Extracellular nucleotides activate either P2X ionotropic receptors or P2Y receptors; the latter coupled to various G proteins. We assessed the distribution of P2Y₁ and P2Y₂ receptors along the human placenta vasculaure and investigated their relevance to maternal foetal blood flow regulation, extending the study of Valdecantos et al., 2003. Term Caesarean human placentas were perfused; the perfusion pressure was monitored, the nitric oxide (NO) outflow was determined by chemiluminescence. Bioassays measured vascular reactivity using rings prepared from segments of umbilical or superficial chorionic arteries or veins with or without endothelium; half-maximal effects (EC₅₀) were derived from concentration-response curves. The guidelines on ethical regulations for research with human samples were strictly adhered to. The perfusion of cotyledons with 1-1000nM 2-MeSADP, a preferential P2Y₁ receptor ligand, elicited endothelium and concentration-dependent vasodilatation with an EC₅₀ of 7.2±0.6nM (n=6). In addition, the 2-MeSADP EC₅₀ to evoke a surge in NO outflow was 83±8nM; the maximal NO production elicited by 100nM amounted to 353±51pmol; this value was reduced 70% by eNOS inhibition and 85% by 100nM MRS2179 (n=5 each). 1-1000nM UTP, a preferential P2Y₂ receptor ligand, also dilated these vessels; its EC₅₀ was 86±7nM. Receptor activation elicited a subsequent rise in NO outflow with an EC₅₀ of 1843±124nM; 1μM UTP produced 120±17pmol NO (n=8), an effect blocked by eNOS inhibition, but not by MRS2179. In contrast, 2-MeSADP or UTP contracted the circular smooth muscle layer from umbilical or chorionic vessel rings; their EC₅₀ in chorionic arteries were 4.2±1 and 5±2 nM respectively, (n=5 each). The contractile responses are mediated probably by an arachidonate metabolite since the vasomotor responses were reduced 80-90% by either 100nM indomethacin or 10 nM GR32191, a thromboxane receptor antagonist, suggesting that the response are indirect in origin and involve the synthesis of a thromboxane. RT-PCR demonstrated the presence of the mRNAs coding for the P2Y₁ and P2Y₂ receptors, in addition to P2Y₆ and P2Y₁₁ receptors. Western blot analysis of the P2Y₁ receptor protein confirmed its expression in both endothelial and vascular smooth muscle cells of the umbilical and chorionic vessels; however its distribution towards the cotyledons is uneven, showing a more intense expression in the endothelium of the smaller sized vessels, most likely micro vessels of the cotyledons. The expression of multiple P2Y receptors coupled to vasocontractile or vasodilator mechanisms highlights the complexity of purinergic receptor distribution and their intracellular signalling along the human placenta vasculature. While the larger placental vessels express the P2Y₁ and P2Y₂ receptors, which promote the synthesis of an arachidonate metabolite, smaller sized vessels release NO.