Investigation of the functional expression of purine and pyrimidine receptors in porcine isolated pancreatic arteries

Abstract

Receptors for purines and pyrimidines are expressed throughout the cardiovascular system. This study investigated their functional expression in porcine isolated pancreatic arteries. Pancreatic arteries (endothelium intact or denuded) were prepared for isometric tension recording and preconstricted with U46619, a thromboxane A 2 mimetic; adenosine-5′-diphosphate (ADP), uridine-5′-triphosphate (UTP) and MRS2768, a selective P2Y 2 agonist, were applied cumulatively, while adenosine-5′-triphosphate (ATP) and αβ-methylene-ATP (αβ-meATP) response curves were generated from single concentrations per tissue segment. Antagonists/ enzyme inhibitors were applied prior to U46619 addition. ATP, αβ-meATP, UTP and MRS2768 induced vasoconstriction, with a potency order of αβ-meATP > MRS2768 > ATP ≥ UTP. Contractions to ATP and αβ-meATP were blocked by NF449, a selective P2X1 receptor antagonist. The contraction induced by ATP, but not UTP, was followed by vasorelaxation. Endothelium removal and DUP 697, a cyclooxygenase-2 inhibitor, had no significant effect on contraction to ATP but attenuated that to UTP, indicating actions at distinct receptors. MRS2578, a selective P2Y 6 receptor antagonist, had no effect on contractions to UTP. ADP induced endothelium-dependent vasorelaxation which was inhibited by MRS2179, a selective P2Y 1 receptor antagonist, or SCH58261, a selective adenosine A 2A receptor antagonist. The contractions to ATP and αβ-meATP were attributed to actions at P2X1 receptors on the vascular smooth muscle, whereas it was shown for the first time that UTP induced an endothelium-dependent vasoconstriction which may involve P2Y 2 and/or P2Y 4 receptors. The relaxation induced by ADP is mediated by P2Y 1 and A 2A adenosine receptors. Porcine pancreatic arteries appear to lack vasorelaxant P2Y 2 and P2Y 4 receptors.

UDP-induced relaxation is enhanced in aorta from female obese Otsuka Long–Evans Tokushima Fatty rats

“…To regulate vascular tone, endothelial cells release relaxant [such as endothelium-derived relaxing factors (EDRFs)] and contractile factors [such as endothelium-derived contracting factors (EDCFs)], and the balance between these factors is altered at various disease states [20][21][22][29][30][31][32][33]. Moreover, purinoceptor ligands release EDCFs [30,33].…”

“…Moreover, purinoceptor ligands release EDCFs [30,33]. Among these factors, vasoconstrictor prostanoids play an important role in regulating vascular tone by functioning as EDCFs [24,25,29,31,32].…”

Characterisation of P2Y receptor subtypes mediating vasodilation and vasoconstriction of rat pulmonary artery using selective antagonists

“…Finally, extracellular ATP and ADP can be progressively dephosphorylated by ectonucleotidases to adenosine, which can act at P1 receptors to elicit vasodilation [ 38 – 40 ]. The role of this mechanism was investigated using the potent P1 receptor antagonist, CGS15943, at a concentration (1 µM) that substantially blocks P1 receptors [ 41 – 43 ].…”

Role of the Purinergic P2Y2 Receptor in Pulmonary Hypertension

“…It should be noted that ATP and ADP are non-selective P2Y2 receptor agonists, and therefore, more studies are required to investigate and clarify any vasodilatory or vasoconstrictive role of endothelial P2Y2 [ 133 ]. However, using PAECs- and PASMCs-cell specific P2Y2 knockout mice, and the application of the only available novel selective P2Y2 receptor agonist MRS2768, can provide more insights into the role of P2Y2 in pulmonary vascular regulation [ 134 , 135 , 136 , 137 ].…”

“…Thus, treatment with MRS2768 enhanced stability and protected the heart from ischemic damage in vitro and in vivo [ 78 ]. MRS2768 induced vasoconstriction of porcine pancreatic arteries via P2Y2, whereas ADP induced vasorelaxation [ 134 ].…”