Acid Perfusion Research Articles

C-Fos immunoreactivity in the brain after esophageal acid stimulation

The goal of this study was to use c-Fos immunohistochemistry to establish a rat model for studying the central projection of the esophageal afferent neurons during acid exposure. A cannula was placed in the esophagus of anesthetized Wistar rats with the tip approximately 2 cm above the lower esophageal sphincter (LES). Hydrochloric acid (0.1 N HCl, 50 mmol/L) with pepsin (3,200–4,500 U/mL), at pH 1.6, was then perfused into the esophagi of the experimental rats (n = 8) at 10 mL/hr continuously for 50 minutes. Normal saline solution (0.9% NaCl) was used in control rats (n = 6), and home cage control animals (n = 6) were given no stimulation. Thirty minutes after the perfusion, the rat was killed and the brain was removed and processed for c-Fos immunohistochemistry. A transverse section of the esophagus, 2 cm above the LES, was stained with hematoxylin and eosin stain for light microscopy. c-Fos immunoreactivity was significantly increased in a number of brain regions in the rats receiving the acid plus pepsin perfusion. These areas included the central amygdala, the Kölliker-Fuse nucleus, the nucleus of the solitary tract (NTS), the medial part of the NTS, the interstitial part of the NTS, the commissural part of the NTS, the paratrigeminal nucleus, the ambiguus nucleus, and the rostroventrolateral recticular nucleus. Perfusion with acid–pepsin solution also resulted in morphologic changes in the esophagus on light microscopy. This study suggests that acid plus pepsin perfusion of esophagus results in both neural activation in areas of the central nervous system and damage to the esophagus in an animal model.

Esophageal dysmotility and acid sensitivity in patients with mitral valve prolapse and chest pain.

Mitral valve prolapse (MVP) patients often experience non-cardiac chest pain. The aims of this study were to determine, in patients with non-cardiac chest pain: (i) whether esophageal dysmotility is more common in patients with MVP than in patients without MVP; and (ii) if acid sensitivity is an important cause of the chest pain in MVP patients. Esophageal manometry and acid perfusion testing were performed in 277 consecutive patients with non-cardiac chest pain. Patients with MVP (13 female, one male; mean age 49 years) were more likely (P = 0.01) to have esophageal dysmotility, while acid perfusion was less likely (P < 0.05) to provoke their chest pain, than in patients without MVP. The most common esophageal motor abnormalities detected in patients with and without MVP were diffuse esophageal spasm (prevalence, 57%) and non-specific motor disorder (prevalence, 9%), respectively. This study, the first large prospective series examining possible esophageal sensorimotor correlates of chest pain in MVP patients, demonstrates that in the absence of a cardiac cause for chest pain, a specific esophageal motility disorder should be excluded, rather than assuming the chest pain is likely to be due to acid sensitivity.

Effect of acid perfusion of duodenum on induction of dyspeptic symptoms in healthy volunteers

Effect of acid perfusion of duodenum on induction of dyspeptic symptoms in healthy volunteers

Diagnosis of symptomatic gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) encompasses a heterogeneous group of patients with differences in sensitivity to esophageal acid exposure, perception of pain, and physiological tissue involvement. The most difficult patients to understand are those who have a great symptom burden but no endoscopic evidence of esophageal mucosal involvement. These patients with symptomatic GERD (also called nonerosive reflux disease and endoscopy-negative reflux disease) present a diagnostic challenge. Diagnostic tests, like ambulatory pH monitoring, the acid perfusion test, and intraesophageal balloon distension, have limited reliability in patients with this form of GERD whose symptoms may exhibit poor correlation with acid exposure or mechanostimulation. The recent interest in a proton pump inhibitor therapeutic trial to identify the group of symptomatic GERD patients (having ruled out risk factors for more morbid conditions) who will respond to these agents has considerable appeal. It has been shown effective in about 75% of patients, and offers a simple approach to managing the difficult-to-diagnose patient even while further diagnostic procedures are carried out.

Glutamate transporters in the guinea-pig cochlea: partial mRNA sequences, cellular expression and functional implications.

In the cochlea, glutamate plays a major role in synaptic transmission between the inner hair cell and the primary auditory neurons. Extracellular glutamate concentration must be regulated to prevent excitotoxicity. This regulation is mediated by excitatory amino acid transporters, membrane proteins that remove glutamate from the synaptic cleft. In this study, we investigated the distribution and activity of three excitatory amino acid transporters subtypes in the guinea-pig cochlea: glutamate aspartate transporter, glutamate transporter and excitatory amino acid carrier. A partial messenger ribonucleic acid sequence was determined for each of these transporters, by polymerase chain reaction with degenerate primers, using guinea-pig brain complementary deoxyribonucleic acid as the template. Primers specific for each transporter were then designed and used to screen a dissected organ of Corti complementary deoxyribonucleic acid library. The cellular distribution of each transporter was examined by immunocytochemistry. We investigated the functional consequences of inhibiting glutamate uptake by recording cochlear potentials during intracochlear perfusion with either l-trans-pyrrolidine-2,4-dicarboxylic acid or dihydrokainate. At the end of the electrophysiological session, cochleas were processed for electron microscopy. Only the glutamate aspartate transporter messenger ribonucleic acid was detected in the organ of Corti. Consistently, glutamate aspartate transporter protein was detected in the inner hair cell-supporting cells and in the ganglion of Corti satellite cells. Glutamate transporter and excitatory amino acid carrier were found in the afferent auditory neurons. Only intracochlear perfusions with l-trans-pyrrolidine-2,4-dicarboxylic acid resulted in a dose-dependent decrease in the amplitude of the cochlear compound action potential, leaving cochlear microphonic potential unaffected. After l-trans-pyrrolidine-2,4-dicarboxylic acid perfusion, cochleas displayed a swelling of the afferent endings typical of excitotoxicity. [(-)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamyl-2,3-benzodiazepine], a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist protects the cochlea against l-trans-pyrrolidine-2,4-dicarboxylic acid effect.

Mechanisms underlying domoic acid-induced dopamine release from striatum: an in vivo microdialysis study.

The brain microdialysis technique has been used to examine the in vivo effects of the neurotoxin domoic acid (an ionotropic glutamate receptor agonist) on dopamine (DA) release in the striatum of conscious and freely moving rats. Local application of domoic acid (500 microM) through the microdialysis probe produced an increase in striatal DA content (597 +/- 96% with respect to basal levels). The release of DA induced by domoic acid was not attenuated in a Ca(+2)-free medium (469 +/- 59%) or after pretreatment with 10 mg/kg reserpine (533 +/- 79%). Intrastriatal infusion of 1 microM tetrodotoxin (TTX) partially reduced the domoic acid-evoked DA release (278 +/- 34%). Moreover, domoic acid perfusion had no effect on K+-evoked DA release. The results suggest that domoic acid increases the striatal DA release according to a reserpine-independent, calcium-independent and partially TTX-insensitive mechanism, suggesting that these effects probably involve a nonexocytotic process. On the other hand, the inhibitor of DA uptake nomifensine (10 microM) reduced the domoic acid-evoked DA release (356 +/- 59%), suggesting that a carrier-dependent mechanism could be involved in the effect of domoic acid on the striatal DA levels.

Effects of Esophageal Acid Perfusion on Cough Responsiveness in Patients With Bronchial Asthma

The effect of gastroesophageal reflux (GER) on cough responsiveness in patients with bronchial asthma has yet to be studied in significant detail. The purpose of this study was to assess the effect of distal esophageal acid perfusion on cough responsiveness in patients with bronchial asthma. In seven patients with mild persistent bronchial asthma (mean +/- SD age, 57.7 +/- 3.7 years; four women and three men), esophageal pH was monitored by a pH meter and cough responsiveness was evaluated by single-breath aerosol inhalation of capsaicin with increasing dosage from 0.30 to 9.84 nmol. Simultaneously, esophageal perfusion was performed through an esophageal tube filled with either saline solution or 0.1 N hydrochloric acid (HCl), the order of which was selected at random, in 1-week intervals. Results were expressed as the lowest concentration of capsaicin eliciting three coughs (PD3). Spirometry was also performed during esophageal pH monitoring. A significant decrease in the geometric mean of log PD3 was observed during distal esophageal HCl perfusion (0.45 +/- 0.04 nmol) compared with that of the saline solution perfusion (0.04 +/- 0.06 nmol) [p < 0.01]. However, no significant changes were observed either in FVC, FEV1, or peak expiratory flow during the periods of the saline solution or HCl perfusion. The present data demonstrate that an increase in cough responsiveness may be induced when HCl stimulates the distal portion of esophagus in patients with bronchial asthma, suggesting that the GER would be one of the important factors that influence asthmatic status.

Acidic HEPES-KH reperfusion enhances myocardial protection in immature rabbits.

To study the effects of different pH HEPES-KH reperfusate solution on immature myocardial protection, isolated perfused Langendorff model from immature rabbit hearts were developed formed. Control group (C) was perfused only with pH 7.4 HEPES-KH solution for 90 min. Ischemia/reperfusion group (group I/R) was perfused with pH 7.4 HEPES-KH solution before ischemia or after ischemia. Experimental group (group E), after ischemia, was perfused with pH 6.8, pH 7.1 and pH 7.4 HEPES-KH solutions for 5 min, 5 min, and 20 min, respectively. The left ventricular function recovery, MWC, LDH and CK leakage, MDA, ATP content, and SOD activity were determined. Our results showed that the left ventricular function recovery, ATP content and SOD activity in group E were higher than those of group I/R (P < 0.05). MWC, MDA content, LDH and CK leakage in group E were lower than those of group I/R (P < 0.05). These findings suggested that pH paradox might be one of important mechanisms for immature myocardial ischemia-reperfusion injury, and acidic perfusate, at the beginning of reperfusion, might attenuate pH paradox and ameliorate functional recovery in isolated perfused immature rabbit hearts.

Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective

Calcium-independent phospholipase A2 (iPLA2) is the predominant phospholipase A2 present in myocardium, and its pathophysiological role in acute myocardial infarction has been suggested by the rapid increase in membrane-associated iPLA2 activity during myocardial ischaemia and reperfusion (I/R). We therefore examined iPLA2 in mitochondrial fractions prepared from Langendorff-perfused adult rabbit hearts. Our studies indicate that iPLA2β is present in rabbit heart mitochondrial inner membranes with no apparent translocation during ischaemia, I/R or preconditioning. Mitochondrion-associated iPLA2 was catalytically competent and exhibited 2-, 3- and 2.5-fold increases in measured iPLA2 activity following ischaemia, I/R and preconditioning, respectively, when compared with the activity of iPLA2 measured in mitochondria from control hearts. Mitochondrial phospholipids are essential for maintaining the ordered structure and function of the organelle. I/R resulted in a rapid overall decrease in phosphatidylcholine and phosphatidylethanolamine glycerophospholipid species, as determined by electrospray ionization MS, that was partially alleviated by pretreatment of hearts with the iPLA2-specific inhibitor, bromoenol lactone (BEL). Pretreatment of I/R hearts with 10μM BEL significantly reduced the infarct size almost to that of continuously perfused hearts and was cardioprotective only when administered prior to ischaemia. Cardioprotection by BEL was reversed by the simultaneous perfusion of 100μM 5-hydroxydecanoate, implicating the mitochondrial KATP channel in BEL-mediated protection from I/R. Preconditioning also significantly reduced the infarct size in response to I/R but protection was lost by concurrent perfusion of 10μM arachidonic acid. Taken together, these data strongly implicate mitochondria-associated iPLA2 in the signal transduction of myocardial I/R injury.

Luminal acid elicits a protective duodenal mucosal response.

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 protective 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 (NHE1). 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 does not increase during acid perfusion but increases following acid challenge. Inhibition of cellular alkali uptake by anion transport inhibitors lowers pHi, and increases mucosal injury, whereas inhibition of apical alkali secretion alkalinizes pHi and diminishes injury. 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 alkali loading. The acidic submucosal space activates capsaicin receptors on afferent nerves, increasing MGT and blood flow. With continued acid exposure, a new steady state with thickened mucus gel, increased blood flow, and a higher cellular buffering power protects the mucosa from acid injury. After acid challenge, mucus secretion, blood flow and pHi return to normal, while bicarbonate secretion increases. Through these integrated mechanisms, the epithelial cells are protected from damage due to repeated pulses of concentrated gastric acid.

Effect of acid perfusion on passive electrophysiological properties of rabbit esophagus in vivo.

In the present paper we studied early acid-induced changes in the passive electrical properties of the rabbit esophageal epithelium in vivo by measurements of the transluminal potential difference (PD) during acid perfusion and by estimating the transmucosal electrical resistance (Rm) using cable analysis. Perfusion with acid (pH 1) for 45 min produced a rapid (<1 min) negative shift in the lumen-negative PD followed by a slow lumen-negative drift. The acid-induced change in PD was dependent on the accompanying anion, the largest anion (sulfate) producing the largest change. The acid-induced changes in PD were parallelled by reductions in Rm, these reductions also being dependent on the accompanying anion. Interpretation of resistance and net current (estimated by Ohm's law) time curves suggest that the initial acid-induced changes of the PD reflect properties of the naive mucosa whereas the later drift will reflect a diffusion driven increase in transmucosal proton permeability. Further, coapplication of the protective drug sucrose octasulfate attenuated the hydrochloric acid-induced changes of all measured and estimated electrophysiological parameters. The electrophysiological results were to some extent corroborated by light microscopic findings, although no large acid-induced change in mucosal appearance was observed.

Studies on the Relationship between Esophageal Acid Exposure, Mucosal Lesions and Heartburn Using an Acid Exposure Sensor

Background: In vitro studies of a recently developed acid exposure sensor show that the sensor response (SR) to acid < pH 4 is linearly determined by the duration and degree of acidity. The aim was to determine whether SR correlates with the severity of acid-induced esophageal mucosal lesions and acid-induced heartburn. Methods: HCl pH 1.5 or saline was infused into the feline esophagus for 5-20 min. Simultaneously, sensor measurements were performed below the infusion port. The histological damage was scored by an independent pathologist. In 15 normal subjects, HCl pH 1 was infused into the esophagus and the severity of the heartburn (0-5) was scored at 5-min intervals. In 10 subjects who experienced heartburn during acid perfusion, initial perfusion with HCl was repeated during heartburn induction time minus 5 min, followed by perfusion with the subject's own gastric juice, titrated to pH 2; heartburn severity was again scored at 5-min intervals. Acid exposure sensors positioned below the infusion port were removed at heartburn scores 1, 2 and 3. Results: A good correlation was found between SR and the histological score for mucosal damage in the cat esophagus ( r = 0.64, P < 0.005). There was a good relation between heartburn severity score and acid exposure time ( r = 0.84, P < 0.001), and a significant but weaker relation between heartburn severity and SR. Conclusion: In cats, there is a good relation between the severity of acid-induced esophageal mucosal lesions and SR. In men, there is a significant correlation between the severity of acid-induced heartburn and the simultaneously measured SR. Therefore, SR measurement has the potential of yielding clinically relevant information in the investigation of GERD.

Sources of Intra-Oesophageal Nitric Oxide Production Following Intraluminal Acid Exposure

Background: The aim of the present study was to assess luminal nitric oxide (NO) levels in the oesophagus during baseline and acidic conditions and to clarify the sources of such oesophageal NO formation. Methods: Healthy volunteers received an intra-oesophageal infusion of either HCl (100 mM) or NaCl (150 mM) on two separate study days. After a low nitrate diet, nitrate load or no dietary restrictions/pretreatment, direct intraluminal measurements of NO formation were performed using a tonometric technique. Endoscopy was performed and mucosal biopsies were taken and analysed by means of immunohistochemistry, Western blot and RT-PCR. Results: No intra-oesophageal NO was detected during baseline conditions with pH neutrality. During the infusion of HCl the NO levels rose dramatically to around 12000 ppb. This high rate of NO formation fell by 95% following deviation of saliva. NO formation after an acute nitrate load was almost doubled during acid perfusion compared to control. Immunohistochemistry demonstrated distinct staining for iNOS in the oesophageal squamous epithelial cells, and Western blot and RT-PCR confirmed the presence of iNOS. Conclusion: Two sources exist for intra-oesophageal NO formation, both dependent on the luminal acidity: 1) chemical reduction of salivary nitrite, a mechanism related to dietary intake of nitrate, and 2) NO formation within the oesophageal mucosal epithelium by enzymatic degradation of L-arginine. In the latter case, the NO synthase has antigenic characteristics, indicating the inducible isoform, although a functional behaviour suggests an unconventional subtype.

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.

Underlying mechanisms of respiratory symptoms with esophageal acid when there is no evidence of airway response

Although a strong association exists between gastroesophageal reflux (GER) and asthma, results of studies designed to maximize the likelihood of identifying that GER worsens pulmonary function in patients with asthma have been negative or inconclusive. Asthma symptoms worsen during symptomatic reflux episodes, and asthma symptom severity correlates with the severity of symptomatic reflux. Various reasons have been proposed to explain these findings. Discomfort associated with GER can cause reflux-associated respiratory symptoms even when pulmonary function is normal. New findings suggest that increases in minute ventilation rather than inhibition of diaphragm activity are responsible for the changes in respiratory sensation during acid perfusion of the esophagus in nonasthmatic subjects. These results may also pertain to asthmatic patients, because increasing minute ventilation can cause dyspnea and bronchospasm in this population. Treating GER, either medically or surgically, may improve asthma symptoms by preventing GER-induced changes in minute ventilation.

Cis-Urocanic Acid Stimulates Neuropeptide Release from Peripheral Sensory Nerves

Previous studies using an antibody to cis-urocanic acid and mast-cell-depleted mice implicated both cis-urocanic acid and mast cells in the mechanisms by which ultraviolet B light suppresses systemic contact hypersensitivity responses in mice. In the absence of a direct stimulatory effect of cis-urocanic acid on connective tissue mast cells, an indirect association was investigated. A blister induced in the rat hind footpad was used to examine the effects of slowly perfused cis-urocanic acid on cutaneous blood flow. cis-Urocanic acid but not trans-urocanic acid increased microvascular flow by a mechanism largely dependent on the combined activity of the neuropeptides, substance P and calcitonin gene-related peptide. Perfusion of cis-urocanic acid over the base of blisters induced in sensory-neuropeptide-depleted rats did not have any stimulatory effect above that seen with perfusion of cis-urocanic acid together with neuropeptide receptor antagonists in control rats. There was a small direct effect of cis-urocanic acid on microvascular blood flow. As both substance P and calcitonin gene-related peptide could directly degranulate connective tissue mast cells, this study suggests that cis-urocanic acid indirectly activates mast cells via its effects on peripheral terminals of unmyelinated primary afferent sensory nerves. cis-Urocanic-acid-induced neuropeptides may also contribute to ultraviolet-B-induced cutaneous inflammation and alterations to Langerhans cell activity.

Severe asthma: definition and mechanisms.

Severe asthma: definition and mechanisms.

Stimulation of ATP secretion in the liver by therapeutic bile acids

ATP receptors are ubiquitously expressed and are potential targets for the therapy of a number of disorders. However, delivery of ATP or other nucleotides to specific tissues is problematic, and no pharmacological means to stimulate the release of endogenous ATP has been described. We examined the effects of the bile acid ursodeoxycholic acid (UDCA) on ATP release into bile, since this bile acid is the only agent known to be of therapeutic benefit in secretory disorders of the liver, and since its mechanism of action is not established. Both UDCA and its taurine conjugate stimulated secretion of ATP by isolated rat hepatocytes, and produced measurable increases in ATP in bile of isolated rat liver. Perfusion of ATP into microdissected bile-duct segments induced Ca2+ signalling in bile-duct epithelia, while perfusion of bile acid did not. Thus UDCA may promote bile flow by inducing hepatocytes to release ATP into bile, which then stimulates fluid and electrolyte secretion by bile-duct epithelia downstream via changes in cytosolic Ca2+. Moreover, these findings demonstrate the feasibility of using pharmacological means to induce secretion of endogenous ATP. Since the liver and other epithelial organs express luminal ATP receptors, these findings more generally suggest that a mechanism exists for pharmacological activation of this paracrine signalling pathway. This strategy may be useful for treatment of cystic fibrosis and other secretory disorders of the liver and other epithelial tissues.

Stimulation of ATP secretion in the liver by therapeutic bile acids.

ATP receptors are ubiquitously expressed and are potential targets for the therapy of a number of disorders. However, delivery of ATP or other nucleotides to specific tissues is problematic, and no pharmacological means to stimulate the release of endogenous ATP has been described. We examined the effects of the bile acid ursodeoxycholic acid (UDCA) on ATP release into bile, since this bile acid is the only agent known to be of therapeutic benefit in secretory disorders of the liver, and since its mechanism of action is not established. Both UDCA and its taurine conjugate stimulated secretion of ATP by isolated rat hepatocytes, and produced measurable increases in ATP in bile of isolated rat liver. Perfusion of ATP into microdissected bile-duct segments induced Ca(2+) signalling in bile-duct epithelia, while perfusion of bile acid did not. Thus UDCA may promote bile flow by inducing hepatocytes to release ATP into bile, which then stimulates fluid and electrolyte secretion by bile-duct epithelia downstream via changes in cytosolic Ca(2+). Moreover, these findings demonstrate the feasibility of using pharmacological means to induce secretion of endogenous ATP. Since the liver and other epithelial organs express luminal ATP receptors, these findings more generally suggest that a mechanism exists for pharmacological activation of this paracrine signalling pathway. This strategy may be useful for treatment of cystic fibrosis and other secretory disorders of the liver and other epithelial tissues.

Pancreatic phospholipase A2 from the small intestine is a secretin-releasing factor in rats.

A secretin-releasing activity exists in the upper small intestine and pancreatic juice in the rat and the dog. Group I pancreatic phospholipase A2 (PLA2) in canine pancreatic juice and porcine pancreatic PLA2 stimulate the release of secretin from both STC-1 cells and a secretin-producing cell (S cell)-enriched preparation isolated from rat duodenal mucosa. We investigated the distribution and release of pancreatic PLA2-like immunoreactivity in the gastrointestinal tract and the role of PLA2 on the release of secretin and pancreatic exocrine secretion in response to duodenal acidification in anesthetized rats. PLA2-like immunoreactivity was detected in the mucosa throughout the gastrointestinal tract. High concentrations of PLA2 were found in both the small intestine and the pancreas. Duodenal acidification significantly increased the release of PLA2 from the upper small intestine (385% over basal secretion). Intravenous infusion of an anti-PLA2 serum (anti-PLA2) dose-dependently inhibited the release of secretin and pancreatic exocrine secretion in response to duodenal acid perfusion. Preincubation of the concentrate of intestinal acid perfusate (10-fold) from donor rats with the anti-PLA2 significantly suppressed its stimulation of secretin release and pancreatic exocrine secretion in recipient rats. We conclude that pancreatic PLA2 also functions as a secretin-releasing factor in the small intestine that mediates acid-stimulated release of secretin in rats.