Abstract
Cocaine- and amphetamine-regulated transcript (CART) is a neurotransmitter and hormone, involved in the regulation of e.g. food intake, body weight, reward and addiction, and stress response. CART has also been found to affect insulin secretion and beta cell morphology, both in vivo and in vitro. Furthermore, CART affects regulation of the cardiovascular system and helps to modulate vascular tone. The present study evaluated the local effect of CART on the pancreatic and islet circulation and function. CART (25 μg/h) or saline, combinations of CART and endothelin-A receptor antagonist (BQ123; 100 μg/kg), and glucose (2 g/kg) were intravenously infused in Sprague Dawley rats followed by blood flow measurements using a microsphere technique. Separately, CART-infused animals underwent an intravenous glucose tolerance test (ivGTT). The direct effect of CART on insulin release was investigated using isolated islets from Sprague Dawley rats. CART reduced islet blood flow, without reduction in total pancreatic blood flow. The normal glucose-induced islet blood flow increase was diminished by CART, albeit still present. Simultaneously, CART had no effect on systemic-, intestinal- or renal blood flow. The endothelin-A receptor antagonist BQ123 together with CART had no pancreatic vascular effects. We found that CART has pronounced vascular constrictive actions restricted to the pancreatic islet circulation but had no effect on insulin release neither in vivo nor in vitro. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels.
Highlights
Cocaine and amphetamine regulated transcript (CART) is a peptide transcribed from the CARTPT gene, which is widely expressed in the central- and peripheral nervous system, as well as in the endocrine cells in the pituitary [1], adrenal medulla [1], antral gastrin producing G-cells in the stomach [2], and in pancreatic islets and neural tissue of the endocrine pancreas [3]
The pancreatic blood flow (PBF) was similar in the control and CART group with or without simultaneous glucose administration, (Fig. 1a) and the addition of BQ123 had no effect on the PBF (Fig. 1b)
islet blood flow (IBF) was markedly decreased by CART infusion (Fig. 1c) and the increase in IBF normally induced by glucose was partly prevented by CART (Fig. 1d-e)
Summary
Cocaine and amphetamine regulated transcript (CART) is a peptide transcribed from the CARTPT gene, which is widely expressed in the central- and peripheral nervous system, as well as in the endocrine cells in the pituitary [1], adrenal medulla [1], antral gastrin producing G-cells in the stomach [2], and in pancreatic islets and neural tissue of the endocrine pancreas [3]. CART is expressed both by islet endocrine cells and by parasympathetic and sensory nerves innervating the islets This suggests that CART may interact in the parasympathetic control of islet function, in the regulation of insulin secretion and in the stimulation of pancreatic exocrine secretion [3,8,9]. In humans CART has been found to be Abbreviations: ANOVA, Analysis of variance; BQ–123, Selective ETAendothelin receptor antagonist; cAMP, cyclic adenosine monophosphate; CART, Cocaine and amphetamine regulated transcript; CNS, Central nervous system; ELISA, Enzyme Linked ImmunoSorbent Assay; ET-1, Endothelin-1; ETA, Endotelin-1 receptor type A; ETB, Endotelin-1 receptor type B; GLP-1, Glucagon-like peptide-1; GSIS, Glucose stimulated insulin secretion; HEPES, Hydroxyethyl-piperzine-ethanesulfonic acid; ivGT, Tintravenous Glucose Tolerance Test; IBF, Islet Blood Flow; K2 EDTA, Di-Potassium Ethylenediaminetetraacetic acid; KO, Knock Out; KRBHKrebs, Ringer Bicarbonate Buffer; NO, Nitric Oxide; PBF, Pancreatic Blood Flow; PK, Aprotein kinase A; SEM, Standard error of the mean
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