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Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y(2) and P2Y(6) receptors on cardiomyocytes and release of UTP in man during myocardial infarction

Wihlborg, Anna-Karin LU ; Balogh, Johanna LU ; Wang, Lingwei LU ; Cedercrantz-Borna, Catharina LU ; Dou, Y; Joshi, BV; Lazarowski, E; Jacobson, KA; Arner, Anders LU and Erlinge, David LU (2006) In Circulation Research 98(7). p.970-976
Abstract
The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors ( a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y(2/4) agonist UTP gamma S increased contraction by 52%, similar to... (More)
The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors ( a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y(2/4) agonist UTP gamma S increased contraction by 52%, similar to beta(1)-adrenergic stimulation with isoproterenol (65%). The P2Y(6)-agonist UDP gamma S also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y(6)-blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDP beta S and the UTP gamma S-induced inotropic effect, indicating an IP3-mediated effect via P2Y(6) receptors. The P2Y(14) agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y(2) as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y(6) receptor mRNA was detected in both species and confirmed at protein level with Western blot and immunohistochemistry in man. In conclusion, UTP levels are increased in humans during myocardial infarction, giving the first evidence for UTP release in man. UTP is a cardiac inotropic factor most likely by activation of P2Y(2) receptors in man. For the first time we demonstrate inotropic effects of UDP, mediated by P2Y(6) receptors via an IP3-dependent pathway. Thus, the extracellular pyrimidines ( UTP and UDP) could be important inotropic factors involved in the development of cardiac disease. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
P2-receptors, heart, UDP, UTP, inotropy
in
Circulation Research
volume
98
issue
7
pages
970 - 976
publisher
American Heart Association
external identifiers
  • wos:000236791100017
  • pmid:16543499
  • scopus:33646159063
ISSN
0009-7330
DOI
10.1161/01.RES.0000217402.73402.cd
language
English
LU publication?
yes
id
8c5d4ff3-fe13-49b9-b940-4691175f1416 (old id 414142)
date added to LUP
2007-10-20 17:10:45
date last changed
2019-08-07 02:47:35
@article{8c5d4ff3-fe13-49b9-b940-4691175f1416,
  abstract     = {The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors ( a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y(2/4) agonist UTP gamma S increased contraction by 52%, similar to beta(1)-adrenergic stimulation with isoproterenol (65%). The P2Y(6)-agonist UDP gamma S also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y(6)-blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDP beta S and the UTP gamma S-induced inotropic effect, indicating an IP3-mediated effect via P2Y(6) receptors. The P2Y(14) agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y(2) as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y(6) receptor mRNA was detected in both species and confirmed at protein level with Western blot and immunohistochemistry in man. In conclusion, UTP levels are increased in humans during myocardial infarction, giving the first evidence for UTP release in man. UTP is a cardiac inotropic factor most likely by activation of P2Y(2) receptors in man. For the first time we demonstrate inotropic effects of UDP, mediated by P2Y(6) receptors via an IP3-dependent pathway. Thus, the extracellular pyrimidines ( UTP and UDP) could be important inotropic factors involved in the development of cardiac disease.},
  author       = {Wihlborg, Anna-Karin and Balogh, Johanna and Wang, Lingwei and Cedercrantz-Borna, Catharina and Dou, Y and Joshi, BV and Lazarowski, E and Jacobson, KA and Arner, Anders and Erlinge, David},
  issn         = {0009-7330},
  keyword      = {P2-receptors,heart,UDP,UTP,inotropy},
  language     = {eng},
  number       = {7},
  pages        = {970--976},
  publisher    = {American Heart Association},
  series       = {Circulation Research},
  title        = {Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y(2) and P2Y(6) receptors on cardiomyocytes and release of UTP in man during myocardial infarction},
  url          = {http://dx.doi.org/10.1161/01.RES.0000217402.73402.cd},
  volume       = {98},
  year         = {2006},
}