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Important role of P2Y receptors for islet blood flow regulation in anesthetized rats during acute and chronic hyperglycemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Per-Ola Carlsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Pancreatic islet blood flow is regulated through a complex interplay between nervous, metabolic and local endothelial factors. We have previously shown that adenosine is an important vasodilator in the metabolic regulation of islet blood flow and now wanted to examine whether also ATP/ADP/AMP could affect islet blood perfusion through P2Y receptors. To achieve this we examined local blood flow values in normoglycemic and acutely hyperglycemic Sprague-Dawley rats as well as GK rats, a type 2 diabetes model. We inhibited P2Y receptors in general with suramine and, since P2Y13 receptors are known to inhibit insulin secretion, we also examined the effects of a selective P2Y13 receptor inhibitor, viz. MRS2211. We found that all GK rats were hyperglycemic and hypertensive when compared to SD rats. Basal islet blood flow in SD rats was decreased by MRS2211, and there was a trend for this to occur also after suramine administration. The glucose-induced islet blood flow increase in SD rats was impaired after suramine and MRS2211 treatment. GK rats had higher islet blood flow, but not islet vascular conductance, than SD rats, which did not react to acute hyperglycemia or the P2Y receptor inhibitors. Similar findings were made in an islet arteriole perfusion model, suggesting that local P2Y receptors are involved. A surprising finding was that especially suramine markedly increased colonic blood flow in SD rats, and decreased this blood flow in GK rats. We conclude that not only adenosine, but also also ATP and especially ADP stimulate both basal and glucose-stimulated islet blood flow in anesthetized SD rats, but this response is not seen in GK rats. Also colonic blood flow seems to be sensitive to P2Y receptors and increase its blood flow when these receptors are inhibited. The mechanisms behind this are unknown.

Keyword [en]
Pancreatic islets, Islet blood flow, Islet arterioles, Colonic blood flow, P2Y receptors
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-230768OAI: oai:DiVA.org:uu-230768DiVA: diva2:741732
Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2015-01-22
In thesis
1. Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli
Open this publication in new window or tab >>Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Local control of regional blood flow is exerted mainly through the arterioles. An adequate minute-to-minute regulation of blood perfusion of the kidney and the pancreas is obtained by the modulation of arteriolar reactivity, which will influence the organ function. The importance of purinergic signaling in this concept has been addressed, with special emphasis on the role of the adenosine A1 receptor. The effects of adenosine on two specialized vascular beds, namely the renal glomerulus and the pancreatic islets, have been examined. Characteristic for these regional circulations is their very high basal blood flow, but with somewhat different responses to vasoconstrictor and vasodilator stimuli. By adapting a unique microperfusion technique it was possible to separately perfuse isolated single mouse arterioles with attached glomeruli or pancreatic islets ex vivo. Microvascular responses were investigated following different additions to the perfusion fluid to directly examine the degree of dilation or constriction of the arterioles. This has been performed on transgenic animals in this thesis, e.g. A1 receptor knockout mice. Also effects of P2Y receptors on islet arterioles were examined in both normoglycemic and type 2 diabetic rats. Furthermore, interference with adenosine transport in glomerular arterioles were examined.. Our studies demonstrate important, yet complex, effects of adenosine and nucleotide signaling on renal and islet microvascular function, which in turn may influence both cardiovascular and metabolic regulations. They highlight the need for further studies of other purinergic receptors in this context, studies that are at currently being investigated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1024
Keyword
afferent arteriole, islet arteriole, adenosine, A1 receptor, ATP, P2Y receptor, microperfusion, angiotensin II, type 2 diabetes, hypertension, oxidative stress, nitric oxide, tubuloglomerular feedback
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-230770 (URN)978-91-554-9018-8 (ISBN)
Public defence
2014-10-16, C2: 301, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Supervisors
Available from: 2014-09-24 Created: 2014-08-28 Last updated: 2015-01-22

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Gao, XiangSandberg, MonicaBodin, BirgittaPersson, A. Erik G.Jansson, Leif

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