Other studies have shown that the secretin gene is expressed in serotoninergic mesencephalic neurons during development It was shown that secretin has trophic effects on these neurons, effects that are lost in neurodegenerative disorders Additional evidence suggests that secretin can act as a neuropeptide within the CNS Sympathetic and parasympathetic nerve fibers have been shown to regulate cardiovascular function through an autonomic system Indeed, several neuropeptides are secreted in the heart 95 - 97 and may play an important role in the autonomic regulation of cardiac function as neurotransmitters or neuromodulators In this review, we discuss the role of secretin in the regulation of heart function, which acts not only a hormone, but also as a neurotransmitter or neuromodulators Generally speaking, secretin effects are mediated by activation of cAMP synthesis that is decreased during cardiac pathologies.
For example, reduced responsiveness of cardiac secretin-stimulated adenylate cyclase was observed in the spontaneous hypertensive rat heart model 99 , Similarly, in the hypertrophic rat heart model there was reduced secretin stimulated adenylate cyclase that was likely due to a decrease in the number of secretin receptors in cardiac myocytes In cats and dogs, secretin has been shown to increase cardiac output and heart rate, whereas it decreases systemic arteriolar resistance and left ventricular end-diastolic pressure, with no significant change in stroke volume , Consistent with these data regarding the role of cAMP in the modulation of secretin-induced choleresis, a study has shown that chronic administration of cAMP agonists i.
Other studies have shown that maintenance of the bile acid pool is important for bile secretion, an effect that is mediated by the function of the chloride-bicarbonate exchange AE2 Further mechanistic studies have also shown that secretin-stimulated bile secretion is mediated by the microtubule-dependent insertion of aquaporin-1 water channels AQP1 into the apical membrane of rodent cholangiocytes.
Recent studies have demonstrated that large but not small cholangiocytes lining small and large bile ducts, respectively 3 , 57 , are the anatomical sites of secretin-stimulated water and bicarbonate secretion 3 , 56 , 57 Figure 3.
Large but not small bile ducts have also been shown to express SSTR2 receptors and to respond to somatostatin with inhibition of cAMP levels, exocytosis and ductal bile secretion 56 , For example, adenosine triphosphate release and purinergic P2 receptor-mediated secretion has been demonstrated in small mouse cholangiocytes Several studies have shown that secretin-stimulated choleresis is modulated by a number of factors including gastrointestinal hormones, peptides and nerve agonists For example, somatostatin has been shown to inhibit secretin-stimulated ductal bile secretion both in vivo and in vitro by selectively interacting with SSTR2 receptors by downregulation of cAMP-dependent exocytosis While a study has shown that bombesin enhances bile flow, stimulated by infusion of acid into the duodenum by increasing secretin secretion, somatostatin inhibits bile flow produced likely by decreasing the release of secretin from the duodenal mucosa Similarly, another study has demonstrated that gamma-interferon decreases collagen content and intrahepatic ductal mass in cirrhotic mice, which was associated with inhibition of secretin-induced choleresis An inhibitory effect on secretin-stimulated choleresis has been demonstrated for the vasoactive peptide, endothelin-1 ET-1 , by interaction with ET A receptors by downregulation of cAMP levels The role of nerve fibers in the modulation of biliary secretion has been supported by additional studies as follows.
Interruption of the parasympathetic system by total vagotomy in BDL rats induces biliary apoptosis and functional damage of cholangiocytes with loss of cAMP signaling and secretin-stimulated choleresis , that was prevented by the administration of forskolin or feeding bile acids such as taurocholic acid and both ursodeoxycholic and tauroursodeoxycholic acids A recent study by Francis et al. Bile acids have also been shown to prevent biliary damage e.
For example, feeding the bile acid, taurocholic acid, to cholestatic rats prevents caffeic acid-induced biliary damage by enhanced cholangiocyte vascular endothelial growth factor VEGF expression Regarding the mechanisms of secretin-stimulated ductal secretion, a study has shown that the adenylyl cyclase isoform, AC8, is mostly expressed by large cholangiocytes that are the only cell types expressing the secretin receptors and the target of secretin choleresis 57 , Thus, this study suggests that AC8 may be a key player in the regulation secretin-induced choleresis in large bile ducts A number of sex hormones have been shown to modulate biliary functions.
Following castration in cholestatic rats, testosterone serum levels decreased prevented by the administration of testosterone , and were associated with reduced biliary proliferation and secretin-stimulated cAMP levels and bile and bicarbonate secretion Also, follicle-stimulating hormone increases biliary proliferation and secretin-stimulated cAMP-dependent bile secretion Some of the factors regulating secretin-stimulated choleresis are also summarized in Table 1.
A number of studies have suggested that the functional expression of SR may be an index of biliary growth since in models with enhanced biliary hyperplasia there is increased expression of SR and augmented response to secretin 7 , 8 , 17 , 56 , 62 - 65 , , Secretin producing cells have been identified as a specific type of enteroendocrine cell by immunohistochemistry and are located in the duodenal and jejunal mucosa 18,63,83, Chey et al also reported the presence of secretin containing cells in the gastric antral mucosa but this has not been confirmed These cells are of the open type with apical surface exposed to the intestinal luminal contents.
Ultrastructurally, they possess small dense granules of diameter nm located in the basal pole of the cell which have been identified as containing secretin by immunogold staining , Their differentiation as part of the secretory lineage and the importance of the transcription factors NeuroD in the endocrine lineage has been reviewed These studies have shown decreasing concentration of secretin from the duodenum to ileum 76, One early report identified immunoreactive secretin mRNA in the brain 82 and this has subsequently been confirmed and studied in detail by quantitative PCR and in-situ hybridization.
Both secretin and its receptor have been found in the cerebellum, amygdala, hippocampus and other areas 66, Thus secretin clearly belongs to the general family of brain — gut peptides. Figure 1. The domain structure and amino acid sequence of secretin. Individual amino acids serving to localize processing sites are shown in the domain structure.
The primary physiological stimulus for release of secretin is acidification of the duodenal lumen which brings about an increase in plasma secretion and thereby pancreatic bicarbonate secretion 7,32, In dogs, both a normal meal and infusion of acid into the duodenum brings about secretion with a duodenal pH threshold of about 4. Increased gastric acid secretion or experimental infusion of acid brings about more secretin release both by being a stronger stimulus to individual S-cells and by extending acidification further down the small intestine thereby stimulating more S-cells Inhibition of acid secretion as brought about by H2 blocker cimetidine inhibits the plasma secretin increase.
The plasma half life is about minutes In humans, either feeding a normal meal or infusing acid into the duodenum increased plasma secretin with a similar pH threshold of 4.
No significant changes occurred after intraduodenal infusion of glucose, amino acids, fat emulsion or ethanol The secretin response was also reported similar in normal subjects, patients with duodenal ulcers and after vagotomy The half life of secretin in human plasma was reported to be 4 minutes Studies in other species include the showing that luminal acid stimulates secretin release in anesthetized pigs 88 , in the perfused pig intestine 44 and in fasting rats The mechanism by which acid brings about secretin release is not fully understood but probably involves acid sensing ion channels of the Trp family present in the brush border of S-cells.
An alternative mechanism presented by Chey and colleagues based on studies in rats was for the existence of a intestinal derived secretin releasing peptide, analogous to the CCK releasing peptide concept, that was released in response to acid A secretin releasing peptide was also reported in dog pancreatic juice The existence of such a mechanism has not been further confirmed. What is currently needed is the development of a mechanism to sort and study S-cells similar to methods being used for CCK release from I-cells.
For more detailed coverage of the older literature on secretin secretion see Walsh In addition to acid, there is a considerable amount of evidence that fatty acids can stimulate secretin release in dogs 31,79, , humans 92 and rats 95 although the plasma secretin levels are usually lower than the response to acid. Oleic acid is the most common form of fat used and some studies show no response although this could be due to limits on the RIAs used. One report indicated that intraduodenal oligopeptides could also increase plasma secretin and stimulate pancreatic bicarbonate output in rats The secretin receptor has seven membrane-spanning domains and characteristics typical of a G protein-coupled receptor.
Secretin is secreted in response to one known stimulus: acidification of the duodenum, which occurs most commonly when liquified ingesta from the stomach are released into the small intestine. The principal target for secretin is the pancreas, which responds by secreting a bicarbonate-rich fluid, which flows into the first part of the intestine through the pancreatic duct.
Bicarbonate ion is a base and serves to neutralize the acid, thus preventing acid burns and establishing a pH conducive to the action of other digestive enzymes. A similar, but quantitatively less important response to secretin is elicited by bile duct cells , resulting in additional bicarbonate being dumped into the small gut. Secretin helps regulate the pH to a more neutral to basic state of the duodenum. Secretin inhibits the secretion of gastric acid when it is no longer required from the parietal cells of the stomach.
Secretin functions by stimulating the production of various digestive chemicals and enzymes that help enhance the digestion and absorption process. The bicarbonate is stimulated by the secretin hormone from the ductal cells of the pancreas. Secretin also stimulates the liver for bile production that helps in emulsifying the dietary fats in the duodenum. Alkalization of bile is also regulated by the secretin hormone. Secretion function by regulating the water homeostasis in the entire body.
Secretin plays an important role in osmoregulation which is the active regulation of the osmotic pressure of an organism's body fluids by acting on the hypothalamus, pituitary gland, and kidneys.
In concert with secretin's actions, simultaneously cholecystokinin CCK , another hormone is issued by the duodenum, that stimulates the gallbladder contraction which enables the delivery of stored bile.
Secretin hormone modulates water and transportation of electrolytes in epididymis epithelial cells, liver cholangiocytes and in pancreatic duct cells. It plays a vital role in the vasopressin-independent regulation in the kidneys for renal water reabsorption. Secretin is an important hormone for the regulation of water and other fluids in the body and often its functional activity extends beyond just the small intestine.
It activates the pancreatic enzymes which lend themselves to the absorption of the nutrients from the digested food. When the pancreas fails to respond to the activated secretin it is to be assumed that one suffers from cystic fibrosis, chronic pancreatitis, and pancreatic cancer.
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