Jejunal Perfusion Research Articles

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir (SQV) oral absorption. With use of single-pass jejunal perfusion (in situ) and portal vein-cannulated rats (in vivo), SQV absorption was studied under chemical inhibition of Pgp [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2 isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918)], Mrp2 [(3-(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F(a) = 0.07%) and in vivo [C(max) = 0.068 microg/ml; area under the curve (AUC) = 6.8 microg x min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation = 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2- to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapy-limiting drug-drug transporter and enzyme interactions.

EVALUATION OF INTESTINAL PRECONDITIONING IN A PORCINE MODEL USING CLASSIC ISCHEMIC PRECONDITIONING OR LUNG RECRUITMENT MANEUVERS

To test the hypotheses that repeated brief intestinal ischemic insults would elicit an intestinal preconditioning response to a subsequent intestinal I/R injury and that a similar response would be elicited by repeated lung recruitment maneuvers (RMs). Randomized experimental controlled animal study. University hospital animal laboratory. Eighteen anesthetized pigs. Animals were randomized to one of three groups, with six animals in each group. Control group 75-min superior mesenteric artery (SMA) occlusion followed by 60-min reperfusion. Ischemic preconditioning group, three 5-min-long SMA occlusions preceding 75-min SMA occlusion and 60-min reperfusion. Recruitment maneuver (RM) group, three 2-min-long RMs preceding 75-min SMA occlusion and 60-min reperfusion. We measured systemic and mesenteric hemodynamic parameters, jejunal mucosal perfusion, net mesenteric lactate flux, jejunal tissue oxygen tension, and mesenteric oxygenation. Every 15 min, jejunal microdialysate samples were collected and analyzed for glucose, lactate, and glycerol. Jejunal tissue samples were collected postmortem. After occlusion of SMA, regional parameters in all groups indicated abolished perfusion and gradually increasing intraluminal microdialysate lactate and glycerol levels. At reperfusion, regional parameters indicated mesenteric hyperperfusion, whereas microdialysis markers of mucosal anaerobic metabolism and cell injury decreased, although not reaching baseline. Histological examination revealed severe mucosal injury in all groups. There were no significant differences between groups in the observed parameters. No protective preconditioning response could be observed when performing repeated brief intestinal ischemic insults or repeated lung RMs before an intestinal I/R injury.

Assessment of Intestinal Absorption of Vitexin-2″-O-Rhamnoside in Hawthorn Leaves Flavonoids in Rat Using In Situ and In Vitro Absorption Models

The purpose of this study was to investigate the absorption mechanism of vitexin-2″-O-rhamnoside, the index component in hawthorn leaves flavonoids (HLF) in the rat intestine, using two different absorption models, the in situ single-pass intestinal perfusion and the in vitro everted gut sac model. The effective permeability coefficients (Peff) in the in situ single-pass intestinal perfusion experiments and the apparent permeability coefficients (Papp) in the in vitro everted gut sac experiments were calculated. Furthermore, the influences of the P-glycoprotein inhibitors, verapamil and digoxin, on the intestinal absorption of vitexin-2″-O- rhamnoside in HLF were studied using the above-mentioned two models. Results showed that there were no significant differences in the absorption of vitexin-2″-O-rhamnoside in HLF in four segments of the rat intestine, duodenum, jejunum, ileum, and colon, and at different concentrations of HLF ranging from 0.05 mg/ml to 0.5 mg/ml (P > 0.05). The Peff values for vitexin-2″-O-rhamnoside in the rat jejunal perfusion at the concentration of 0.05, 0.1, 0.25, and 0.5 mg/ml were (2.48 ± 0.33) × 10−5; (2.23 ± 0.67) × 10−5; (2.18 ± 0.48) × 10−5; and (2.25 ± 0.17) × 10−5 cm/s, respectively. But there was significant difference between absence and presence of verapamil or digoxin (P < 0.05). Peff and Papp values of vitexin-2″-O-rhamnoside in HLF were increased in the presence of verapamil or digoxin. In conclusion, vitexin-2″-O-rhamnoside can be classified into high permeability class drug according to the biopharmaceutical classification system. Passive diffusion dominates the absorptive transport behavior of vitexin-2″-O-rhamnoside in HLF. The absorption and secretion are mediated by the efflux transport system, P-gp. The absorption of vitexin-2″-O-rhamnoside in HLF can be enhanced administered together with P-gp inhibitors.

NOREPINEPHRINE AND INTESTINAL MUCOSAL PERFUSION IN VASODILATORY SHOCK AFTER CARDIAC SURGERY

Patients with norepinephrine-dependent vasodilatory shock after cardiac surgery (n = 10) were compared with uncomplicated postcardiac surgery patients (n = 10) with respect to jejunal mucosal perfusion, gastric-arterial PCO2 gradient, and splanchnic oxygen demand/supply relationship. Furthermore, the effects of norepinephrine-induced variations in MAP on these variables were evaluated in vasodilatory shock. Norepinephrine infusion rate was randomly and sequentially titrated to target MAPs of 60, 75, and 90 mmHg (0.25 +/- 0.24, 0.37 +/- 0.21, and 0.55 +/- 0.39 microg/kg per minute, respectively). Data on jejunal mucosal perfusion, jejunal mucosal hematocrit, and red blood cell (RBC) velocity (laser Doppler flowmetry) as well as gastric-arterial PCO2 gradient (gastric tonometry) and splanchnic oxygen and lactate extraction (hepatic vein catheter) were obtained. Splanchnic oxygen extraction was 71 +/- 16% in the vasodilatory shock group and 41 +/- 9% in the control group (P < 0.001), whereas splanchnic lactate extraction did not differ between the two groups. Jejunal mucosal perfusion (61%; P < 0.001), RBC velocity (35%; P < 0.01), and gastric-arterial mucosal PCO2 gradient (150%; P < 0.001) were higher in the vasodilatory shock group compared with those of the control group. Jejunal mucosal perfusion, jejunal mucosal hematocrit, RBC velocity, gastric-arterial mucosal PCO2 gradient, splanchnic oxygen extraction, and splanchnic lactate extraction were not affected by increasing infusion rates of norepinephrine. In patients with norepinephrine-dependent vasodilatory shock after cardiac surgery, intestinal mucosal perfusion was higher, whereas splanchnic and gastric oxygen demand/supply relationships were impaired compared with postoperative controls, suggesting that intestinal mucosal perfusion is prioritized in vasodilatory shock. Increasing MAP from 60 to 90 mmHg with norepinephrine in clinical vasodilatory shock does not affect intestinal mucosal perfusion and gastric or global splanchnic oxygen demand/supply relationships.

Negative mesenteric effects of lung recruitment maneuvers in oleic acid lung injury are transient and short lasting

To test the hypothesis that repeated recruitment maneuvers (RMs) have sustained negative effects on mesenteric circulation, metabolism, and oxygenation 60 mins after RMs in pigs with oleic acid lung injury. Further, we aimed to test the hypothesis that an infusion of prostacyclin (PC) at 33 ng.kg.min would attenuate such possible negative mesenteric effects. Randomized, experimental, controlled study. University hospital animal laboratory. A total of 31 anesthetized, fluid-resuscitated pigs with oleic acid lung injury. : Animals were randomized to one of the following four groups: a control group (n = 7) that received no intervention, recruitment group (n = 8) that underwent the RM sequence, a prostacyclin group (n = 8) that received an infusion of PC, and a recruitment-prostacyclin group (n = 8) that received an infusion of PC and concomitant RM sequence. We measured systemic and mesenteric hemodynamic variables, jejunal mucosal perfusion, mesenteric lactate flux, jejunal tissue oxygen tension, and mesenteric oxygen delivery, uptake, and extraction ratio. Five minutes after RMs, mesenteric oxygen extraction ratio and mesenteric lactate flux were more prominently increased in the recruitment group, giving evidence of worsened mesenteric conditions after RMs. These signs of worsened conditions were further supported by more decreased jejunal tissue oxygen tension and portal vein oxygen saturation in the recruitment group. PC preserved mesenteric oxygenation, as indicated by less of a decrease in portal vein oxygen saturation at the time corresponding to 5 mins after RM and less of a decrease in mesenteric oxygen delivery at the time corresponding to 15 mins after RM. PC preserved mesenteric oxygenation as indicated by less of a decrease in portal vein oxygen saturation at 5 mins after RM and an attenuated increase in mesenteric oxygen extraction ratio at 5 mins after RM. There was a trend toward worsened jejunal mucosal perfusion, although not significant. In an oleic acid lung injury model, three repeated RMs did not improve systemic oxygenation or lung mechanics. Negative effects on mesenteric oxygenation and metabolism were transient and short lasting. The intestinal effects of PC during RMs were minor and opposing, showing preserved oxygenation but a trend toward worsened mucosal perfusion.

Nutrient modulation of intestinal gas dynamics in healthy humans: dependence on caloric content and meal consistency

The actions of nutrients on gut transit of liquids and solids have been extensively studied, but the effects of meal ingestion on intestinal gas flow are unexplored. We hypothesized that meals of varying caloric content and consistency modulate gas transit to different degrees. Nine healthy volunteers underwent jejunal perfusion of physiological gas mixtures at 12 ml.min(-1).3 h, with ingestion of nothing (control), water (240 ml), 240-kcal liquid meals, and 240-kcal solid meals at the end of the second hour in separate studies. Gas was quantified from an intrarectal catheter. After an initial lag phase, gas evacuation approached steady state by the end of the fasting period. Solid and liquid caloric meals increased total gas volumes evacuated from 5-40 min after ingestion vs. control studies (P < 0.05). These increases resulted from increased numbers of bolus gas evacuations (P < 0.05), whereas bolus volumes, pressures, and flow rates were similar for all test conditions. Solid and liquid caloric meals elicited similar effects on bolus gas dynamic parameters, whereas water did not affect these measures vs. control (NS, not significant). Both caloric meals and the noncaloric liquid meal increased continuous gas flow, which represented <2% of total gas expulsion. In conclusion, caloric meals promote bolus gas transit in healthy humans, whereas noncaloric liquids have no effect. Solids stimulate early postprandial gas dynamics to the same extent as liquid meals of similar caloric content. Thus modulatory effects of meals on intestinal gas transit depend on their caloric content but not their consistency.

Modulation of Intestinal Gas Dynamics in Healthy Human Volunteers by the 5-HT4Receptor Agonist Tegaserod

Bloating in irritable bowel syndrome (IBS) may result from impaired intestinal gas transit and is reduced by the 5-HT4 agonist tegaserod. Abnormal serotonergic function underlies many IBS symptoms, but the role of 5-HT4 pathways in regulating gas dynamics under healthy conditions is unexplored. We hypothesized that 5-HT4 activation by tegaserod stimulates gas transit in healthy individuals. Sixteen normal volunteers underwent jejunal perfusion of gas mixtures (88% N2, 5.5% O2, 6.5% CO2) at 11.2 mL/min x 3 h under control conditions and 3 h after oral tegaserod 6 mg on separate days. Gas collected from an intrarectal catheter was quantified using a barostat. Under control conditions, gas evacuation after a lag period (1,959 +/- 428 s) was predominantly pulsatile with expulsion of 1,984 +/- 90 mL. A mean of 29 +/- 2 boluses with volumes of 72 +/- 5 mL were expelled. In 10 subjects with physiologic degrees of gas retention in control studies (248 +/- 73 mL), tegaserod increased expulsion from 1,768 +/- 73 to 1,973 +/- 37 mL and decreased retention to 43 +/- 37 mL (p < 0.05). Total volumes expelled as boluses were greater after tegaserod (1,708 +/- 73 vs 1,846 +/- 59 mL, p < 0.05) from increased bolus numbers in four subjects and increased bolus volumes in seven. Nonpulsatile continuous flow tended to increase with tegaserod (43 +/- 7 vs 126 +/- 43 mL, p= 0.10). Tegaserod did not increase evacuation in individuals without physiologic gas retention. The 5-HT4 agonist tegaserod promotes evacuation of jejunally perfused gas mixtures in healthy humans. These findings provide the foundation for future investigations into use of 5-HT4 agonists in conditions of pathologic gas retention.

Autoregulation of Human Jejunal Mucosal Perfusion During Cardiopulmonary Bypass

Animal studies have suggested that autoregulation of intestinal blood flow is severely impaired during cardiopulmonary bypass (CPB). We investigated the jejunal mucosal capacity to autoregulate perfusion during nonpulsatile CPB (34 degrees C) in 10 patients undergoing elective cardiac surgery. Changes in mean arterial blood pressure (MAP) were induced by altering the CPB flow rate randomly for periods of 3 min from 2.4 L/min/m2 to either 1.8 or 3.0 L/min/m2. Jejunal mucosal perfusion (JMP) was continuously recorded by laser Doppler flowmetry. A typical pattern of flow motion (vasomotion) was recorded in all patients during CPB. Variations in CPB flow rates caused no significant changes in mean JMP, jejunal mucosal hematocrit, or red blood cell velocity within a range of MAP from 50 +/- 15 to 74 +/- 16 mm Hg. The vasomotion frequency and amplitude was positively correlated with CPB flow rate. IV injections of prostacyclin (10 microg, Flolan) blunted vasomotion and increased JMP from 192 +/- 53 to 277 +/- 70 (P < 0.05) perfusion units despite a reduction in MAP from 59 +/- 12 to 45 +/- 10 mm Hg (P < 0.05). Prostacyclin-induced vasodilation resulted in loss of mucosal autoregulation (pressure-dependent perfusion). We conclude that autoregulation of intestinal mucosal perfusion is maintained during CPB in humans.

Effects of norepinephrine-induced variations in perfusion pressure on jejunal mucosal perfusion in vasodilatory shock after cardiac surgery

Effects of norepinephrine-induced variations in perfusion pressure on jejunal mucosal perfusion in vasodilatory shock after cardiac surgery

FIRST-PASS EFFECTS OF VERAPAMIL ON THE INTESTINAL ABSORPTION AND LIVER DISPOSITION OF FEXOFENADINE IN THE PORCINE MODEL

The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E(H); mean +/- S.E.M.), and the given doses of verapamil did not affect the E(H) (0.13 +/- 0.04, 0.16 +/- 0.03, and 0.12 +/- 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E(H) for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E(H) values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.

Vasopressors and intestinal mucosal perfusion after cardiac surgery: Norepinephrine vs. phenylephrine

To evaluate the potential differential effects of norepinephrine, an alpha1-, beta1-, and beta2-receptor agonist, to the alpha1-agonist phenylephrine on jejunal mucosal perfusion, gastric-arterial PCO2 gradient, and the global splanchnic oxygen demand-supply relationship after cardiac surgery. A randomized, prospective, interventional crossover study. A university cardiothoracic intensive care unit. Ten patients were studied during propofol sedation and mechanical ventilation after uncomplicated coronary artery bypass surgery. Each patient received randomly and sequentially norepinephrine (0.052+/-0.009 microg/kg/min) and phenylephrine (0.50+/-0.22 microg/kg/min) to increase mean arterial blood pressure by 30%. Data on jejunal mucosal perfusion, jejunal mucosal hematocrit, and red blood cell velocity (laser Doppler flowmetry) as well as gastric-arterial Pco2 gradient (tonometry) and splanchnic oxygen extraction were obtained before (control) and during a 30-min drug infusion period after the target mean arterial blood pressure was reached. The procedure was sequentially repeated for the second vasopressor. Both drugs induced a 40-46% increase in systemic vascular resistance with no change in cardiac index. Neither jejunal mucosal perfusion, jejunal mucosal hematocrit, red blood cell velocity, nor gastric-arterial Pco2 gradient was affected by any of the vasopressors. Splanchnic oxygen extraction increased from 38.2% to 43.1% (p<.001) with norepinephrine and from 39.3% to 47.5% (p<.001) with phenylephrine. This increase was significantly more pronounced with phenylephrine compared with norepinephrine (p<.05). Mixed venous-hepatic vein oxygen saturation gradient increased with both drugs (p<.01), and the increase was more pronounced with phenylephrine (p<.05). Splanchnic lactate extraction was not significantly affected by any of the vasopressors. Phenylephrine induced a more pronounced global alpha1-mediated splanchnic vasoconstriction compared with norepinephrine. Neither of the vasoconstrictors impaired perfusion of the gastrointestinal mucosa in postcardiac surgery patients. The lack of norepinephrine-induced, alpha1-mediated impairment of gastrointestinal perfusion is not explained by a beta2-mediated counteractive vasodilation but instead by possible mucosal autoregulatory escape.

Überempfindlichkeit gegenüber Capsaicin bei Personen mit dyspeptischen Beschwerden: Potential als neuer diagnostischer Test

Lack of understanding of the pathogenesis of functional dyspepsia is one reason for the paucity of effective treatment options. Whereas mechanical sensitivity in persons suffering from dyspepsia might be impaired, chemically induced hypersensitivity has received little attention. The aim of this study was to evaluate whether vanilloid receptors stimulated by capsaicin are hypersensitive in persons with dyspepsia. Six volunteers with un-investigated dyspepsia who never had consulted a physician (4 women; age, 26.2 +/- 4.1 years) and six controls (3 women; age, 27.5 +/- 5.9 years) underwent jejunal perfusion with capsaicin. All participants swallowed a tube with an infusion site at the ligament of Treitz and 7 cm distally a barostat balloon that was used for pressure-controlled distension. Capsaicin solution (40 microg/ml, 2.5 ml/min) was infused for 60 minutes or until discomfort was induced. Perceptions of seven different sensations were evaluated using a graded questionnaire during capsaicin infusion and jejunal distension. During infusion of capsaicin, the length of time until occurrence of the first sensation (P < 0.01) and discomfort (P < 0.001) was significantly shorter in those with dyspepsia than in the control group. Mechanical distension induced first sensation and discomfort at lower balloon volumes in those with dyspepsia but this difference was not significant. Jejunal sensitivity to capsaicin is increased in persons with un-investigated dyspepsia, and vanilloid receptors might be involved in the pathophysiology of this condition. Patients with hypersensitivity to chemical stimuli may represent a distinct subpopulation based on the underlying pathophysiology and may require specific treatment to restore normal visceral sensitivity.

Cardiopulmonary Bypass in Humans—Jejunal Mucosal Perfusion Increases in Parallel With Well-maintained Microvascular Hematocrit

Cardiopulmonary Bypass in Humans—Jejunal Mucosal Perfusion Increases in Parallel With Well-maintained Microvascular Hematocrit

Intestinal circulation, oxygenation and metabolism is not affected by oleic acid lung injury

This study was performed to establish a platform for further studies on effects of ventilatory treatment modalities on the intestines during mechanical ventilation of acute lung injury (ALI). We tested the hypotheses that oleic acid (OA) infusion causes changes in intestinal circulation, oxygenation and metabolism, and that OA is distributed to tissues outside the lung. This was performed as an experimental, prospective and controlled study in an university animal research laboratory. Thirteen juvenile anaesthetized pigs were used in the main study, where seven were given an intravenous infusion of 0.1 ml kg(-1) OA and six served as control (surgery only). In a separate study, four animals were given an intravenous infusion of 0.1 ml kg(-1) (3)H-labelled OA. We measured systemic and mesenteric (portal venous blood flow, jejunal mucosal perfusion) haemodynamic parameters, mesenteric oxygenation (jejunal tissue oxygen tension) and systemic cytokines (tumour necrosis factor-alpha and interleukin-6). We calculated mesenteric lactate flux and mesenteric oxygen delivery, uptake and extraction ratio. In the animals given 3H-OA, we measured 3H-OA in different tissues (lungs, heart, liver, kidney, stomach, jejunum, colon and arterial blood). We found that OA given intravenously is distributed in small amounts to the intestines. This intestinal exposure to OA does not cause intestinal injury when evaluating mesenteric blood flow, metabolism or oxygenation. OA infusion induced a moderate increase in mean pulmonary arterial pressure and a decrease in PaO2/Fraction inspired O2 (P/F) ratio, giving evidence of severe lung injury. Consequently, the OA lung injury model is suitable for studies on intestinal effects of ventilatory treatment modalities during mechanical ventilation of ALI.

Cardiopulmonary bypass in humans – jejunal mucosal perfusion increases in parallel with well‐maintained microvascular hematocrit

An imbalance between splanchnic oxygen supply and demand occurs during cardiopulmonary bypass (CPB) in man, which might disrupt the intestinal mucosal barrier function. The aim of the present study was to evaluate the effects of mild hypothermic CPB on intestinal mucosal perfusion in man undergoing cardiac surgery. Additionally we aimed to identify variables, which independently could predict changes of intestinal mucosal microcirculatory variables during CPB. Jejunal mucosal perfusion (JMP), jejunal mucosal hematocrit (JMHt), red blood cell (RBC) velocity and arteriolar vasomotion using endoluminal jejunal laser Doppler flow metry were studied in eight cardiac surgical patients before and during CPB at a temperature of 34 degrees C. Cardiopulmonary bypass and the accompanied hemodilution (25-30%) induced a 44% increase in JMP (P < 0.05) and a 42% increase in RBC velocity (P < 0.01), with no change in JMHt. The oscillation amplitude of JMP, at a fundamental frequency of 2.8 cycles min(-1), increased with 175% (P < 0.05) during CPB. Splanchnic oxygen extraction increased by 64% during CPB (P < 0.05). Stepwise multiple regression analysis identified systemic hematocrit, arterial O2 and CO2 tension and splanchnic oxygen extraction as independent predictors of RBC velocity during CPB (R2=0.63, P < 0.001). The oscillation amplitude of JMP was predicted by RBC velocity and splanchnic oxygen extraction (R2= 0.68, P <0.0001). The increase in RBC velocity and enhanced arteriolar vasomotion, as well as maintained jejunal mucosal hematocrit, are microcirculatory, compensatory mechanisms for the splanchic oxygen supply/demand mismatch seen during cardiopulmonary bypass in humans.

Do Elevated Plasma Vasoactive Intestinal Polypeptide (VIP) Levels Cause Small Intestinal Motor Disturbances in Humans?

Increased VIP plasma levels cause severe secretory diarrhea. Moreover, VIP is a major regulator of human intestinal motility. We hypothesized that VIP-mediated intestinal motility disturbances contribute to symptoms in elevated plasma VIP. Ten healthy volunteers were intubated twice with an orojejunal multilumen tube for duodenal manometry, jejunal perfusion of electrolyte and marker solution, and aspiration 10 and 40 cm more distally. All subjects randomly received intravenous infusion of saline and 300 pmol/kg x hr VIP for 5 hr. Results showed that VIP but not saline infusion induced netjejunal sodium secretion, watery diarrhea, and cardiovascular effects (P < 0.04). VIP did not alter intestinal motor activity or the mean duration of the interdigestive motility cycle or of phases I and II but nearly halved the duration of phase III (P = 0.0002). We conclude that increased plasma VIP markedly shortens human phase III activity without influencing other motility parameters. Hence, it is unlikely that VIP-mediated small intestinal motor disturbances cause symptoms in VIPOMA. Yet VIP may contribute to terminate phase III motility.

Effect of peptide YY on pancreatico-biliary secretion in humans

Objective. The negative feedback on pancreatico-biliary secretion induced by ileal nutrients has been well documented but the role of the distal gut peptide YY (PYY) as mediator is less well defined. We determined the effect of PYY on basal, sham feeding and feeding-stimulated pancreatico-biliary secretion in humans. Material and methods. Eight healthy volunteers participated in a placebo-controlled, double-blind, randomized study with intravenous infusion of a physiological dose of PYY. Subjects were intubated with a naso-jejunal tube. Duodenal samples were aspirated continuously while a recovery marker perfused the duodenum. Outputs were measured in the basal state, in response to modified sham feeding (MSF) and during jejunal perfusion with a liquid meal. Blood samples were drawn for plasma cholecystokinin (CCK) and PYY measurements. Results. PYY infusion significantly (p<0.01) increased plasma PYY, from 16±2 to 55±6 pM. Basal outputs of amylase, lipase, trypsin and bilirubin were not affected by PYY. In the placebo experiment, MSF significantly increased amylase, lipase, trypsin and bilirubin outputs. However, during PYY infusion lipase, trypsin and bilirubin outputs did not significantly increase in response to MSF. Jejunal feeding, however, significantly (p<0.01) increased the outputs of bilirubin and enzymes equally during both the placebo and PYY infusions. Conclusions. Infusion of PYY to physiological plasma levels exerts an inhibitory effect on pancreatico-biliary secretion during the cephalic phase of digestion, but not in the basal state or during the intestinal phase. PYY suppresses pancreatico-biliary secretion during the cephalic phase but not during the intestinal phase of nutrient digestion.

Modulation of small intestinal nitric oxide synthase by gum arabic.

Preceding studies have revealed that gum arabic (GA), a natural proteoglycan (>/= 250,000 Da), has proabsorptive properties-as shown by increased sodium and water absorption-in normal rats, and especially in two animal models of diarrhea. Because nitric oxide (NO) metabolism is linked to gastrointestinal physiology, the goals of this study were to determine whether GA modulated NO and to determine intestinal function in vivo when NO production was enhanced by l-arginine (Arg), added at either 1 or 20 mM. Mechanistically, the goal was also to determine whether GA was a NO scavenger and a small intestinal NO synthase (NOS) inhibitor. Using a glucose-electrolyte solution in rat jejunal perfusions we found that GA at +/-10 microM (2.5 g/l) decreased nitrite and nitrate formation, tending to normalize water, sodium, and glucose absorption when modified by Arg addition. In vitro tests, with oxyhemoglobin as a marker, showed that GA at >/= 5 microM scavenged NO. For GA effects on NOS, small intestinal homogenate supernatants (10,000 g) from frozen tissues of either adult or 2-day-old rats were incubated for 1 hour at 37 degrees C in the presence of 2 mM Arg and increasing GA concentrations (0-100 microM). GA produced a concentration-dependent inhibition of NOS, reaching approximately 31% inhibition with 5 microM GA and up to 51% with 50 microM GA. GA at 100 microM produced no further inhibition. The data indicate that GA, in addition to its ability to remove NO diffused into the intestinal lumen, may also partially inhibit intestinal NOS and thus modulate intestinal absorption through these mechanisms. Use of GA as a food additive may help in restoring or improving small intestinal function in conditions where functional damage has occurred.

St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism*1

Objective Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans. Methods Jejunal single-pass perfusion experiments with 120-mg/L (244 μmol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4–formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively. Results St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration–time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P < .0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P < .0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P < .01) and 63% (P < .0001), respectively. Conclusions Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers. Clinical Pharmacology & Therapeutics (2004) 75, 298–309; doi:10.1016/j.clpt.2003.12.012

Proabsorptive effect of gum arabic in isotonic solutions orally administered to rats: effect on zinc and other solutes

We have previously shown that the addition of gum arabic (GA) to oral rehydration solution (ORS) enhances water and electrolyte absorption during jejunal perfusion in rats under anesthesia. This study investigates whether GA by oral administration could be equally effective in rats. Isotonic solutions containing 25 g/L GA (A G), or without GA (A 0) were administered via oral tube to lightly anesthetized adult female rats. Similar experiments were conducted with hypertonic solutions containing no GA (B 0), or either 10 (B 10) or 50 g/L GA (B 50). Blood concentrations of sodium, glucose, glutamate, zinc, and tritiated water were determined at 0, 15, 30, 60, 90, 120, and 180 minutes, and results between treatments were compared. Administration of the isotonic, GA-containing solution (A G) resulted in a higher blood zinc level than with the isotonic GA-free solution (A 0) from 15 minutes throughout 180 minutes. Blood zinc at 15 minutes (means ± SEM) was as follows: for A 0: 69.3 ± 2.0, for A G: 83.4 ± 3.5 nmol/L, P= 0.002. At 180 minutes, A 0: 52.6 ± 1.8; A G: 68.1 ± 4.6 nmol/L, P= 0.004. The corresponding areas under the curve (AUC) were as follows: for A 0: 10,737 ± 214; for A G: 13,919 ± 765 nmol × min/L, P< 0.001). Glucose, glutamate, sodium, and tritiated water body distribution presented no differences in blood concentrations. For sodium and tritiated water body distribution, there was a significant time effect ( P< 0.0001). In hypertonic solutions, blood zinc levels declined over time, possibly due to their osmotic, counter-absorptive action, thus obscuring possible opposite effects of GA. GA appears to be an effective enhancer of zinc absorption when orally administered in isotonic solutions to laboratory animals. This proabsorptive capacity could be attributed to some of the physicochemical and biochemical properties of GA and suggest possible applications of GA in liquid formulas and solid food preparations.