Uridine adenosine tetraphosphate is a novel vasodilator in the coronary microcirculation which acts through purinergic P1 but not P2 receptors.
Uridine adenosine tetraphosphate (Up4A) has been identified as an endothelium-derived contracting factor, which acts through purinergic P2X and P2Y receptors. Since the coronary vascular actions of Up4A are unknown, we investigated the vasoactive profile of Up4A in coronary microvessels, and studied the involvement of purinergic receptor subtypes. Studies were performed in isolated porcine coronary small arteries (diameter∼250 μm), with and without endothelial denudation, mounted on a Mulvany wire myograph. Purinergic receptor expression was assessed by real-time PCR. Up4A (10(-9)-10(-5) M) failed to induce contraction at basal tone, but produced concentration-dependent vasorelaxation in precontracted microvessels. Up4A was slightly less potent than adenosine, ATP, and ADP in producing vasorelaxation, but significantly more potent than UTP and UDP. mRNA expression of P2X(4), P2Y(1), P2Y(2), P2Y(4), P2Y(6) and A(2A), but not P2X(1), receptors was observed. Up4A-induced vasodilation was unaffected by non-selective P2 receptor antagonist PPADS, P2X(1) antagonist MRS2159, P2Y(1) antagonist MRS2179 and P2Y(6) antagonist MRS2578, but was markedly attenuated by non-selective P1 receptor antagonist 8PT and A(2A) antagonist SCH58261. Up4A-induced vasodilation was not affected by ectonucleotidase inhibitor ARL67156, suggesting that A(2A) stimulation was not the result of Up4A breakdown to adenosine. Up4A-induced vasodilation was blunted in denuded vessels; additional A(2A) receptor blockade further attenuated Up4A-induced vasodilation, suggesting that A(2A) receptor-mediated vasodilation is only partly endothelium-dependent. In conclusion, Up4A exerts a vasodilator rather than a vasoconstrictor influence in coronary microvessels, which is mediated via A(2A) receptors and is partly endothelium-dependent.
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Zhichao
Z
Zhou
Daphne
D
Merkus
Caroline
C
Cheng
Henricus J
HJ
Duckers
A H
AH
Jan Danser
Dirk J
DJ
Duncker
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008833:Microcirculation / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D015226:Dinucleoside Phosphates; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D014665:Vasodilator Agents; C529314:uridine adenosine tetraphosphate