Noradrenaline and extracellular nucleotide cotransmission involves activation of vasoconstrictive P2X 1,3 ‐ and P2Y 6 ‐like receptors in mouse perfused kidney

1 Nucleotides like ATP and UTP act as potent extracellular signalling molecules. Released from sympathetic nerve endings as cotransmitters of noradrenaline or paracrine from nonexcitatory cells, they activate specific receptors (ion‐gated P2X 1–7 and G‐protein‐coupled P2Y 1,2,4,6,11–15 ). Which of these subtypes, however, are able to modulate vasoconstriction in the kidney is unclear. 2 Wild‐type‐ and P2Y 4 ‐receptor‐deficient mice kidneys were isolated and perfused with Krebs–Henseleit solution. Pressor responses to renal nerve stimulations (RNS) and added drugs were recorded. Release of endogenous noradrenaline was measured by HPLC. 3 RNS (1–15 Hz) induced a frequency‐dependent increase in the perfusion pressor (14.2±5.1–67.3±6.9 mmHg) and noradrenaline release (1.4±0.3–24.2±3.4 ng g −1 kidney). 4 Pressor responses to RNS were not (1–2 Hz) or only partially (5–15 Hz) blocked by the α ‐adrenoceptor antagonist phentolamine (1  μ M ). Combination of phentolamine and the P2‐receptor blocker PPADS (5  μ M ) prevented RNS‐induced pressor responses. The P2X 1,3 ‐receptor selective antagonist NF279 (10  μ M ) reduced RNS‐induced pressor responses in a frequency‐dependent manner. 5 Perfusion of ATP, ADP, UTP, UDP and α,β ‐meATP concentration dependently increased perfusion pressor with the following rank order of potency α,β ‐meATP>ADP≈ATP≈UDPUTP. NF279 (10  μ M ) reduced α,β ‐meATP‐ (0.1  μ M ) (21.7±3.9% of control) but not UTP‐ (0.3  μ M ) (102.6±15.3% of control) induced pressor responses. No differences in nucleotide‐induced effects were detected among wild‐type and P2Y 4 ‐receptor knockout mice. 6 Continuous perfusion of α,β ‐meATP (0.01  μ M ) potentiated UTP‐, UDP‐ and ATP‐ γ S‐induced pressor responses. 7 Neuronally and paracrine‐released nucleotides evoked renal vasoconstriction by activation of P2X 1,3 ‐ and P2Y 6 ‐like receptors in mice. Pretreatment with the P2X 1,3 ‐receptor agonist α,β ‐meATP potentiated P2Y 6 ‐like receptor‐mediated vasoconstrictions.British Journal of Pharmacology (2005) 145 , 66–74. doi: 10.1038/sj.bjp.0706151