Transmural Potential Difference Research Articles

Pectus carinatum, small pneumothorax, and Brugada patterns: First description and pathophysiological analysis

Pectus carinatum is a chest wall deformity where the breastbone and ribs protrude outward, sometimes referred to as “pigeon chest” due to the bird-like appearance of the chest. This condition occurs in approximately 1 in 1000 children, more commonly affecting boys than girls. Pectus carinatum tends to worsen as a child grows, especially during puberty, with about 15% of the children experiencing associated conditions like scoliosis. We present a case report of a young patient with pectus carinatum who experienced a small right apex pneumothorax and exhibited Brugada patterns on electrocardiogram tracing. This is the first clinical case reporting Brugada pattern presentation in both a patient with pectus carinatum and a small pneumothorax. We have conducted a clinical anatomical and electrocardiographic analysis to explore a physiopathological explanation for these findings, considering that our patient has no history or clinical signs of Brugada Syndrome. To further elucidate the clinical, anatomical, and electrocardiographic findings observed in our patient, detailed analyses were conducted. These investigations focused on how the pectus carinatum may influence electrocardiographic patterns through structural alterations of the thoracic wall, potentially modifying the transmural electrical field across the myocardium. This analysis aimed to explore a physiopathological explanation for the Brugada patterns observed, considering our patient’s unique thoracic anatomy and the absence of clinical Brugada Syndrome. We conclude that: 1. Pectus carinatum may create a window that facilitates the less resistive measurement of cardiac action potentials; 2. Small pneumothoraces can induce modifications in the cardiac electrical signal detected by surface electrodes, and pectus carinatum could unmask these modifications; and 3. Surface electrodes may measure subepicardial potentials that include and are modified by adjacent pericardial tissues, potentially resulting in alterations in transmural potential differences, thus producing fictitious Brugada patterns. Similarly, there is a possibility that the right ventricular outflow tract may be included within the subendocardial potentials.

Associations among neurophysiology measures in irritable bowel syndrome (IBS) and their relevance for IBS symptoms

Abnormal gut-brain interactions are common in irritable bowel syndrome (IBS), but the associations between neurophysiological measures and their relation to gastrointestinal (GI) symptoms are poorly understood. Our aim was to explore these relationships and define the most relevant neurophysiology measures for GI symptom severity in IBS. IBS patients underwent small intestinal motility (manometry; fasted and fed contraction frequency, phase III time) and secretion (transmural potential difference), rectal sensorimotor (barostat; sensory thresholds, tone response, compliance), autonomic nervous system (baroreceptor sensitivity and effectiveness), and colonic motor function (transit time) examinations. GI symptom severity (GSRS-IBS), and anxiety and depression (HAD) as a proxy measure of central nervous system (CNS) dysfunction, were assessed. In total 281 IBS patients (Rome II criteria) were included (74% females, median age 36 [interquartile range 28–50] years). Significant correlations between neurophysiology measures were stronger within, rather than between, different neurophysiological examinations. The strongest neurophysiology-symptom correlations occurred between a combination of CNS and visceral sensitivity parameters, and GSRS-IBS total score and pain domain (ρ = 0.40, p < 0.001, and ρ = 0.38, p < 0.001). Associations between GI symptoms in IBS and individual and combinations of neurophysiological factors occurred, primarily in CNS and visceral sensitivity measures, providing new insights into the clinical presentation of IBS.

Allicin Induces Electrogenic Secretion of Chloride and Bicarbonate Ions in Rat Colon via the TRPA1 Receptor.

Allicin, an antioxidant from garlic, is known to regulate intestinal contractions, but its effect on intestinal ion transport is unclear. The aim of this study was to examine the role of allicin in the regulation of electrogenic ion transport in rat intestine by measuring the transmural potential difference (ΔPD). Allicin induced significant positive ΔPD, when administered to the serosal side of the colonic mucosal-submucosal preparation. Allicin-induced colonic ΔPD was largely diminished by incubation in the chloride-free solution, although the transient peak of ΔPD after application of allicin remained. This transient peak of ΔPD was significantly diminished in both the chloride- and the bicarbonate-free incubation solution. Induction of ΔPD by allicin was greatly diminished by AP-18, an inhibitor of the transient receptor potential (TRP) cation channel subfamily A member 1, TRPA1. Both alliin and S-allylcysteine, the analogues of allicin, had no effect on ΔPD and did not affect allicin-induced ΔPD in the colon. These results suggest that allicin mainly evokes the electrogenic chloride secretion and only partially increases the electrogenic bicarbonate secretion via TRPA1.

The effect of efflux bomb and the transmural potential difference in the permeation of azidothymidine across the small intestine of the rat

The effect of efflux bomb and the transmural potential difference in the permeation of azidothymidine across the small intestine of the rat

The Colon as the Potassium Target: Entering the Colonic Age of Hyperkalemia Treatment?

The Colon as the Potassium Target: Entering the Colonic Age of Hyperkalemia Treatment?

Stimulating effects of a diet negative in dietary cation-anion difference on calcium absorption from the rumen in sheep.

The concept of feeding anionic salts in late gestation is widely used to prevent milk fever in dairy cows. While the effects of these diets on renal Ca excretion and tissue responsiveness towards parathyroid hormone have clearly been demonstrated, data on a potential impact on gastrointestinal Ca absorption are conflicting. Therefore, the aim of this study was to investigate the influence of feeding a diet negative in dietary cation-anion difference (DCAD) on ruminal mineral concentrations, fermentation products, electrophysiological properties of rumen epithelia and Ca flux rates. For this purpose, sheep were kept for 3 weeks on diets that were either positive or negative in DCAD. The induction of a compensated hyperchloremic metabolic acidosis could be demonstrated by increased plasma Cl and enhanced concentrations of ionised Ca, while plasma concentrations of HCO3- and base excess were decreased with the low DCAD diet. Neither transmural potential differences nor fermentation products were affected, but ruminal concentrations of Cl and Mg as well as the relation of ionised to total Ca were increased. Ussing chamber experiments revealed alterations of electrophysiological parameters and an increase in the electroneutral component of Ca flux rates from the mucosal to the serosal side of rumen epithelium. As plasma calcitriol concentrations were not affected, it can be concluded that the administration of anionic salts results in a vitamin D-independent stimulation of ruminal Ca transport.

Effects of Salmon Nasal Cartilage Proteoglycan on Plasma Glucose Concentration and Active Glucose Transport in the Small Intestine

Recently, proteoglycan was purified from the nasal cartilage of salmon. Although several physiological effects have been reported, the effect of salmon nasal cartilage proteoglycan (salmon PG) on glucose metabolism remains unclear. We studied the effect of salmon PG on rat plasma glucose levels. Oral administration of 1% salmon PG significantly attenuated the increase in portal plasma glucose levels following an oral glucose tolerance test (OGTT). Additionally 1% salmon PG delayed the increase in peripheral glucose concentration induced by the OGTT. Mucosal administration of 1% salmon PG significantly decreased active glucose transport using the everted jejunal sac method. Furthermore, transmural potential difference (ΔPD) measurements using the everted jejunum revealed that 1% salmon PG significantly decreased glucose-dependent and phlorhizin (inhibitor of sodium-glucose co-transporter 1; SGLT1)-sensitive ΔPD. These results suggest that salmon PG decreases glucose absorption via SGLT1 in the jejunum, thereby attenuating the increase in portal and peripheral plasma glucose levels in rats.

6]-gingerol induces electrogenic sodium absorption in the rat colon via the capsaicin receptor TRPV1.

[6]-Gingerol possesses a variety of beneficial pharmacological and therapeutic properties, including anti-carcinogenic, anti-inflammatory, and anti-emetic activities. Although [6]-gingerol is known to regulate the contraction of the intestine, its effect on intestinal ion transport is unclear. The aim of this study was to examine the role of [6]-gingerol in the regulation of electrogenic ion transport in the rat intestine by measuring the transmural potential difference (ΔPD). [6]-Gingerol induced significant positive ΔPD when administered to the serosal but not mucosal side of the colon, ileum, and jejunum; the highest effect was detected in the colon at a concentration of 10 μM. [6]-Gingerol-induced increase in ΔPD was suppressed by ouabain, an inhibitor of Na(+)/K(+)-ATPase, whereas no effect was observed in response to bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) co-transporter. In addition, ΔPD induction by [6]-gingerol was greatly diminished by capsazepine, an inhibitor of the capsaicin receptor TRPV1. These results suggest that [6]-gingerol induced the electrogenic absorption of sodium in the rat colon via TRPV1.

Electrophysiological response of chicken’s jejunal epithelium to increasing levels of T-2 toxin

The present investigations were conducted to test the effects of T-2 toxin on electrophysiological variables of jejunal epithelium of chicken. Jejunal segments of broilers were monitored in Ussing chambers in the presence of T-2 toxin at the levels of 0(negative control), 0(methanol/vehicle control), 0.1, 1, 5, and 10μg/ml of buffer. T-2 toxin did not affect basal values of short circuit current (I(sc)), transmural potential difference, or tissue conductivity in the jejunal epithelium. T-2 toxin also did not statistically affect glucose-induced electrophysiological variables during the first 3min of glucose induction. Compared to the vehicle control, the ouabain-sensitive I(sc) was negatively affected (P = 0.008) only under 5μg of T-2 toxin/ml. Increasing levels of T-2 toxin negatively affected the ouabain-sensitive I(sc) in a cubic (P = 0.007) fashion. These data indicate that acute exposure to moderate levels of T-2 toxin may progressively impair the cation gradient across the jejunal epithelium.

Effect of dietary phytic acid on performance and nutrient uptake in the small intestine of piglets1

An experiment was conducted with piglets to determine the effect of dietary phytic acid supplementation on performance, electrophysiological properties of jejunum mounted in Ussing chambers, sodium-dependent glucose transporter 1 (SGLT1) protein expression in jejunum, and plasma glucose and Na concentrations. Sixteen piglets with an average initial BW of 7.40 ± 0.36 kg were randomly assigned to 2 experimental diets with 8 piglets per diet. The diets were casein-cornstarch-based and were either unsupplemented or supplemented with 2% phytic acid (as Na phytate). The basal diet was formulated to meet the recommendation of NRC (1998) for energy, AA, minerals, and vitamins for piglets. The experiment lasted for 21 d, and at the end, BW gain and feed consumption were determined, and blood samples were collected for determination of plasma glucose and Na concentrations. The piglets were then euthanized to determine jejunal electrophysiological properties (transmural potential difference and short-circuit current) and SGLT1 protein expression. Phytic acid supplementation reduced ADG (P = 0.002), ADFI (P = 0.017), and G:F (P = 0.001) from 316.1 to 198.2 g, 437.4 to 360.3 g, and 0.721 to 0.539 g/g, respectively. Phytic acid supplementation also tended to reduce (P = 0.088) potential difference (-3.80 vs. -2.23 mV) and reduced (P = 0.023) short-circuit current from 8.07 to 0.1 μA/cm(2). However, phytic acid supplementation did not affect SGLT1 protein, and blood plasma glucose and Na concentrations. In conclusion, dietary phytic acid reduced growth performance and transmural short-circuit current in the jejunum of piglets. The reduced transmural short-circuit current in the jejunum by phytic acid implies reduced active Na transport in the jejunum by the phytic acid. Therefore, it seems that dietary phytic acid reduces growth performance of pigs partly through reduced capacity of the small intestine to absorb Na.

Gender Differences in Motility of the Large and Small Intestine in Patients With IBS

Background: Visceral hypersensitivity, and altered gastrointestinal motility and secretion, are considered to be key pathophysiological factors in irritable bowel syndrome (IBS), and of great importance for symptom generation. The symptom pattern differs between female and male IBS patients , with more severe abdominal pain, bloating and constipation in females (Khatai et al. DDW 2010). Whether this can be explained by gender differences in pathophysiological alterations is incompletely understood. Aim: To evaluate potential gender differences in small intestinal motility and secretion, colonic motility and rectal sensorimotor function in patients with IBS. Methods: We included 36 male and 36 female IBS patients, matched for age (mean age 39 (20-64) years), who fulfilled the ROME II criteria. All patients underwent investigations to assess colonic motility (colonic transit time using radiopaque markers), small intestinal motility and secretion (antroduodenojejunal manometry with jejunal transmural potential difference (PD) measurement in the fasting state (3h) and after meal intake (1h)) and rectal sensorimotor function (rectal balloon distensions before and after meal intake; 800kcal; 60% fat). Results: Colonic transit time differed between female and male IBS patients, with slower transit in females (2.1±1.3 (mean±SD) vs. 1.2±0.8 days; p<0.0001). Differences were also found in the small intestinal motility with slower propagation velocity of phase III in females (8.7±4.5 vs. 15±9.4 cm/min; p<0.01), and a tendency towards shorter duration of phase III in females (p<0.1). The motility indices in the jejunum also tended to be lower in female versus male IBS patients, but this only reached statistical significance in the fasting state (last 30 min of phase II) (3310±1040 vs. 4510±2730 mmHg x sec; p<0.05). No gender differences were seen in PD measurements in the small intestine, reflecting chloride secretion, or in rectal compliance, tone or sensitivity. Conclusion: We have demonstrated gender differences in small and large intestinal motility in IBS patients, but not in small intestinal secretion or rectal sensorimotor function. These findings are of potential importance for observed differences in the symptom pattern between male and female IBS patients.

Stimulatory Effects of 5-Hydroxytryptamine on Fluid Secretion and Transmural Potential Difference in Rat Small Intestine are Mediated by Different Receptor Subtypes

The rise in transmural potential difference (PD) and the fluid secretion induced by 5-hydroxytryptamine (5-HT) were measured in rat small intestine in-vivo. Both cisapride and ketanserin abolished the 5-HT-induced rise in systolic blood pressure mediated by 5-HT2 receptors. Cisapride inhibited the 5-HT-induced increases in the transintestinal PD, but over the same dose range it had no effect on the fluid secretion induced by 5-HT. In contrast, ketanserin caused a dose-dependent reduction in 5-HT-induced fluid secretion at doses that failed to influence the rise in PD. It is concluded that different receptors are responsible for the effects of 5-HT on fluid secretion and electrical activity in the rat small intestine.

Local and systemic actions of loperamide on fluid transport and transmural potential difference across rat small intestine.

The ability of loperamide to influence intestinal fluid transport was assessed using a dual loop preparation. Loperamide was applied to the lumen of the oral, but not the aboral loop, yet basal and prostaglandin-stimulated fluid transport was affected in both, indicating that the drug can act systemically in addition to any local actions. Loperamide had both pro-absorptive and anti-absorptive effects, the latter only occurring when basal fluid absorption was high. The effects of loperamide were greater in the aboral loop to which it was available only via the systemic route. This difference may reflect the absence of counteracting local influences in the aboral loop or a variation in the sensitivity of different regions of the gut to loperamide.

Involvement of prostaglandins in histamine-induced fluid and electrolyte secretion by rat colon.

Histamine increased the transmural potential difference across rat colon in-vivo and induced a net secretion of fluid. Both effects were inhibited by indomethacin. Histamine increased the potential difference and short-circuit current, and reduced tissue resistance in colonic sheets in-vitro. This response was reduced in the absence of chloride in the bathing medium or in the presence of serosal frusemide, suggesting that histamine stimulated electrogenic chloride secretion by the colon. The rise in short-circuit current induced by histamine was calcium-dependent since it was reduced in the absence of serosal calcium or in the presence of serosal verapamil. Indomethacin, a cyclo-oxygenase inhibitor, and mepacrine, a phospholipase inhibitor, both caused a dose-dependent inhibition of the electrical response of colonic sheets to histamine, without affecting the rise in short-circuit current induced by prostaglandin E2. The stimulation of chloride secretion induced by histamine in rat colon therefore appears to be mediated by an increased production of prostaglandins.

In vitro aflatoxin B1 exposure decreases response to carbamylcholine in the jejunal epithelium of broilers

The study was conducted to evaluate if aflatoxin B(1) (AFB(1)) has the capacity to affect the electrophysiological variables and active glucose uptake in jejunal epithelium of chicken. For this purpose, intestinal segments from the middle jejunum of broilers (35 to 39 d old) were incubated in Ussing chambers in the presence of 0 (vehicle control), 1.25, 2.50, and 3.75 microg of AFB(1)/mL of buffer. After 40 and 60 min of incubation with AFB(1), d-glucose (20 mmol/L) and carbamylcholine (200 micromol/L; an analog of acetylcholine and inducer of apical Cl(-) secretion) were respectively added to the incubation medium. Addition of 3.75 microg of AFB(1) caused an increase (P < 0.04) in short-circuit current (I(sc)) and transmural potential difference (V(t)) between 12 to 27 min postexposure as compared with the control. Glucose-induced DeltaI(sc) and percentage of DeltaV(t) were reduced (P < 0.04) at 2.5 and 3.75 microg of AFB(1)/mL, respectively, as compared with the control. The carbamylcholine-induced DeltaI(sc) and DeltaV(t) were both lower (P < 0.05) at 3.75 microg of AFB(1)/mL as compared with the control (-0.05 microA/cm(2), 0.1 mV vs. 1.1 microA/cm(2), and 0.6 mV, respectively). These observations indicate that acute exposure to AFB(1) may increase apical anion secretion in the jejunal epithelium of chicken. The negative effect of this increased anion secretion on active glucose uptake was, however, not prominent and may be considered as moderate or progressive in nature.

Angiotensin II receptors are expressed and functional in human esophageal mucosa

Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT(1)) and type 2 (AT(2)) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT(1) and AT(2) receptors. Immunoreactivity to AT(1) and AT(2) was localized to stratum superficiale and spinosum in the epithelium. ACE, AT(1), and AT(2) were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT(1) receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was -6.4 mV, epithelial current (I(ep)) 34 muA/cm(2), and epithelial resistance (R(ep)) 321 Omega.cm(2). Serosal exposure to Ang II increased PD as a result of increased I(ep), whereas R(ep) was constant. Ang II given together with the selective AT(1)-receptor antagonist losartan, or AT(2) agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT(2)-receptor antagonist PD123319 did not influence PD, but I(ep) decreased and R(ep) increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT(2)-receptor stimulation increases epithelial ion transport, whereas the AT(1) receptor inhibits ion transport and increases R(ep).

S1245 ROME III Subtyping Is Associated with Alterations in Intestinal Motility and Secretion, But Not with Sensitivity or Psychosocial Factors

Background: Visceral hypersensitivity, altered gastrointestinal motility and secretion, and psychosocial factors are considered to be of great importance for the symptom pattern in irritable bowel syndrome (IBS). The Rome III criteria propose subtyping of IBS patients based on stool form alone (Longstreth et al Gastroenterology 2006), but the association with the underlying pathophysiology is unknown. Aim: To evaluate the link between pathophysiological factors and Rome III subtyping. Methods: We included 129 IBS patients (96 females, 33 males; mean age 37 (19-67) years). The patients were subtyped according to the Rome III criteria based on one-week diaries, where the stool form (Bristol Stool Form scale) was reported. All patients underwent investigations to assess colonic motility (colonic transit time), small intestinal motility and secretion (antroduodenojejunal manometry with jejunal transmural potential difference (PD) measurement) and rectal sensorimotor function (rectal balloon distensions before and after meal intake). The patients also completed questionnaires to assess the severity of psychological, gastrointestinal and extraintestinal symptoms. Results: Fifty-five patients had IBS-D (diarrhea), 29 IBS-C (constipation), 11 IBS-M (mixed) and 34 IBS-U (unsubtyped). For the analyses M+U was combined into one group (“NonCNonD”). Colonic transit time differed between the subgroups (p<0.0001), with slower transit in IBS-C (1.8±2.9 (mean±SD) days), faster in IBS-D (1.0±1.4 days), and intermediate in the NonCNonD-group (1.4±2.0 days). There were also group differences in small intestinal motility, with higher contraction frequency in the fasted state (p<0.05), longer phase III duration (p<0.01) and faster propagation velocity of phase III (p<0.01) in IBS-D. The small intestinal secretion during phase III (mean PD × length of the secreting segment, calculated from duration and propagation velocity) also differed between the subtypes, with enhanced secretion in IBS-D (p<0.001). Also the mean fasted PD tended to be higher in IBS-D (p<0.05). Rectal sensitivity, compliance and the rectal tone response, as well as psychological or extraintestinal symptom severity was similar in the subtypes. The perceived severity of constipation (p<0.01) and diarrhea (p<0.01), but not other GI symptoms, also differed between the subtypes. Conclusion: Subtyping of IBS patients based on the stool form is associated with alterations small intestinal and colonic motility, as well as small intestinal secretion. However, other pathophysiological factors, as well as symptoms other than constipation and diarrhea, seem unrelated to the different Rome III-based IBS subtypes.

Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo

The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10, and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by intravenous (iv) administration of the ganglionic blocker hexamethonium and the NK(1) receptor antagonist SR-140333. Serosal TTX and iv SR-140333 significantly reduced the sustained response, which was also reduced by the NK(3) receptor antagonist talnetant and by the vasoactive intestinal polypeptide (VPAC) receptor antagonist [4Cl-d-Phe(6), Leu(17)]-VIP. Serosal lidocaine and iv hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK(1) receptors, and a slow component operating via VIP-ergic transmission and involving both NK(1) and NK(3) receptors.

Elevated motility‐related transmucosal potential difference in the upper small intestine in the irritable bowel syndrome

The pathophysiology of irritable bowel syndrome (IBS) is complex and incompletely known. Very little has been studied regarding the role of submucous neuronal activity. We therefore measured small intestinal transmural potential difference (PD, reflecting mainly electrogenic chloride secretion), and its linkage with fasting motor activity [migrating motor complex (MMC)] in controls (n = 16) and patients with IBS [n = 23, 14 diarrhoea predominant (d-IBS) and nine constipation predominant (c-IBS)]. Transmural-PD and its relation to MMC phase III was measured by modified multilumen manometry for 3 h in the fasting state using one jejunal and one duodenal infusion line as flowing electrodes. The amplitude and duration of motor phase III was similar in controls and IBS patients, but the propagation speed of phase III was higher in IBS patients. In IBS patients, maximal PD during MMC phase III was significantly elevated in both the duodenum and jejunum (P < 0.05) and the PD decline after phase III was significantly prolonged in the jejunum (P < 0.01). The PD elevation was seen in both duodenum and jejunum in d-IBS patients, but only in the jejunum in the c-IBS patients. On the basis of previous modelling studies, we propose that the enhanced secretion may reflect disturbed enteric network behaviour in some patients with IBS.

PH stat studies on bicarbonate secretion in the isolated mouse ileum

Bicarbonate secretion occurs in almost all segments of the gastrointestinal tract. This study examined HCO(3)(-) secretion in the ileum, since it is less understood than HCO(3)(-) secretion in other intestinal segments. Mouse ileal mucosa was mounted in vitro in Ussing chambers, and the mucosal alkalinization rate (J(OH)) was determined by pH stat titration, while the mucosal side was bathed with a buffer-free solution (100% O(2)) and the serosal side with a HCO(3)(-)/CO(2)-buffered solution. The transmural potential difference (PD) was recorded. The mucosal alkalinization rate (J(OH)) was higher in the presence of mucosal Cl(-) than in its absence. Forskolin, an activator of adenylate cyclase, enhanced J(OH) and PD in both the presence and absence of mucosal Cl(-). Mucosal SO(4)(2-) also caused an increase in J(OH), although the magnitude was smaller than that induced by Cl(-). Mucosal Cl(-)-dependent J(OH) was partially inhibited by acetazolamide, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), tenidap and probably also by niflumic acid, but not by glibenclamide, DIDS or bumetanide. The forskolin-induced J(OH) value and PD were both inhibited by NPPB and probably also by tenidap. It is concluded that HCO(3)(-)- secretion in the ileum follows a mucosal Cl(-)-dependent pathway and a cAMP-activated pathway, each being distinct from each other. The Cl(-)-dependent pathway is probably mediated by the slc26a6 anion exchanger, and possibly also by the slc26a3 anion exchanger. The cAMP-activated HCO(3)(-) secretion is probably mediated by the cystic fibrosis transmembrane conductance regulator.