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A novel mechanism of vasoregulation: ADP-induced relaxation of the porcine isolated coronary artery is mediated via adenosine release

Sarah J. Rayment^*, Vera Ralevic^*, David A. Barrett, Rebecca Cordell and Stephen P. H. Alexander^*,1

^* School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, UK; and

School of Pharmacy, University of Nottingham, University Park, Nottingham, UK

¹ Correspondence: School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK. E-mail: steve.alexander{at}nottingham.ac.uk

In this study, we have investigated the mechanism of ADP-induced relaxation of porcine coronary artery (PCA) rings. The P2Y receptor agonists ADP and ADPßS produced concentration-dependent relaxation of endothelium-denuded PCA smooth muscle with pD₂ values of 5.3 and 4.9, respectively. RT-polymerase chain reaction (RT-PCR) and immunoblotting demonstrated mRNA and protein expression of P2Y₁ and A_2A adenosine receptors in the PCA. The nonselective P2 antagonist PPADS or the P2Y₁-selective antagonist MRS2179 failed to alter ADP- or ADPßS-induced relaxations. Relaxations to ADP were, however, blocked by the A_2A adenosine receptor-selective antagonists ZM241385 and SCH58261 (apparent pK_B values of 9.2 and 8.9, respectively). We excluded roles for direct occupancy of A_2A adenosine receptors by ADP or ADPßS as well as metabolism to adenosine as mechanisms for ADP-evoked relaxations. However, ADP responses were significantly enhanced in the presence of the ENT1 nucleoside transporter inhibitors dipyridamole and NBTI and were significantly inhibited by adenosine deaminase, indicating a role for extracellular adenosine. Suprafusion of [³H]-adenine-labeled PCA segments showed that ADP induced the release of a number of purines, including adenosine. These data suggest that ADP mediates relaxation of the PCA via a novel mechanism that involves adenine nucleotide-evoked adenosine release and the subsequent activation of A_2A receptors.—Rayment, S. J., Ralevic, V., Barrett, D. A., Cordell, R. and Alexander, S. P. H. A novel mechanism of vasoregulation: ADP-induced relaxation of the porcine isolated coronary artery is mediated via adenosine release

Key Words: RT-PCR • adenosine A_2A receptor • purine release • adenine nucleotides

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