P2X 7 Receptor Activation–Induced Contraction and Lysis in Human Saphenous Vein Smooth Muscle

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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 hP2X 1 receptors, already identified in other smooth muscles, and, surprisingly, hP2X 7 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 contraction induced by 2-methylthio-ATP was more transient than that evoked by the other P2X agonists. The effect of hP2X 1 agonists involved the activation of a rapidly desensitizing cation current recorded in freshly isolated myocytes. The action of hP2X 7 receptor agonists was related to a maintained nondesensitizing cation current. In addition, hP2X 7 receptor activation formed membrane pores that were permeable to large molecules. hP2X 1 and hP2X 7 receptors coexpressed in COS cells did not associate to form heteromultimers. Our data indicate that both hP2X 1 and hP2X 7 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 hP2X 7 receptor–induced pore formation contributes to the disorganization and decrease in the amount of contractile myocytes in the media of varicose veins.