NPS reduces duodenal bicarbonate secretion and mucosal net fluid secretion, dependence on NO activity.

<p><b>A)</b> Continuous i.v. infusion of NPS at 8–833 pmol·kg^-1·min^-1 reduced duodenal bicarbonate secretion and <b>C)</b> decreased duodenal mucosal net fluid secretion. <b>B & D)</b> Pre-treatment with L-NAME abolished the effects of NPS. # indicates a significant (<i>P</i><0.05) reduction compared with baseline (0–30 min) in the same group. * indicates significantly (<i>P</i><0.05) higher compared with baseline (0–30 min) in the same group. § indicates a significant (<i>P</i><0.05) reduction compared to time-matched control animals.</p

Co-administration of luminal hydrochloric acid 1.0 mM (pH 3) with intravenous NPS increases duodenal bicarbonate secretion and mucosal paracellular permeability in a NO-activity-dependent manner.

<p><b>A)</b> Luminal HCl pH 3 alone had no effect, but co-administration with NPS continuous i.v. infusion 83 pmol·kg^-1·min^-1 significantly increased duodenal bicarbonate secretion and <b>B)</b> inhibited the duodenal mucosal paracellular permeability reduction except in animals pretreated with L-NAME. <b>C)</b> No significant changes were observed in duodenal motility. <b>D)</b> NPS had no effect on HCl-induced net fluid absorption. Pretreatment with L-NAME stimulated net fluid secretion. # indicates a significant (<i>P</i><0.05) difference compared with baseline (0–30 min) in the same group. * indicates significantly (<i>P</i><0.05) higher than the other groups.</p

Representative experiment of NPS reducing 15% EtOH-induced increases in intraduodenal pressure (motility).

<p>All rats were pretreated with i.v. parecoxib 10 mg/kg approximately 60 min before the experiment started to reverse surgery-induced paralytic ileus. <b>A)</b> Saline perfusion with migrating motor complex (MMC) pattern. <b>B)</b> Luminal 15% EtOH increased motility. <b>C)</b> Continuous i.v. infusion of NPS reduced basal motility (time 0–30 min) and the motility effect of 15% EtOH. <b>D)</b> NPS at 10× concentration further decreased basal motility (time 0–30 min) and further dampened the effect of 15% EtOH.</p

Effects of ethanol and hydrochloric acid on duodenal bicarbonate secretion, paracellular permeability and fluid flux.

<p>A). The effects of luminal perfusion of the duodenum with 1.0 mM hydrochloric acid on duodenal bicarbonate secretion were investigated. Hydrochloric acid induced a significant increase in duodenal bicarbonate secretion. A combination of 15% ethanol and 1.0 mM hydrochloric acid induced a significantly larger increase in bicarbonate secretion than hydrochloric acid alone. B). No statistically significant effects on the duodenal net fluid flux were observed in response to hydrochloric acid alone or the combination of 15% ethanol and hydrochloric acid. C). The combination of 15% ethanol and hydrochloric acid caused a potent increase in the duodenal epithelial blood-to-lumen clearance of ⁵¹Cr-EDTA. However, 1.0 mM hydrochloric acid alone did not influence the clearance of ⁵¹Cr-EDTA. The values are the mean ± SEM; 1.0 mM hydrochloric acid (pH 3, n = 6), and a combination of 15% ethanol and 1.0 mM hydrochloric acid (n = 7). * indicates a significant (p<0.05) increase compared with baseline in the same group, and § indicates a significantly lower value compared with the corresponding time point in the other group.</p

Ethanol-induced stimulation is critically dependent on luminal Cl⁻.

<p>A). The effects of luminal perfusion of the duodenum with 15% ethanol during luminal Cl⁻- free conditions on duodenal bicarbonate secretion was investigated. Ethanol did not induce increases in duodenal bicarbonate secretion during Cl⁻-free conditions. B). No statistically significant effects on duodenal net fluid flux were observed in response to the perfusion of ethanol during Cl⁻-free conditions. C). Ethanol precipitated a potent increase in the duodenal-epithelial blood-to-lumen clearance of ⁵¹Cr-EDTA during Cl⁻-free conditions. The increase in permeability in response to ethanol was in the same magnitude as that observed when luminal Cl⁻ was present (not shown). The values are the mean ± SEM, n = 11 in both groups. * indicates a significant (p<0.05) increase compared with baseline in the same group, and § indicates a significantly lower value compared with the corresponding time point in the other group.</p

Effects of ethanol on duodenal mucosal bicarbonate secretion and duodenal fluid flux.

<p>A). The effects of luminal perfusion of the duodenum with 10% (n = 6) and 15% (n = 11) ethanol on duodenal bicarbonate secretion. Ethanol caused a concentration-dependent increase in duodenal bicarbonate secretion. In the control animals (n = 8, perfusion with isotonic saline only), the bicarbonate secretion was stable during the experiment. B). The luminal perfusion of the duodenum with 10% and 15% ethanol did not have any effects on the duodenal net fluid flux. Similarly, isotonic saline did not influence the net fluid flux in the control animals. However, the basal net fluid flux was significantly (p<0.05) higher in controls compared with that for both ethanol 10% and 15%. The values are the mean ± SEM. *indicates a significant (p<0.05) increase compared with baseline in the same group.</p

Nicotinic receptor inhibition reduces ethanol-induced increases in duodenal bicarbonate secretion.

<p>A). The effects of luminal perfusion of the duodenum with 15% ethanol pretreated with hexamethonium administered as an i.v. bolus dose of 10 mg·kg?¹ followed by a continuous i.v. infusion of 10 mg·kg?¹·h?¹ throughout the experiment. Hexamethonium significantly reduced the bicarbonate secretory response to ethanol. However, during the ethanol exposure in this group, duodenal bicarbonate secretion was significantly increased compared with the preceding basal period. B). The hexamethonium treatment significantly decreased the net fluid flux. In response to luminal ethanol, the net fluid flux was not significantly different from that of the controls. The values are the mean ± SEM; 15% ethanol (n = 11), hexamethonium alone (n = 4), and 15% ethanol + hexamethonium (n = 9). * indicates a significant (p<0.05) increase compared with baseline in the same group, # indicates a significant decrease compared with baseline in the same group and § indicates a significantly lower value compared with the corresponding time point in the ethanol 15% group of animals.</p

Histology of the duodenal mucosa.

<p>The duodenum perfused with isotonic NaCl for 30(group I) had a normal morphological appearance (n = 4, Fig. 6A). The perfusion of the duodenal segment with 15% ethanol for 30 min (group II) caused mild villous tip damage observed as edema and the beginning of desquamation of the epithelium at the tip of less than 10% of the total villi (n = 4, Fig. 6B). The duodenal segment following perfusion of with 1.0 mM hydrochloric acid (pH 3) for 30 min (group III) had a normal morphological appearance (n = 4, Fig. 6C). The perfusion of the duodenal segment with 15% ethanol mixed in a hydrochloric acid solution of 1.0 mM for 30 min (group IV) caused mild villous tip damage observed as edema and the beginning of desquamation of the epithelium at the tip of less than 10% of the total villi (n = 4, Fig. 6D). The morphological changes in this group were not different from the group perfused with 15% ethanol alone.</p