title: Functional contribution of P2Y1 receptors to the control of coronary blood flow.
abstract: Activation of ADP-sensitive P2Y(1) receptors has been proposed as an integral step in the putative "nucleotide axis" regulating coronary blood flow. However, the specific mechanism(s) and overall contribution of P2Y(1) receptors to the control of coronary blood flow have not been clearly defined. Using vertically integrative studies in isolated coronary arterioles and open-chest anesthetized dogs, we examined the hypothesis that P2Y(1) receptors induce coronary vasodilation via an endothelium-dependent mechanism and contribute to coronary pressure-flow autoregulation and/or ischemic coronary vasodilation. Immunohistochemistry revealed P2Y(1) receptor expression in coronary arteriolar endothelial and vascular smooth muscle cells. The ADP analog 2-methylthio-ADP induced arteriolar dilation in vitro and in vivo that was abolished by the selective P2Y(1) antagonist MRS-2179 and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester. MRS-2179 did not alter baseline coronary flow in vivo but significantly attenuated coronary vasodilation to ATP in vitro and in vivo and the nonhydrolyzable ATP analog ATPγS in vitro. Coronary blood flow responses to alterations in coronary perfusion pressure (40-100 mmHg) or to a brief 15-s coronary artery occlusion were unaffected by MRS-2179. Our data reveal that P2Y(1) receptors are functionally expressed in the coronary circulation and that activation produces coronary vasodilation via an endothelium/nitric oxide-dependent mechanism. Although these receptors represent a critical component of purinergic coronary vasodilation, our findings indicate that P2Y(1) receptor activation is not required for coronary pressure-flow autoregulation or reactive hyperemia.
authors.affiliation: Dept. of Biomedical Sciences, Univ. of Missouri, Columbia, MO 65211, USA. benders@missouri.edu
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Berwick
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D006940:Hyperemia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058472:Receptors, Purinergic P2Y1 / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; C002480:methylthio-ADP; C022571:adenosine 5'-O-(3-thiotriphosphate); D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate