Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y2 and P2Y6 receptors on cardiomyocytes and release of UTP in man during myocardial infarction.
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 UTPgammaS increased contraction by 52%, similar to beta1-adrenergic stimulation with isoproterenol (65%). The P2Y6-agonist UDPbetaS also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y6-blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDPbetaS and the UTPgammaS-induced inotropic effect, indicating an IP3-mediated effect via P2Y6 receptors. The P2Y14 agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y2 as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y6 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 P2Y2 receptors in man. For the first time we demonstrate inotropic effects of UDP, mediated by P2Y6 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.
Wihlborg
Anna-Karin
AK
Department of Cardiology, Lund University, Sweden. anna-karin.wihlborg@kard.lu.se
Balogh
Johanna
J
Wang
Lingwei
L
Borna
Catharina
C
Dou
Ying
Y
Joshi
Bhalchandra V
BV
Lazarowski
Eduardo
E
Jacobson
Kenneth A
KA
Arner
Anders
A
Erlinge
David
D
D000368:Aged; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology; D002637:Chest Pain / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D014530:Uridine Diphosphate / Q000378:metabolism*; D014544:Uridine Triphosphate / Q000378:metabolism*
D000925:Anticoagulants; D002316:Cardiotonic Agents; C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D014544:Uridine Triphosphate