Functional Evidence for a Novel Suramin-Insensitive Pyrimidine Receptor in Rat Small Pulmonary Arteries

Abstract

Uridine nucleotides are known to cause constriction of pulmonary arterial smooth muscle. However, the P2 receptor subtypes underlying the contractile effects of these nucleotides in the pulmonary circulation have not been determined. We have used myography and the patch-clamp recording technique to compare the effects of UTP and UDP in isolated small pulmonary arteries (diameter 100 to 400 microm) and their constituent smooth muscle cells. In endothelium-denuded arteries, both UTP and UDP (0.01 to 3 mmol/L) induced concentration-dependent increases in tension that were independent of P2X receptor stimulation. The UDP-mediated increase in tension was significantly less sensitive to the nonselective P2 receptor blocker suramin than the UTP-mediated increase in tension. In single isolated arterial myocytes, voltage-clamped at -50 mV (close to the resting membrane potential of these cells), application of both UTP and UDP evoked periodic oscillations of inward current primarily because of a Ca2+-activated Cl- current (ICl,Ca). Oscillations of ICl,Ca evoked by UTP were reversibly inhibited by suramin, although those evoked by UDP were insensitive to the antagonist. In addition to confirming the presence of classical P2Y2 receptors, these results also provide functional evidence for the existence of a novel UDP receptor in pulmonary arterial myocytes, which may contribute to pyrimidine-evoked vasoconstriction. This notion is supported by molecular evidence that demonstrates the presence of P2Y6 receptor transcripts in rat pulmonary arterial smooth muscle.

Knockout Mice Reveal a Role for P2Y6 Receptor in Macrophages, Endothelial Cells, and Vascular Smooth Muscle Cells

“…Since then, several reports have shown contractile effects of UDP on various arteries, associated with the expression of P2Y 6 messengers (Hartley et al, 1998;Rubino et al, 1999;Lewis et al, 2000;Wang et al, 2002;Malmsjö et al, 2003). In P2X 1 Ϫ/Ϫ mice, the contractile effect of ATP on mesenteric arteries was abolished, whereas the vasoconstriction by nerve stimulation was reduced by approximately 50% (Vial and Evans, 2002).…”

Impaired NO-dependent inhibition of store- and receptor-operated calcium entry in pulmonary vascular smooth muscle after chronic hypoxia

“…ROCE was induced with the G protein-coupled P2Y receptor agonist UTP (14). To assess ROCE independently of SOCE and to eliminate other UTP-mediated Ca 2ϩ entry mechanisms, vessels were pretreated with diltiazem (50 M) and CPA (10 M), and a stable SOCE response was obtained (described above) before the addition of UTP (100 M).…”

Purinergic Signaling in the Airways

“…ATPand ADP-induced increase in [Ca 2ϩ ] i in rat pulmonary artery myocytes was found to be mediated by P2X and P2U (P2Y 2 and/or P2Y 4 ) receptors (Guibert et al, 1996;Hartley and Kozlowski, 1997). In endothelium-denuded rat pulmonary arteries, P2Y 2 and a UDP-sensitive receptor (presumably P2Y 6 ) were identified on myocytes (Hartley et al, 1998). Although ATP was a potent vasoconstrictor in perfused rat lung (Rubino and Burnstock, 1996), it was only a weak agonist in isolated rat pulmonary artery (Rubino et al, 1999).…”