P2X7 receptor activation-induced contraction and lysis in human saphenous vein smooth muscle

Abstract

In cutaneous veins where purinergic neurotransmission is more prominent compared with in deep vessels, physiological and pathological roles of nerve- released ATP have been described. Neuronally released ATP has been reported to act through activation of unidentified ionotropic P2X receptor(s). This study analyzed P2X receptor subtypes expressed in human saphenous vein smooth muscle and their physiological functions. Transcripts for both hP2X1 receptors, already identified in other smooth muscles, and, surprisingly, hP2X7 receptors known to be responsible for the cytotoxic effect of ATP in macrophages were detected by Northern blot analysis in total RNA from saphenous vein smooth muscle. ATP and other P2X receptor agonists [αβ- methylene-ATP, 2-methylthio-ATP, and 2',3'-(4-benzoyl)benzoyl-ATP] dose- dependently contracted venous rings, but the contracion induced by 2- methylthio-ATP was more transient than that evoked by the other P2X agonists. The effect of hP2X1 agonists involved the activation of a rapidly desensitizing cation current recorded in freshly isolated myocytes. The action of hP2X7 receptor agonists was related to a maintained nondesensitizing cation current. In addition, hP2X7 receptor activation formed membrane pores that were permeable to large molecules. hP2X1 and hP2X7 receptors coexpressed in COS cells did not associate to form heteromultimers. Our data indicate that both hP2X1 and hP2X7 receptors are expressed as 2 separated populations of channels in human saphenous vein myocytes and are involved in ATP-induced tension. We suggest that cell lysis consequent to hP2X7 receptor-induced pore formation contributes to the disorganization and decrease in the amount of contractile myocytes in the media of varicose veins.