Endothelium-dependent relaxation evoked by ATP and UTP in the aorta of P2Y2-deficient mice.
Based on pharmacological criteria, we previously suggested that in the mouse aorta, endothelium-dependent relaxation by nucleotides is mediated by P2Y1 (adenosine diphosphate (ADP)), P2Y2 (adenosine triphosphate (ATP)) and P2Y6 (uridine diphosphate (UDP)) receptors. For UTP, it was unclear whether P2Y2, P2Y6 or yet another subtype was involved. Therefore, in view of the lack of selective purinergic agonists and antagonists, we used P2Y2-deficient mice to clarify the action of UTP. Thoracic aorta segments (width 2 mm) of P2Y2-deficient and wild-type (WT) mice were mounted in organ baths to measure isometric force development and intracellular calcium signalling. Relaxations evoked by ADP, UDP and acetylcholine were identical in knockout and WT mice, indicating that the receptors for these agonists function normally. P2Y2-deficient mice showed impaired ATP- and adenosine 5'[gamma-thio] triphosphate (ATPgammaS)-evoked relaxation, suggesting that in WT mice, ATP and ATPgammaS activate predominantly the P2Y2 subtype. The ATP/ATPgammaS-evoked relaxation and calcium signals in the knockout mice were partially rescued by P2Y1, as they were sensitive to 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179), a P2Y1-selective antagonist. In contrast to ATP, the UTP-evoked relaxation was not different between knockout and WT mice. Moreover, the action of UTP was not sensitive to MRS2179. Therefore, the action of UTP is probably mediated mainly by a P2Y6(like) receptor subtype. In conclusion, we demonstrated that ATP-evoked relaxation of the murine aorta is mainly mediated by P2Y2. But this P2Y2 receptor has apparently no major role in UTP-evoked relaxation. The vasodilator effect of UTP is probably mediated mainly by a P2Y6(like) receptor.
Guns
Pieter-Jan D F
PJ
Division of Pharmacology, University of Antwerp, Universiteitsplein 1 (building T2), B-2610 Wilrijk, and Laboratory of Medical Chemistry, Erasme Hospital, Belgium. pieter-jan.guns@ua.ac.be
Van Assche
Tim
T
Fransen
Paul
P
Robaye
Bernard
B
Boeynaems
Jean-Marie
JM
Bult
Hidde
H
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D014544:Uridine Triphosphate / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium; D014544:Uridine Triphosphate