Biomedical subjects
Publications and source records attributed to V Varró.
The author critically analyses the involvement of prostaglandins in peptic ulceration. Clinical evidence suggests that for the treatment of peptic ulcer other available drugs (e.g. H2-blockers) are as effective and have fewer side-effects. A potential role in prevention of drug induced gastric mucosal damage (NSAID, ASA) may be verified in further studies.
The effects of lorglumide (CR 1409), a potent cholecystokinin (CCK) receptor blocker developed recently by the Rotta Research Laboratories, were studied on pancreatic growth and enzyme composition. In secretory studies, the inhibitory effect of 4 mg/kg of lorglumide administered subcutaneously proved to last more than 3 h. The trophic effect of exogenous CCK (600 ng/kg given three times daily for 2 weeks) was significantly decreased by the simultaneous administration of 4 mg/kg of lorglumide. To study the role of endogenous CCK released by feeding while maintaining pancreatic trophism, 4 mg/kg of lorglumide was administered subcutaneously four times daily during the feeding period for 2 weeks. Lorglumide significantly decreased pancreatic weight, pancreatic content of soluble protein, trypsinogen, and chymotrypsinogen, while decreases in DNA, lipase, and amylase failed to reach statistical significance. According to our experiments, high-doses of lorglumide could inhibit not only the trophic effect of exogenous CCK but also the effect of endogenous CCK released by food and lorglumide itself.
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With the isolated jejunum loop technique investigations of prostaglandin E2 and F2 alpha were made on canine intestinal absorption and transport of glucose and on the circulation of the intestinal loop. These compounds decreased glucose absorption; intra-arterial prostaglandin administration decreased the portal transport of glucose, but intraluminal administration caused an increase. PGE2 enhanced the circulation of the intestinal loop; intra-arterial PGF2 alpha diminished this circulation, whereas on intraluminal PGF2 alpha had no significant effect.
The effect of intraarterial glucagon injection on the glycogen content of the intestinal mucosa of the dog and the rat has been investigated. In both species significant glucagon-induced reduction of mucosal glycogen contents was revealed.
In vitro experiments were carried out to examine the enzymatic activity in various organ homogenates of the dog, which inactivates the biological activity of the synthetic cholecystokinin-octapeptide (CCK-OP). The highest splitting activity was found in the renal cortex; substantially lower activities were registered in the lung, pancreas and small intestine. It seems interesting that neither the gallbladder nor the saliva and the serum contained measurable amount of the CCK-OP splitting activity. An effort was made to characterize the CCK-OP inactivating principle found in the renal cortex. It was ascertained that the CCK-OP was inactivated by a peptidase which is heat sensitive, has a pH optimum of 7,4 and could be inhibited by chelating agents (EDTA) and epsilon-aminocaproic acid. The fact that most of the enzyme function is associated with the sediment obtained at 12 000 g speaks in favour of its mitochondrial origin.
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The metabolism of labelled BOC-14 C-glycine-pentapetide was investigated in rats, both in blood and urine. We report on the following findings: --radioactivity could be measured in the blood even after the disappearance of the bioactive- and immunoreactive pentapeptide. --the bulk of the radioactivity in the blood after 8 minutes originates from a metabolite which, after subsequent systematic chemical identification, proved to be the BOC-14C-glycine fragment of the pentapeptide. --the radioactivity in the urine comes entirely from this split product of the labelled pentapeptide --the organ distribution of radioactivity of labelled pentapeptide was checked after i.v. administration; 1 minute after the injection, most of the radioactivity was found in the liver, followed by the kidney, pancreas, jejunum and lung. After 1 hour, radioactivity could be detected only in the kidneys. It was concluded that the N-terminal amino-acid of the naturally occurring pentagastrin (glycine) remains linked to the BOC protecting group in the course of the catabolism of the molecule and this fragment is excreted in the urine.
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Nine new pentagastrin analogs containing a free or protected alpha-aminooxy acid at the N-terminus were synthesized stepwise. Analogs containing leucyl, norleucyl, norvalyl, L- and D-2-aminodecanoyl residues instead of methionyl residue were also prepared. The peptides were synthesized by the active ester method with subsequent removal of the protecting groups. The purification of the end products was performed by crystallization or column chromatography on silica gel.
Twenty-seven new pentagastrin analogs containing free or protected aminooxy acids at the N-terminus and D-2-aminooxy-3-phenyl-propionic acid, L-(4-chlorophenyl)glycine, L- and D-phenylglycine, or L- or D-cyclohexyglycine instead of the C-terminal L-phenylalanine and analogs extended by aminooxyacetic acid at the C-terminus, were synthesized stepwise. The end products were purified by chromatography on DEAE-cellulose or silica gel.
The stimulation of gastric acid flow by thirty-six new pentagastrin analogs administered intravenously, intrajejunally and intrarectally was determined in rats. Some of the analogs are several times more active than the pentagastrin (Peptavlon, I.C.I.) used as control. Unlike the control, some analogs are absorbed in active form from the jejunum. The N-terminal substitution with alpha-aminooxy acids seems to increase the gastric secretory response, probably by improving the enzymatic resistance of the molecule to various enzymes. None of the analogs tested significantly inhibit the gastric acid output in rats induced by pentagastrin. Structure-activity relationships are discussed.
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Total and mucosal blood flow in the nonsecreting stomach and the interrelation between local blood flow changes and gastric hydrochloric acid secretion as influenced by various drugs or hormones were investigated in 188 anaesthetized dogs. Substances acting on gastric acid secretion (histamine, pentagastrin, atropine and metiamide) and those showing vasoactive properties (norepinephrine, epinephrine, Hypertensin, nicotinic acid and glucagon) were used. Instillation of 0.1 N HCl solution into the stomach provided a good estimate of the mucosal blood flow of the nonsecreting stomach as measured by the aminopyrine clearance technique of Jacobson et al. Simultaneous recording of the total gastric blood flow with an electromagnetic blood flowmeter revealed the distribution of blood flowing through the mucosal and non-mucosal (submucosa-muscle) tissues of the resting stomach. During acid stimulation a shift of the gastric blood flow to the mucosa was observed, which may reach even 75--80% of the total amount of the blood supply during a given period. Metiamide entirely inhibited the gastric acid secretion induced by both histamine and pentagastrin, but did not parallelly diminish mucosal blood flow. Given during histamine infusion, glucagon strongly inhibited acid secretion while it did not decrease mucosal blood flow.