric pit lumens had the most divergent pH from luminal superfusates; (b) qualitatively similar results were observed with and without superfusion flow; (c) local mucus gel thickness was a poor predictor of surface pH values; and (d) no channels carrying primary gastric gland fluid through the mucus were observed. The model of gastric defense that includes an alkaline mucus gel and viscous fingering of secreted acid through the mucus may be appropriate at the intragastric pH of the fasted, but not fed, animal.

Animals↗

PubMed1999

Barrier function of gastric mucus.

A viscoelastic mucus gel layer covers the gastric mucosa in a continuous sheet. The functions of the mucus gel have been one of the least studied aspects of gastric barrier function. Although the role of gastric mucus in providing physical protection against ingested particles, and preventing contact between digestive enzymes such as pepsin and the underlying mucosa is generally accepted, the barrier role function of gastric mucus with regard to luminal acid is still conjectural. The modest proton diffusion barrier that mucus provides is negligible in relation to the overall barrier properties of the gastric mucosa; nevertheless, stabilization of unstirred layers and damping of rapid shifts in luminal pH are potentially important functions. Associative studies have suggested a possible role of a hydrophobic barrier in strengthening the barrier functions of mucus. One of the most actively investigated areas of mucus function in recent times has been the mechanism by which secreted acid traverses the gel. Although compelling and complementary data obtained in vivo and in vitro have been consistent with secretion of acid under pressure, creating temporary viscous fingers through the gel, recent evidence obtained with in vivo confocal microscopy suggests that secreted acid diffuses through the gel. Since Helicobacter pylori exists solely in the juxtamucosal portion of the gastric mucus gel, detailed knowledge concerning the pH microenvironment in which the organism thrives is important in understanding the pathophysiology of peptic ulcer disease and related conditions.

Animals↗

PubMed1998

Pentagastrin gastroprotection against acid is related to H2 receptor activation but not acid secretion.

BACKGROUND: Pentagastrin enhances gastric mucosal defense mechanisms against acid and protects the gastric mucosa from experimental injury. AIMS: To investigate whether this gastroprotection is mediated by histamine receptors or occurs as a secondary effect of acid secretion stimulation. METHODS: The effects of omeprazole (100 mumol/kg), ranitidine (20 mg/kg), and pyrilamine (10 mg/kg) on pentagastrin (80 micrograms/kg/h) induced gastroprotection against acidified aspirin injury were examined in a luminal pH controlled model. The effects of these compounds on pentagastrin enhanced gastroprotective mechanisms were investigated using intravital microscopy, in which intracellular pH of gastric surface cells (pH1), mucus gel thickness, gastric mucosal blood flow, and acid output were measured simultaneously. RESULTS: Pentagastrin protected rat gastric mucosa from acidified aspirin injury. This gastroprotection was abolished by ranitidine, but not omeprazole or pyrilamine. Pentagastrin induced a hyperaemic response to luminal acid challenge, increased mucus gel thickness, and elevated pHi during acid challenge. Ranitidine reversed these enhanced defence mechanisms, whereas omeprazole and pyrilamine preserved these effects. CONCLUSIONS: These data indicate that pentagastrin associated gastroprotection and enhanced defence mechanisms against acid result mainly from activation of histamine H2 receptors, and not as an effect of the stimulation of acid secretion.

Animals↗

PubMed1998

Decreased endothelial nitric oxide synthase in gastric mucosa of rats with chronic renal failure.

According to recent reports, chronic renal failure (CRF) increases the susceptibility of gastric mucosa to injury. Since nitric oxide plays a major role in gastric mucosal defense and injury, we investigated, in rats with CRF produced by five-sixths nephrectomy and in control rats, the expression of nitric oxide synthase(NOS) in the stomach and measured mucosal and submucosal gastric blood flow. In CRF rats, gastric mucosal blood flow was significantly reduced compared with control rats, whereas submucosal and serosal blood flow was significantly increased. CRF significantly decreased endothelial NOS (eNOS) mRNA abundance by 53% (P < 0.01) and reduced expression of eNOS protein by 42% (P < 0.01) compared with the controls. Enzyme activity of eNOS was significantly reduced in gastric mucosa of CRF rats (P < 0.05). These data are consistent with reduced gastric mucosal blood flow in CRF rats and can explain altered susceptibility of gastric mucosa to injury in CRF rats.

Animals↗

PubMed1997

Cytoprotective effect of bismuth subsalicylate in indomethacin-treated rats is associated with enhanced mucus bismuth concentration.

BACKGROUND: Bismuth compounds prevent gastric injury from the short-term administration of nonsteroidal anti-inflammatory drugs. We studied the mechanisms underlying the gastroprotective actions of bismuth subsalicylate against indomethacin-induced injury in rats. METHODS: An in vivo microscopic technique was used in which acid output, surface cell intracellular pH (pHi), gastric mucus gell thickness and mucosal blood flow were measured simultaneously. Concentrations of bismuth in mucus were measured by atomic absorption. RESULTS: Indomethacin (60 mg/kg) significantly thinned the mucus gel layer and augmented the decrease of pHi during luminal acid superfusion, consistent with a weakened gastric mucosal barrier to acid. Bismuth subsalicylate partially reversed this effect of indomethacin on pHi, consistent with gastroprotection. Neither a prostaglandin-inhibiting but non-injurious dose of indomethacin (5 mg/kg), bismuth subsalicylate, or their combination affected mucus gel thickness or pHi homeostasis. In separate experiments, indomethacin (60 mg/kg) significantly increased gastric mucus bismuth concentration in rats given bismuth subsalicylate. CONCLUSION: Bismuth accumulation in the gastric mucus during the evolution of mucosal injury may play an important role in the gastroprotective effect of bismuth subsalicylate against indomethacin injury.

Animals↗

PubMed1997

Central vagal activation increases mucus gel thickness and surface cell intracellular pH in rat stomach.

BACKGROUND & AIMS: Central vagal stimulation induced by the thyrotropin-releasing hormone analogue RX 77368 injected intracisternally in urethane-anesthetized rats is gastroprotective. In an in vivo system, the effects of central RX 77368 on discrete components of the rat gastric mucosal barrier were studied to determine if these effects were prostaglandin synthesis dependent. METHODS: Using intravital microscopy, intracellular pH of gastric surface cells, mucus gel thickness, gastric mucosal blood flow, and acid output were measured simultaneously in vivo. RESULTS: Intracisternal RX 77368 significantly increased acid output, gel thickness, and blood flow. Indomethacin enhanced the RX 77368-induced increase in acid output but had no effect on measures of gastric defense during mucosal superfusion with neutral solutions. During acid superfusion, RX 77368 delayed acidification and enhanced recovery of surface cell intracellular pH. These latter effects were reversed partially by indomethacin. Omeprazole abolished RX 77368-induced acid secretion but did not alter its effects on gastric defense mechanisms. CONCLUSIONS: In response to central vagal stimulation with RX 77368, gastric defense mechanisms were enhanced through prostaglandin-dependent and -independent pathways, in contrast to the prostaglandin-independent effects of intravenous pentagastrin. RX 77368-induced enhancements of gastric defense mechanisms did not occur as a result of acid secretion.

Animals↗