L.J.D. O'Donnell

Effect of octreotide on mouth-to-caecum transit time in healthy subjects and in the irritable bowel syndrome

The effect of a single subcutaneous injection of octreotide (50 μg) on mouth‐to‐caecum transit time was determined in patients with the irritable bowel syndrome who complained of bowel frequency, and in healthy volunteers. The assessment of mouth‐to‐caecum transit time was performed by monitoring breath hydrogen concentration and noting a sustained 10 p.p.m. rise after ingestion of lactulose 40 ml. Measurements were performed fasting, and on a separate day, after a standard breakfast which included 40 ml lactulose. The studies were performed double‐blind in a pre‐determined random order. Octreotide prolonged mouth‐to‐caecum transit time in irritable bowel syndrome patients and healthy subjects by factors of 2.4 and 2.6 after lactulose when fasting, respectively, and by factors of 2.8 and 2.6 after the breakfast which contained lactulose. The upper gastrointestinal transit rate was similar in irritable bowel syndrome patients and healthy controls.

Indomethacin and postprandial gallbladder emptying

Patients with gallstone disease commonly have impaired gallbladder emptying. To see whether non-steroidal anti-inflammatory drugs (NSAIDs) prevent gallstone formation by improving gallbladder emptying, we assessed the effect of indomethacin on postprandial emptying in healthy subjects and in patients with gallstone disease. Subjects received indomethacin 25 mg three times a day for a week and matching placebo for another week. Compared with placebo, indomethacin improved postprandial gallbladder emptying in all 7 patients with gallstone disease. This finding was not recorded in healthy subjects with normal gallbladders. The prevention of gallstone formation associated with ingestion of NSAIDs may be due mainly to a prokinetic effect on the gallbladder since there is no evidence to suggest that these drugs affect cholesterol crystal nucleation at ordinary therapeutic doses in man or animals.

Characterization of endothelin (ET) receptors in the isolated gall bladder of the guinea‐pig: evidence for an additional ET receptor subtype

1 We have characterized the receptors mediating contractions induced by endothelin‐1 (ET‐1), ET‐2, ET‐3 and the ETB‐selective receptor agonists, sarafotoxin 6c (SX6c), IRL 1620, BQ‐3020, [Ala1,3,11,15]ET‐1 and ET (16–21) in strips of the isolated gall bladder of the guinea‐pig (GPGB). We used as antagonists BQ‐123 (ETA receptor selective) and PD 145065 (ETA/ETB receptor non‐selective). 2 ET‐1, ET‐2 and ET‐3 (10−10 M to 3 × 10−7 M) caused similar slowly‐developing concentration‐dependent contractions of the GPGB. Contractile effects induced by ET‐1, ET‐2 or ET‐3 (at 3 × 10−7 M) were also similar (230 ± 25, 241 ± 7 and 287 ± 37% of that to histamine at 5 × 10−6 M, n = 7, 6, 12, respectively). However, the threshold concentration for ET‐1 or ET‐2 was 10−1 M whereas it was 3 × 10−9 M for ET‐3. 3 SX6c (10−10 M to 3 × 10−7 M) also caused slowly‐developing concentration‐dependent contractions at a threshold concentration of 10−1 M (n = 16). However, the contraction caused by SX6c at 3 × 10−7 M was 116 ± 9% of that to histamine at 5 × 10−6 M, which was half of that induced by the same concentration of the ET isopeptides. The contraction induced by IRL 1620 at 3 × 10−7 M (n = 9) was 43 ± 9% of that to histamine at 5 × 10−6 M, which was one fifth of that produced by the same concentration of ET‐1. Contractions induced by BQ‐3020 or [Ala1,3,11,15]ET‐1 at 3 × 10−7 M were even less than those produced by IRL 1620. ET (16–21) was inactive up to 10−5 M. Addition of a concentration of 3 × 10−7 M of ET‐1 to tissues with developed contractions induced by the bolus addition of 3 × 10−7 M SX6c caused a further contraction of the GPGB to the level observed with ET‐1 alone at 3 × 10−7 M (n = 8). 4 BQ‐123 (10−5 M) did not affect the concentration‐response curve to ET‐1 and the contraction induced by 3 × 10−7 M was also not affected (n = 5; 239 ± 19% of histamine at 5 × 10−6 M). PD 145065 (10−5 M) shifted the ET‐1 concentration‐response curve to the right and the contraction induced by ET‐1 at 3 × 10−7 M was inhibited by 15% (n = 6; NS). A higher concentration of BQ‐123 (10−4 M) caused a significant shift to the right of the ET‐1 concentration‐response curve similar to that caused by PD 145065 (10−5 M) and caused a 24% (n = 6; NS) inhibition of the contractions induced by ET‐1 at 3 × 10−7 M. PD 145065 (10−4 M) abolished contractions induced by ET‐1 (up to 10−7 M) and inhibited the response to ET‐1 at 3 × 10−7 M by 52% (n = 4; P < 0.05). 5 Contractions induced by ET‐3 were more sensitive to inhibition by the antagonists. BQ‐123 (10−6, 10−5 or 10−4 M) inhibited responses to 3 × 10−7 M ET‐3 by 66, 71 and 83%, respectively (n = 5, 5, 3; P < 0.05). PD 145065 (10−6, 10−5 or 10−4 M) attenuated more strongly than did BQ‐123 the contractions induced by ET‐3. For instance, the contractions caused by ET‐3 at 3 × 10−7 M were decreased by 73 and 80% (n = 5, 5; P < 0.05) in the presence of PD 145065 (10−6 or 10−5 M, respectively). PD 145065 (10−4 M) completely abolished contractions to ET‐3 (n = 4; up to 3 × 10−7 M). 6 Contractions induced by SX6c, especially those observed at concentrations lower than 10−8 M, were attenuated by BQ‐123 (up to 10−4 M). PD 145065 (10−5 M) shifted to the right the concentration‐response curve to SX6c and inhibited by 38% (P < 0.05) the contractions induced by 3 × 10−7 M. However, the contractions induced by a bolus addition of a high concentration of SX6c (3 × 10−7 M) and the subsequent addition of an identical concentration of ET‐1 on top of SX6c were not affected by BQ‐123 (10−6 or 10−5 M). 7 These results suggest that ETB receptors are involved in the contractions induced by endothelins in the GPGB. However, SX6c and other selective ETB agonists produced only half or less than half of the contractile response induced by non‐selective agonists. In addition, the responses to ET‐1 but not to ET‐3, were insensitive to the antagonist action of BQ‐123 at 10−5 M whereas BQ‐123 or PD 145065 at 10−5 M strongly antagonized contractions induced by ET‐3. Finally, BQ‐123 at 10−4 M inhibited contractions to ET‐1 and SX6c. Thus, within the GPGB there may well be additional ET receptor(s) not conforming to the established ETA/ETB receptor subtype classification, as well as ETB receptors.

Promotion of gallbladder emptying by intravenous aminoacids

Patients receiving total intravenous nutrition have inert gallbladders; gallbladder sludge and gallstones often develop, but are preventable if gallbladder emptying can be improved. We measured the effect of giving rapid intravenous infusions of aminoacid solutions in eight normal subjects. Four regimens were tested (250 mL over 30 min, 250 mL over 10 min, 125 mL over 5 min, and 50 mL over 5 min). Gallbladder emptying, as measured by ultrasound and cholecystokinin release, depended on both the amount and the rate of aminoacid infusion. Rapid infusion of 125 mL of an aminoacid mixture (Synthamin 14 without electrolytes) over 5 min (2.1 g per min) produced a 64% reduction in gallbladder volume within 30 min, whereas a 50 mL infusion over 5 min produced only a 22% reduction. Intermittent rapid infusion of small amounts of aminoacids may prevent gallstones in patients receiving intravenous nutrition.

Differential Effect of Prostaglandins on Gallstone-Free and Gallstone-Containing Human Gallbladder

Nonsteroidal antiinflammatory drugs, inhibitors of prostaglandin synthesis, have different effects on gallbladder contractility in normal and diseased human gallbladders in vivo. We investigated this differential effect by comparing the effects of prostaglandins PGE2 and PGF2α, the thromboxane A2 mimetic U46619, and PGI2 on in vitro contractility in gallstone-free and gallstone-containing human gallbladders. Isometric tension was measured in gallbladder muscle strips mounted in organ baths. EC50 was calculated for each agonist. The rank order of potency in gallstone-free gallbladders was PGE2 > CCK > U46619 > PGF2α and in gallstone-containing gallbladders was U46619 > PGE2 > CCK > PGF2α. PGI2 produced contraction of gallstone-free gallbladder and relaxation of gallstone-containing gallbladder in the basal state. Further, PGI2 produced no relaxation in gallstone-free muscle strips precontracted with CCK, but significant relaxation in CCK precontracted gallstone-containing strips. PGE2, PGF2α, and U46619 are potent contractors of gallstone-free and gallstone-containing gallbladders, whereas PGI2 relaxes only gallstone-containing gallbladders. Since gallbladders containing cholesterol-supersaturated bile produce increased PGI2, this PGI2-induced relaxation may be a determinant of the impaired gallbladder motility of gallstone disease.

Effect of oral clarithromycin on gall-bladder motility in normal subjects and those with gall-stones.

Motilin receptor stimulation with erythromycin has been shown to have a prokinetic effect on gall‐bladder motility in human beings.

Prokinetic effect of indoramin, an α‐adrenergic antagonist, on human gall‐bladder

Background : The effects of α‐ and β‐adrenergic agents on gall‐bladder motility remain undefined.

Contractile activity of endothelin precursors in the isolated gallbladder of the guinea-pig : presence of an endothelin-converting enzyme

1 We have compared the activities of the endothelin precursors (human big ET‐1–38, porcine big ET‐l1–39, big ET‐21–38 and big ET‐31–41 amide) and their respective mature 21 amino acid peptides as contractors of isolated gallbladder strips of the guinea‐pig. We have also used different protease inhibitors and/or epithelial cell removal to investigate the nature and the location of the endothelin‐converting enzyme (ECE) activity responsible for the conversion of porcine big ET‐l1–39 in this isolated preparation. In addition, we have conducted binding studies to investigate whether porcine big ET‐l1–39 interacts directly with ET receptors.

Inhibition of 5-hydroxytryptamine re-uptake impairs human gall-bladder emptying

Background: 5‐Hydroxytryptamine (5‐HT) is an important neurotransmitter in the enteric nervous system. The intrinsic neural plexus of the gall‐bladder resembles the enteric nervous system and similarly contains 5‐HT neurones. The action of 5‐HT on gallbladder motility has been investigated in animals but its effect on the human gall‐bladder in vivo is unknown.

Endothelin Content, Expression, and Receptor Type in Normal and Diseased Human Gallbladder

The aims of this study were to characterize the endothelin (ET) system in human gallbladder by determining (1) the tissue content of ET-1 and ET-2 by ELISA; (2) the expression of mRNA of the ET precursors preproendothelin-1, -2, and -3; and (3) mRNA expression for the ETA and ETB receptors. Median content of ET-1/2 was significantly reduced in severely inflamed gallbladders compared to gallbladders with mild inflammation. There was an inverse correlation between content of ET-1/2 and inflammation score. mRNA for preproendothelin-2 was highly expressed in all samples, whereas mRNA for preproendothelin-1 was present in negligible quantities and mRNA for preproendothelin-3 was undetectable. mRNA for ETA receptors was expressed in all samples analyzed, whereas mRNA for ETB receptors was expressed at a much lower level. This study demonstrates the presence of ET-1/2 in human gallbladder. ET-1/2 content is decreased with increasing degrees of histological inflammation. ET-2 is likely to be the physiologically significant endothelin isopeptide expressed and ETA receptors appear to predominate in the human gallbladder.