Role of P2 receptors in vascular tone regulation

P2 receptors, the main endogenous agonist of which is adenosine triphosphate (ATP), are widely distributed in mammalian tissues and organs, including the cardiovascular system. In human blood vessels, various types of the P2Y (metabotropic, G-protein coupled receptors) and P2X (ligand-gated ion channels) family of receptors are present. Several subtypes of P2X and P2Y receptors have been found on the surface of endothelial cells as well as smooth muscle cells of the vessels. Activation of various subtypes of P2 receptors located in different cells of the blood vessel can have multidirectional action on the tone of the vessel’s wall, thereby causing both vasoconstriction and vasodilatation. To date, two main physiologic mechanisms have been identified, via which Р2 receptors participate in controlling the vascular tone: (1) neuronal - ATP is released as a co-transmitter from perivascular sympathetic nerve terminals and activates P2 receptors located on vascular smooth muscle cells; (2) endothelial - ATP is released into the vessel’s lumen by endothelial cells and blood cells and activates P2 receptors located on the endothelial cells. In the first mechanism, simultaneous release of ATP and norepinephrine from sympathetic nerve terminals results in vasoconstriction caused by rapid depolarization, which is completely inhibited by P2X receptor antagonists, and slow depolarization, which is inhibited by alpha-adrenergic blockers. In the second mechanism, during shear stress and hypoxic conditions, ATP activates P2 receptors of endothelial cells causing vasodilatation. These differing effects, mediated via P2 receptors, make it very tempting to develop novel drugs that would regulate vascular tone via these receptors.