Mechanisms underlying uridine adenosine tetraphosphate-induced vascular contraction in mouse aorta: Role of thromboxane and purinergic receptors.
Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COXs). We and others demonstrated that activation of A1 or A3 adenosine receptors (ARs) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10(-9)-10(-5)M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3μM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3AR through an endothelium-dependent mechanism.
Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, WV, USA.
Zhichao
Z
Zhou
Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, WV, USA.
Changyan
C
Sun
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Stephen L
SL
Tilley
Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, WV, USA. Electronic address: sjmustafa@hsc.wvu.edu.
S Jamal
SJ
Mustafa
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058913:Purinergic Agonists / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism; D058474:Receptors, Purinergic P2X1 / Q000187:drug effects* / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013928:Thromboxane A2 / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D015226:Dinucleoside Phosphates; D058913:Purinergic Agonists; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D058474:Receptors, Purinergic P2X1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; C529314:uridine adenosine tetraphosphate; D013929:Thromboxane B2; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase
Endothelium; Mouse aorta; P2X(1); Thromboxane; Up(4)A; Vasoconstriction