P2Y₁ and P2Y₂ receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed

Abstract

1 To assess the role of nucleotide receptors in endothelial-smooth muscle signalling, changes in perfusion pressure of the rat arterial mesenteric bed, the luminal output of nitric oxide (NO) and guanosine 3',5' cyclic monophosphate (cGMP) accumulation were measured after the perfusion of nucleotides. 2 The rank order of potency of ATP and analogues in causing relaxation of precontracted mesenteries was: 2-MeSADP=2-MeSATP4ADP4ATP=UDP=UTP4adenosine. The vasodilatation was coupled to a concentration ± dependent rise in NO and cGMP production. MRS 2179 selectively blocked the 2-MeSATP-induced vasodilatation, the NO surge and the cGMP accumulation, but not the UTP or ATP vasorelaxation. 3 mRNA encoding for P2Y 1 , P2Y 2 and P2Y 6 receptors, but not the P2Y 4 receptor, was detected in intact mesenteries by RT ± PCR. After endothelium removal, only P2Y 6 mRNA was found. 4 Endothelium removal or blockade of NO synthase obliterated the nucleotides-induced dilatation, the NO rise and cGMP accumulation. Furthermore, 2-MeSATP, ATP, UTP and UDP contracted endothelium-denuded mesenteries, revealing additional muscular P2Y and P2X receptors. 5 Blockade of soluble guanylyl cyclase reduced the 2-MeSATP and UTP-induced vasodilatation and the accumulation of cGMP without interfering with NO production. 6 Blockade of phosphodiesterases with IBMX increased 15 ± 20 fold the 2-MeSATP and UTPinduced rise in cGMP; sildena®l only doubled the cGMP accumulation. A linear correlation between the rise in NO and cGMP was found. 7 Endothelial P2Y 1 and P2Y 2 receptors coupled to the NO/cGMP cascade suggest that extracellular nucleotides are involved in endothelial-smooth muscle signalling. Additional muscular P2Y and P2X receptors highlight the physiology of nucleotides in vascular regulation.

Purinergic contraction of the rat vas deferens in L-NAME-induced hypertension: effect of sildenafil

“…The relaxant effects of ATP may be mediated by P2Y receptor subtypes in addition to P2X receptor subtypes. Buvinic et al [34] reported that P2Y 1 and P2Y 2 receptors are coupled to the NO/cGMP pathway. However, in our study, the contractile effects of P2X receptor subtypes are dominant over P2Y receptor effects on ATP, suggesting that the majority of relaxant effects of ATP in VD are mediated by P2X receptors.…”

Purinergic receptors in the splanchnic circulation

“…In general, P2Y receptors are found both on vascular endothelial and smooth muscle cells [40,138]. RT-PCR studies found mRNA fragments for P2Y 1 , P2Y 2 and P2Y 6 receptors in the rat [21] and mouse [177] mesenteric arteries, while P2Y 4 mRNA wasn't detected [21]. Moreover, P2Y 1 -and P2Y 2 -immunoreactivity was present in the smooth muscle of the rat pancreatic vascular bed [29].…”

“…This vasodilation is probably mediated by P2Y 1 and P2Y 2 receptors, through hyperpolarization of the endothelium that correlates with endothelium-dependent vasodilation [105]. This P2Y receptor-induced endotheliummediated vasodilation occurs through the release of NO, via the NO/cGMP pathway [21], and cyclo-oxigenase metabolites [97,105] but also via the release of EDHF [97,98,99,105,148]. In fact, EDHF-mediated vasodilation seems to be the predominant mediator of P2 receptor-mediated regulation of perfusion pressure in the small arteries of the peripheral circulation [96,172].…”

“…The study of Harrington and Mitchell further evidenced, for the first time, the presence of P2X 1 -like immunoreactivity in the surface of the endothelium, and concluded that the ATP-induced endothelium-dependent dilation was mainly mediated by P2X 1 receptors through the release of EDHF. In this context, it is interesting to [21] notice that renal arteries, which express P2X 1 receptors on the smooth muscle cells but not on endothelial cells, contract without subsequent vasodilation in response to α,β-mATP [80]. Table 4 summarizes the information on the potencies of agonists and antagonists at P2X and P2Y receptors in the splanchnic circulation.…”

Estudo dos mecanismos de ação da hidroquinona e fenol sobre o recrutamento leucocitário em respostas inflamatórias

“…Considering that ATP activates P2X ligand-gated ion channels and G-protein coupled P2Y receptors, and that several subtypes of each family are present in endothelial cells (Marrelli, 2001;Buvinic et al, 2002;Ramirez and Kunze, 2002;Volonte et al, 2006), we tested the possibility that melatonin would discriminate between them. The agonists used, 2-methylthio ATP and a,b-methylene ATP, have been shown to stimulate NO-production in endothelial cells Melatonin inhibits NO production CLM Silva et al through P2Y 1 (Marrelli, 2001;Buvinic et al, 2002) and P2X 4 receptors (Burnstock, 2006;Yamamoto et al, 2006), respectively.…”