Vasoactive intestinal peptide and calcitonin gene-related peptide levels and hemodynamics during human liver transplantation.
Explore the source record for details and available documents.
Blood Pressure↗
Biomedical subjects
A Shulkes
Publications and source records attributed to A Shulkes.
Achlorhydria induced changes in gastrin, somatostatin, H+/K(+)-ATPase and carbonic anhydrase in the sheep.
Gastrin, somatostatin, H+/K(+)-ATPase and carbonic anhydrase are principal elements of acid secretion. We investigated in the conscious sheep the effect of 24 h omeprazole (an H+/K(+)-ATPase inhibitor) infusion on these elements at the level of synthesis, storage and secretion. Omeprazole inhibited acid secretion-pH increased from 3.0 to 7.1 at 24 h. Plasma amidated and glycine extended gastrin increased 3-fold while the ratio of amidated to glycine extended gastrins (4:1) remained unchanged. Despite the increase in circulating gastrin, antral gastrin concentration and mRNA did not change significantly. Gastrin-17 (amidated and glycine extended) was the predominant form in the circulation and antrum, although there were preferential increases in larger forms following omeprazole treatment. Omeprazole had no effect on somatostatin mRNA or peptide levels in the fundus. Similarly, plasma somatostatin remained unchanged. However, antral somatostatin increased significantly (63%) following omeprazole treatment accompanied by a 4-fold increase in its mRNA. Fundic H+/K(+)-ATPase mRNA was unchanged but a significant increase (87%) in carbonic anhydrase II mRNA was observed. Omeprazole induced hypergastrinaemia occurred without a measurable reduction in storage or increased synthesis of gastrin at 24 h. Increased antral somatostatin synthesis and storage may result from stimulation by plasma gastrin on antral D cells, independent of acid. The rise in carbonic anhydrase II mRNA in the absence of any change in H+/K(+)-ATPase mRNA may reflect the differential sensitivity of the genes encoding these two enzymes to the stimulatory action of gastrin.
Achlorhydria↗
Pharmacokinetics and organ specific metabolism of glycine-extended and amidated gastrin in sheep.
Glycine (Gly)-extended gastrin has been described as the inactive precursor form of the biologically active amidated gastrin. The ratio of Gly-extended to amidated gastrin is higher in the circulation than in tissue, suggesting either differential secretion and/or metabolism. Although the distribution of the precursor form is similar in tissue and circulation to its amidated product, the significance of measurable levels of precursor peptide in the circulation is unknown. In this study, we have examined the pharmacokinetic properties and organ-specific metabolism of both the Gly-extended and the amidated forms of gastrin-17 (G-17-Gly and G-17-amide) in the conscious sheep. The metabolic clearance rate, half disappearance time, and production rates were similar for both G-17-Gly and G-17-amide. G-17-Gly was extracted across the head, kidney, and lung but not across the gut and liver. Similarly, G-17-amide was extracted across the head, gut, lung, and kidney but not across the liver. G-17-Gly had no biological activity as evidenced by its failure to stimulate somatostatin secretion nor was there any measurable conversion to amidated gastrin in the circulation. We conclude that the presence of G-17-Gly in the circulation is not the result of a slower clearance and that circulating G-17-Gly is not a precursor for circulating gastrin-amide. The results of this study provide important baseline data for understanding the dynamics of the precursor product relationship between G-Gly and G-amide.
Amino Acid Sequence↗
Ontogeny of gastrin, somatostatin, and the H+/K(+)-ATPase in the ovine fetus.
In the term human and ovine fetus, plasma gastrin is elevated, but gastric acid secretion is below adult levels, suggesting a developmentally related immaturity in gastrin and gastric acid regulation. This study investigated a number of elements of the gastric acid regulatory system: gastrin and its glycine-extended precursor, somatostatin, and the H+/K(+)-ATPase. Measurements were made in blood, antrum, and fundus of the ovine fetus during the last half of gestation, of 15-day-old lambs, and of adult sheep at the level of mRNA synthesis, tissue storage, and secretion. Plasma amidated gastrin (gastrin-amide) was elevated at or above adult values from 125 days (term is 145 days) and steadily increased with development, peaking in the lamb. Similar changes occurred with plasma glycine-extended gastrin (gastrin-gly). The peak concentration of antral gastrin-amide was present in the lamb, while the maximum antral gastrin-gly level occurred 1 week before birth. Gastrin mRNA paralleled the changes in antral gastrin-gly. The proportion of higher mol wt species of gastrin decreased during gestation in both plasma and antrum. Low amounts of mRNA for the H+/K(+)-ATPase was present from at least 120 days of gestation and antedated gastric acid secretion. However, there was a 3-fold increase in H+/K(+)-ATPase mRNA from the 140-day-old fetus to the lamb, the period when the greatest reduction in gastric pH occurred (pH 5 to 2). Antral and fundic somatostatin increased rapidly in the fetus at 120 days gestation and were above adult values at term and in the lamb. Somatostatin mRNA changed in parallel to somatostatin peptide. Somatostatin-14 was the major species in antrum and fundus throughout development. The increase in circulating and antral gastrin-amide after birth may be the result of increased amidation of gastrin-gly as well as increased expression of gastrin mRNA. Amidation of gastrin may be a regulatory step in the production of biologically active gastrin during development. The major increase in gastrin and the H+/K(+)-ATPase that occurs in the week before and after gestation correlated with the onset of increased gastric acidity.
Adenosine Triphosphatases↗
Cysteamine can induce duodenal ulceration in rats without depletion of immunoreactive somatostatin.
Single subcutaneous administration of cysteamine (2-aminoethanethiol, CSH) produces duodenal ulceration in rats within 24 h. Depletion of circulating and tissue somatostatin (SOM), hypergastrinemia and gastric acid hypersecretion have all been postulated as the pathophysiological response to CSH leading to ulceration. The purpose of this study was to analyze the synthesis, storage and secretion of gastrin and SOM as well as structural changes in SOM peptide after CSH treatment. Injection of 300 mg/kg (s.c.) of CSH caused macroscopic duodenal ulcers in seven out of eight rats at 24 h. Hypergastrinemia was seen within 30 min (from 23 +/- 4 to 74 +/- 20 pmol/l), and persisted for 4 h. Antral gastrin content was elevated at 30 min (2539 +/- 114 pmol/g) when compared to saline controls (1589 +/- 101 pmol/g). Plasma SOM did not change over the 24 h but antral SOM increased at 30 min (from 120 +/- 3 to 230 +/- 23 pmol/g) and remained elevated at 2 h (374 +/- 48 pmol/g) and 4 h (357 +/- 37 pmol/g). Fundic and duodenal SOM followed a similar pattern. Antral SOM mRNA was also elevated over the first 4 h (3-fold increase, P less than 0.05). HPLC analysis of antral tissue extracts revealed the presence of additional molecular forms of SOM which, however, differed from the major products of in vitro reduction with either CSH or dithiothreitol. Thus, the in vivo effect of CSH on SOM cannot be solely explained by a reductive opening of the disulphide bond. These results suggest that duodenal ulceration in rats treated with CSH is not related in a simple fashion to depletion of immunoreactive SOM. Early induction of hypergastrinemia may be important in the onset of ulceration. The value of CSH as a SOM depleting tool in gastrointestinal tissue must remain in doubt.
Animals↗
Production of calcitonin gene related peptide, calcitonin and PTH-related protein by a prostatic adenocarcinoma.
PTH and calcitonin are the two major hormones controlling calcium metabolism. Recently two new substances related to these hormones have been isolated: calcitonin gene related peptide (CGRP) and PTH-related protein (PTHrP). CGRP is a potent vasodilator and stimulant of intestinal secretion while PTHrP is probably the agent responsible for humoral hypercalcaemia of malignancy. We report here a patient with a prostatic tumour presenting with vasodilation, diarrhoea and hypercalcaemia. Our investigations revealed that the primary prostatic and liver secondary tumour contained CGRP, calcitonin and PTHrP. Most of the immunoreactive CGRP in the tumour and plasma co-eluted with the biologically active form of CGRP. The circulating levels of CGRP correlated with the presence of the diarrhoea. PTHrP concentration in the tumours was one of the highest reported for any tumour although previous studies may have utilized less than optimal extraction procedures. The somatostatin analogue, octreotide (SMS 201-995), did not reduce the plasma CGRP or the diarrhoea, a finding similar to that seen in patients with medullary thyroid carcinoma and high plasma CGRP. The hypercalcaemia was also unaffected by octreotide administration. This is the first report of a prostatic tumour associated with over-production of calcitonin, PTHrP and CGRP. The major life-threatening effects of this unusual case of prostatic carcinoma were diarrhoea and hypercalcaemia. Both these effects could be tentatively ascribed to newly discovered substances, CGRP and PTHrP. With the greater availability of assays to measure CGRP and PTHrP in plasma, a detailed examination of the incidence of over-production of these substances in various cancers will be possible.
Adenocarcinoma↗
Evidence against the involvement of vasoactive intestinal peptide in ovine parotid secretion and blood flow.
1. The proposition that stimulation of the secretomotor nerve to the ovine parotid gland might involve co-release of vasoactive intestinal peptide (VIP) was tested by studying responses to infusion of VIP directly into the gland's arterial blood supply and by assay of VIP in parotid venous blood. 2. In unstimulated glands, an arterial blood concentration of 1.5 - 2.5 X 10(-9) mol/L VIP did not evoke fluid secretion but it increased K+ and phosphate secretion and glandular blood flow. The same blood concentration of VIP potentiated the stimulation of salivary flow rate caused by intraarterial infusion of bethanechol but nerve stimulation was not potentiated. VIP increased glandular blood flow in both conditions of stimulation. 3. Atropine blocked neurally stimulated salivary secretion but an increase in glandular blood flow was still detectable. There was therefore no evidence for a non-cholinergic neural mechanism for salivary secretion. 4. Furthermore, VIP concentrations in glandular venous blood were not increased by nerve stimulation. 5. The results indicate that exogenous VIP can affect the flow and composition of ovine parotid secretion but was not involved in the response to secretomotor nerve stimulation.
Animals↗
Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms.
The regulation of gastric somatostatin is linked to changes in gastric acidity, with a number of studies showing a good correlation between somatostatin secretion and gastrin-stimulated luminal acidity. However, gastrin may also have direct effects on somatostatin secretion independent of the concurrent acid status. We have examined the relative contribution of gastrin itself vs. gastric acid on the increase in somatostatin secretion observed after gastrin administration. Pentagastrin administered to conscious sheep for 2 h caused a 10- to 12-fold increase in both portal venous and peripheral jugular venous plasma somatostatin levels. This was associated with a decrease in gastric pH from 3.5 to 1.7. When the sheep were pretreated with the proton pump inhibitor omeprazole to prevent any change in gastric acidity, pentagastrin caused a similar increase in plasma somatostatin. The increase in somatostatin could also be produced by gastrin-17 infusions. Thus, these studies demonstrate that in the conscious animal gastrin can stimulate somatostatin independent of changes in gastric acidity. It is proposed that there is a negative feedback between somatostatin and gastrin, which may modulate the acid secretory response to gastrin.
Animals↗
Ontogeny of neurotensin in the fetal sheep.
Neurotensin (NT) is a regulatory peptide involved in the control of gastrointestinal function. We have used the chronically cannulated ovine fetus to examine the ontogeny of circulating NT-like immunoreactivity (NTLI) in the fetus and neonatal lamb. In addition the placental transfer and clearance of NT has been determined. NTLI in the ovine fetus circulates at adult concentrations during the third trimester of pregnancy and is of fetal origin. NTLI is present in the fetal ileum, the richest source of NT, at adult concentrations and in the same molecular profile as in the adult. There is a transient increase in circulating NTLI at birth, and a small NT response to feeding in the lamb. While fetal concentrations of plasma NTLI are generally the same as in the adult and originate from the fetus, the fetus clears infused NT(1-13) twice as rapidly as the nonpregnant adult indicating a higher fetal production of NT. Thus it appears that the mechanisms involved in the production and processing of NT are mature some weeks before birth.
Animals↗
Regional brain concentrations of calcitonin gene-related peptide in spontaneously hypertensive and normotensive Wistar-Kyoto rats.
The regional brain and spinal cord concentrations of calcitonin gene-related peptide (CGRP) were measured in age-matched (22-23-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The highest concentration of CGRP in the WKY rats was in the spinal cord (172 +/- 9 pmol/g), followed by the medulla oblongata/pons (88 +/- 5 pmol/g). The relative order of distribution in the remaining regions was: hypothalamus (12.6 +/- 0.8 pmol/g) = striatum greater than thalamus greater than midbrain = hippocampus greater than cortex (2.1 +/- 0.3 pmol/g). The concentration of CGRP in the cerebellum was at the level of the assay's sensitivity (0.5 pmol/g). The relative order of distribution in the SHR strain was essentially the same. However, in comparison with the WKY rats, the SHR had significantly lower levels of CGRP in the hippocampus (-47%), striatum (-49%) and medulla oblongata/pons (-24%), and in the spinal cord (-24%). In younger age-matched (16-17-week-old) rats, the spinal cord and medulla oblongata/pons concentrations of CGRP were also lower in SHR than in WKY rats. CGRP is a putative neurotransmitter which, when administered centrally or peripherally, has potent cardiovascular effects. The reduced levels of this peptide may be an important factor in the cardiovascular and/or behavioural abnormalities of the SHR strain.
Animals↗
Calcitonin gene related peptide: vasodilator in ovine hepatic and renal vasculature.
1. Calcitonin gene-related peptide (CGRP) is a product of alternate splicing of the calcitonin gene. It is found in nerves in the vasculature and is known from in vitro studies to be a potent vasodilator. It is found abnormally in the circulation of patients with medullary thyroid carcinoma (MTC) and has been proposed to be a cause of symptoms. This study was designed to determine the dose-response effects of CGRP infusion in the intact conscious sheep on blood flow to liver and kidney, organs known to be richly innervated by CGRP-containing nerves. 2. Blood flow was measured by an indicator dilution technique using [131I]-labelled iodohippurate. CGRP infusion at both 1 and 5 pmol/kg per min produced significant (P less than 0.05) increases in both renal and hepatic blood flow. This increase in flow occurred despite a significant fall in perfusion pressure (P less than 0.05) at the higher infusion rate. At the highest infusion rate of 10 pmol/kg per min, when fall in perfusion pressure was even more marked, renal and hepatic blood flow was maintained. 3. We conclude that CGRP is vasodilatory in the renal and hepatic vascular beds and propose that nerves containing CGRP in those vessels may have a role in maintaining blood flow to those organs.
Animals↗
Gastrointestinal hormones: from basic science to a clinical perspective.
The gastrointestinal tract is the largest endocrine organ in the body. However, gastrointestinal hormones are not confined to the gut and many of them are delivered to their target tissue by neural and paracrine routes as well as the circulation. Regulatory peptide is therefore a more appropriate term than gastrointestinal hormone. The functions of these regulatory peptides include effects on intake, digestion and absorption of food, and changes in gut secretions, motility and growth. Since these peptides do not act alone but in concert it has been difficult to ascribe particular functions to individual peptides. However, the recent and on-going development of specific regulatory peptide agonists and antagonists has resulted in major advances in our understanding of the physiology of these peptides. In turn these findings are creating new therapeutic avenues providing some return from all the research on these gastrointestinal regulatory peptides. The somatostatin derivative (octreotide or sandostatin) is the most obvious example. Although only approved in Australia for treatment of carcinoids and VIPomas, the prospects include treatment of other gastroenteropancreatic tumours, acromegaly, idiopathic diarrhoea, fistula closure, dumping, and ERCP or post-operative pancreatitis. A new gastrokinetic agent, that acts via the motilin receptor, is undergoing trials for the treatment of impaired gastric emptying. The trophic effect of gastrointestinal peptides has clinical significance. For instance, gastrin antagonists inhibit cell proliferation of colon carcinoma cell lines. Furthermore the trophic effect of gastrin must be considered when potent gastric acid inhibitors, which cause a reflex increase in gastrin, are used. The outlook is for more mammalian regulatory peptides to be discovered adding further to the complexity.(ABSTRACT TRUNCATED AT 250 WORDS)
Gastrointestinal Hormones↗
Metabolism of neurotensin by isolated perfused rat kidney.
Studies in humans and conscious animals have established that the kidney is a key organ involved in the clearance of the brain-gut peptide neurotensin (NT). However, these in vivo studies cannot determine the mechanisms involved in the renal elimination of NT. We have therefore used the isolated perfused rat kidney preparation, which enables renal elimination to be studied in isolation from other organs. NT was measured with both COOH-terminal (biologically active end) and NH2-terminal (biologically active end) directed antisera. NT was stable in control perfusions (no kidney) with a disappearance half-life of greater than 250 min. The disappearance half-life in filtering kidneys was 52 +/- 3 min (COOH terminal) and 67 +/- 3 min (NH2-terminal). High-performance liquid chromatography of perfusate revealed a pattern similar to that seen in vivo with the NT being metabolized to NH2-terminal fragments. When the kidneys were rendered nonfiltering, NH2-terminal clearance was abolished, whereas COOH-terminal clearance was reduced by 75%. There was no release of NT peptidases into the perfusate. These data demonstrate that NT is metabolized directly by the kidney, predominantly by a filtration and reabsorption mechanism and with only a minor role for peritubular metabolism.
Animals↗
Expression of neurotensin in endocrine tumors.
Endocrine tumors are useful sources for determining the synthesis and metabolism of secreted regulatory peptides. The present study was performed to compare the synthesis and metabolism of neurotensin (NT) in normal subjects and four patients with NT-producing tumors. NT mRNA was measured and characterized using oligonucleotide probes and Northern blots, while NT-like peptides were quantitated by RIA with region-specific antisera and high pressure liquid chromatography. Northern blot analysis of mRNA isolated from normal human ileum revealed two species of mRNA hybridizing to a heterologous canine oligonucleotide probe; the apparent sizes of the mRNA were 1.4 and 1.0 kilobases. An identical pattern was found in a pancreatic endocrine tumor, a prostatic adenocarcinoma, and a fibrolamellar hepatoma. The ratio of mRNA to peptide varied between the different tissues. For instance, the hepatoma was the richest source of NT mRNA, but the prostatic tumor contained the highest peptide concentration. Measurements with region-specific antisera showed that N-terminal immunoreactive fragments were more abundant than C-terminal fragments in pancreatic, prostatic, and carcinoid tumors (N/C-teminal ratios, 4.0, 1.6, and 5.0) and in equal concentrations in normal ileum. Reverse phase high pressure liquid chromatography revealed the presence of intact NT in addition to a variable number of smaller N-terminal peptides, presumed to be metabolites. In contrast the hepatoma contained a 5-fold excess of C-terminal immunoreactivity. The excess C-terminal immunoreactivity was also present in the circulation of this patient. The chromatographic properties, immunoreactivity, and unusual stability of the C-terminal fragment found in the hepatoma patient suggest that it is a substance distinct from NT itself and is released specifically by the fibrolamellar hepatoma.
Animals↗
Strain differences in central nervous system concentrations of cholecystokinin between normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats.
The regional brain and spinal cord concentrations of cholecystokinin-octapeptide (CCK-8) were measured in age-matched normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The relative order of distribution of CCK-8 in the WKY strain was hippocampus (20.5 +/- 1.3 pmol/g) greater than cortex greater than striatum = hypothalamus greater than midbrain = thalamus greater than spinal cord greater than medulla oblongata/pons (MO/P, 1.6 +/- 0.2 pmol/g) whereas in the SH strain this order was hippocampus (12.9 +/- 0.8 pmol/g) greater than cortex = striatum greater than hypothalamus greater than midbrain greater than thalamus = spinal cord greater than MO/P (1.4 +/- 0.2 pmol/g). The concentrations of CCK-8 in the cerebellum were at the level of assay sensitivity (0.5 pmol/g in both strains). In comparison to the WKY rats, the SH strain had significantly lower levels of CCK-8 in the hippocampus (-37%), cortex (-28%), spinal cord (-23%) and pituitary (-57%). The lowered levels of CCK-8 in the brain of the SH rat may be causally related to, or result from, the cardiovascular, behavioural or morphological abnormalities of this strain.
Age Factors↗
Calcitonin gene-related peptide: enteric and cardiovascular effects in the dog.
We have measured the effects of intravenous infusion of calcitonin gene-related peptide at doses of 2.5, 10, and 50 pmol/kg.min on net jejunal water and solute fluxes and on plasma somatostatin concentrations in dogs. The hemodynamic effects and the pharmacokinetics of the peptide were also assessed. Using the triple-lumen perfusion technique in unsedated restrained animals it was shown that the highest dose of the peptide stimulated a transient net jejunal water and electrolyte secretion, and induced diarrhea in 4 of 6 animals receiving it. The peptide also induced dose-dependent tachycardia, hypotension, and increases in plasma immunoreactive somatostatin. All three doses of calcitonin gene-related peptide produced plasma immunoreactive peptide levels within the elevated range previously measured in human patients with medullary thyroid carcinoma. Calcitonin gene-related peptide may have a major role in the pathogenesis of secretory diarrhea in medullary thyroid carcinoma.
Animals↗
Regional brain concentrations of cholecystokinin in the rat: the effects of kindled and non-kindled seizures.
In an attempt to understand the neurochemical basis of kindling, this study investigated the effects on brain cholecystokinin (CCK) of amygdaloid kindled and non-kindled seizures. Thirteen brain regions were examined in rats sacrificed either 24 hr or 3 weeks after the last kindled seizure, or 24 hr after a suprathreshold stimulation-induced (non-kindled) seizure; and in sham kindled rats. There were no significant differences in CCK immunoreactivity between any of these groups. These results do not confirm a previous report of an increase in CCK in the hippocampus following amygdaloid kindling in the rat.
Animals↗
Hepatic metabolism of vasoactive intestinal polypeptide (VIP) in the rat.
Vasoactive intestinal polypeptide (VIP) is released into the portal circulation by a meal stimulus, but is rapidly cleared from plasma. Although it is known to bind to receptors on liver cells, the role of the liver in the clearance of VIP is not clearly defined. We therefore studied the disappearance of VIP in recirculating and in single pass isolated perfused rat liver (IPRL) preparations. Disappearance of added VIP was rapid in recirculating IPRL experiments with a half life of ca. 30 min. In single-pass steady-state studies in which livers were perfused at 16 ml/min for 30 min, clearance of VIP was complete (16 ml/min) at concentrations of 500 fmol/ml, but clearance fell to 3 and 1 ml/min at perfusate concentrations of 8 and 40 pmol/ml respectively. Further experiments to evaluate whether VIP was disappearing in perfusate itself demonstrated substantial metabolism of VIP in perfusate which had previously been circulated through a liver for 90 min. The products of metabolism were identical to those found in the IPRL. We conclude that VIP is rapidly cleared as it passes through the isolated perfused rat liver model with a significant proportion of clearance attributable to release of a peptidase from the liver into the perfusate.
Animals↗