Domschke S

Analysis of the Motor Effects Of 13-Norleucine Motilin on the Rabbit, Guinea Pig, Rat, and Human Alimentary Tract in Vitro

Motor effects of 13-norleucine motilin (13-Nle-M), a synthetic analog of motilin and biologically equivalent to the natural polypeptide, on the rabbit, guinea pig, rat, and human alimentary tract were investigated in vitro. Whereas guinea pig and rat preparations proved refractory to 13-Nle-M action, muscle strips of the stomach and upper small intestine from rabbits and man were highly sensitive to 13-Nle-M, contractile responses being elicited with concentrations of less than 2 times 10-minus 9 M. Although circular muscle from rabbit colon responded to 13-Nle-M, Taenia coli preparations were unaffected by the polypeptide; in man, the reverse was observed. Gallbladder, uterine, and vascular smooth muscle were unresponsive to 13-Nle-M. Pharmacological analysis revealed that the effects of 13-Nle-M on the gastrointestinal muscle are not mediated via nervous pathways: ganglion blockade by hexamethonium, blockade of axonal conduction by tetrodotoxin, or anticholinergic action by atropine failed to affect 13-Nle-M actions. It was therefore concluded that 13-Nle-M caused contractions by stimulating receptors on or in the muscle cell. By use of the antihistaminic pheniramine, histamine receptors could be differentiated from the site of 13-Nle-M action. As the contractile response to 13-Nle-M was abolished by the Ca++ antagonistic compound verapamil, a role for 13-Nle-M in the transport of Ca++ to the cytosol of intestinal smooth muscle might be considered.

Effects of Vasoactive Intestinal Peptide on Resting and Pentagastrin-Stimulated Lower Esophageal Sphincter Pressure

Vasoactive intestinal peptide (VIP) administered as an intravenous infusion at different doses (0.8, 1.6, and 3.2 micrograms per kg per hr, respectively) inhibited dose-dependently the response of the lower esophageal sphincter to an intravenous injection of pentagastrin (0.6 microgram per kg) in 4 healthy volunteers. Inhibition ranged from about 20% (not significant) with the low dose to about 55% (P less than 0.05) with the high dose. On the other hand, the VIP doses employed did not substantially decrease basal lower esophageal sphincter pressure. Calculated on the basis of plasma levels of the respective peptides, the inhibitory effect of VIP was about one-third of that of secretin. Even at the smallest dose of VIP, plasma levels of radioimmunoassayable VIP (20 to 100 pmoles per liter) markedly exceeded those encountered normally (1 to 19 pmoles per liter). So, the data presented do not support the suggestion that normally circulating VIP essentially contributes to the physiological regulation of the lower esophageal sphincter pressure; they do not exclude, however, such a role for locally released VIP.

NMR spectrometry. A new method for total stool fat quantification in chronic pancreatitis.

In the present investigation, suitability of nuclear magnetic resonance (NMR) spectrometry for total stool fat quantification in patients with normal or impaired exocrine pancreatic function (chronic pancreatitis) has been analyzed in comparison with a conventional chloroform-methanol extraction technique. Basic temperature-dependence studies of NMR spectrometry (90°/180° radiofrequency pulse sequence) on 21 chloroform-methanol extracted pure total stool lipid standards (weight range: 0.05–1.6 g) revealed significantly (P<0.05) improving correlations between NMR signal amplitudes and corresponding weights at increasing temperatures (r=0.952/40° C,r=0.965/60° C,r=0.988/80° C), thus indicating 80° C as optimal temperature for NMR spectrometric total stool fat quantification. In subsequent comparative measureemnts of lyophilized stool samples, NMR spectrometry (at 80° C) and conventional chloroform-methanol extraction provided significantly (P<0.001) correlated results with respect to total fecal fat contents/day of quantitatively collected and homogenized stools in 93 patients with known exocrine pancreatic function (secretin-pancreozymin test), irrespective of whether correlations were determined for all 93 patients (r=0.983) or separately for patients with normal (N=45;r=0.867), moderately reduced (N=31;r=0.946), or highly reduced (N=17;r=0.992) exocrine pancreatic function and correspondingly increased total fecal fat excretions.

Exocrine Pancreatic Function After Gastrectomy

We compared intraindividually the specificity of indirect pancreatic function tests before and after total (n = 4; Roux-en-Y) or subtotal (n = 6; Billroth II) gastrectomy. Before gastrectomy only 1 patient showed a falsely pathological result with the pancreolauryl test (90% specificity), while the results of all the other tests were correctly normal (100% specificity using the usual cutoff limits). After gastrectomy the respective specificities were as follows: pancreolauryl test 10%, bentiromide test 70%, fecal chymotrypsin 70%, and plasma amino acid consumption test 100%. There was no obvious difference in the reduction of specificity between subtotal and total gastrectomy. The respective preoperative to postoperative changes in the median test data were as follows: plasma amino acid consumption test +21%, bentiromide test -12%, fecal chymotrypsin -51%, and pancreolauryl test -53%. It is concluded that after gastrectomy only the plasma amino acid consumption test is unaffected by postoperative anatomic alterations.

Whipple's procedure plus intraoperative pancreatic duct occlusion for severe chronic pancreatitis: clinical, exocrine, and endocrine consequences during a 3-year follow-up.

The present investigation provides follow-up data (up to 36 months) of exocrine and endocrine pancreatic function, inflammatory activity, pain, and body weight in 23 chronic pancreatitis patients submitted to Whipples procedure plus intraoperative Ethibloc occlusion of the remaining pancreatic duct system between January 1983 and February 1984. Clinically, Whipples procedure plus intraoperative pancreatic duct occlusion resulted in almost complete and continuous cessation of pain as well as significant (p <0.05) increase in body weight. With regard to exocrine pancreatic function (Secretin-Pancreozymin test, plasma amino acid consumption test, Pankreolauryl test, fecal chymotrypsin determination), intraoperative pancreatic duct occlusion was shown to induce high-grade insufficiency and thus exocrine parenchymal atrophy in all patients. Simultaneously, the inflammatory process (represented by serum levels of trypsin, lipase, and pancreatic isoamylase) was terminated in all 23 patients. Endocrine pancreatic function, evaluated by serum levels of insulin and C-peptide measured under fasting conditions and subsequent maximal combined β-cell stimulation as well as corresponding integrated hormone releases, was reduced by partial pancreas resection by about 50%, while there was no further impairment during the 36-month follow-up period in consequence of additional intraoperative pancreatic duct occlusion. Altogether, Whipples procedure plus intraoperative Ethibloc occlusion of the residual pancreatic duct system seems suitable for termination of the inflammatory process and thus preservation of residual endocrine pancreatic function in chronic pancreatitis.

Structure-function studies on gastrointestinal hormones: I. Synthesis of secretin analogs and their biological and immunological properties

Abstract Syntheses by conventional procedures of the three analogs corresponding to the porcine secretin sequence crossed at position 6 by the N-terminal hexapeptide sequences of VIP, GIP, and glucagon are described, viz., Ala 4 ,Val 5 -, Tyr 1 ,Ala 2 ,Glu 3 -, and Gln 3 -secretin (VIP-SN, GIP-SN, and GLU-SN). The analog Phe 1 ,Phe 2 ,Trp 3 ,Lys 4 -secretin (SOMA-SN), designed on the basis of the surprising homology of the sequence portions 10–13 of somatostatin and 5–8 of secretin, was also prepared. Finally, the synthesis of N α -3-(4-hydroxyphenyl)propionyl-β-alanyl-secretin (DATA-SN), a tracer suitable for secretin radioimmunoassay and as an N-terminus modified secretin analog, is reported. The analogs are compared, in terms of their biological and immunological properties in different assay systems, with pure synthetic secretin.

Influence of the hormone analogue 13-nle-motilin and of 1-methyl-3-isobutylxanthine on tone and cyclic 3', 5'-AMP content of antral and duodenal muscles in the rabbit

Abstract 1. By the action of 1-methyl-3-isobutylxanthine (isobutyltheophylline, 2 - 3 × 10−4 M), the content of cyclic 3, 5-AMP in the antral and duodenal muscles of the rabbit is increased by 72 % and 126 %, respectively; by 1.8 × 10−7 M 13-norleucine-motilin and 1.8 × 10−6 M acetylcholine it is not changed. 13-norleucine-motilin is an analogue of the recently discovered duodenal tissue hormone motilin and has identical effects. 1-methyl-3-isobutylxanthine has a more powerful inhibiting effect on phosphodiesterase than has theophylline. 2. 3 × 10−4 M isobutyltheophylline reduces the tone of the duodenal muscle while simultaneously increasing the content of cyclic AMP and negates the tone-enhancing effect of nle-motilin on the duodenal muscle, while nle-motilin increases the muscle tone lowered by isobutyltheophylline. 3. The basic tone of the antral muscle is not reduced by isobutyltheophylline. However, the contraction-promoting effect of nle-motilin after an increase in cyclic AMP due to isobutyltheophylline is significantly lower. 4. It is assumed that the changes in the tone or in the response of the antral and duodenal muscles to nle-motilin observed after the administration of isobutyltheophylline, are due to the increase of cyclic AMP in the tissue. 5. The antagonistic effects of cyclic AMP and motilin on the gastro-intestinal muscles might be of physiological importance for the regulation of the gastro-intestinal motor activity.