ATP, although known mainly as an intracellular energy source, is also capable of acting extracellularly as a vasoactive agent of great potency, at concentrations around lμM or less. ADP is approximately equipotent with ATP in its actions on extracellular receptors in the vasculature.ATP and ADP can arise extracellularly through release from the cytoplasm of cellsexposed to damaging stimuli or by degranulation of platelets. The concentration of the nucleotides in the cytoplasm of most cells (including vascular endothelial and smooth muscle cells) is more than ImM, and the concentration in the dense storage granules of platelets approaches 1M. Thus, there is potential for very high localised concentrations of ATP and ADP in the plasma following platelet degranulation or damageto cells of the vessel well. Release from vascular endothelial and smooth muscle cells can occur with no loss of cell viability or leakage of cytoplasmic proteins.The vasoactivity of ATP and ADP is mediated via P2 purinoceptors. Vasodilation can be induced through the release of EDRF from endothelial cells or through stimulation of PGI2 production (PGI2 is a vasodilator in many, althoughnot all, arterial beds). Purinoceptor-mediated prostacyclin production can be stimulated from perfused vascular beds (e.g. theheart andthe lung), from isolated blood vessels or from cultured endothelial cells.In some blood vessels, purinoceptor-mediated vasoconstriction can be induced by direct actionon the vascular smooth muscle cells. The receptors responsible are sub-classified as P2X (which induce vasoconstriction) and P2Y (whichinduce vasodilation). The P2Y purinoceptor that mediates EDRF production is very similar to that which is responsible for PGI2 production, although there are some intriguing differences inthe potency of ATP analogs at stimulating these two responses, even on the same cells. The intracellular mechanisms responsible have not yet been fully elucidated, but it appears that elevation of intracellular calcium is likely to play a causal role.Adenosine, which is the product of ATP and ADP metabolism by nucleotidases, can also induce vasodilation in many blood vessels, acting via P1] purinoceptors on the smooth muscle cells, but its potency is often less than that of ATP and ADP.The fate of adenine nucleotides released into the plasma is determined by ectonucleotidases on the luminal surface of the endothelial cells, not by enzymes in the blood itself (the half-life of ATP in samples of blood or plasma is many minutes, while in the microcirculation the half-life isless than one second). Endothelial ectonucleotidases have been detected in several vascular beds, and many of their characteristics are now known. These enzymes are distinct entities from the P2 purinoceptors on endothelium, as shown by the marked differences in potency of several ATP analogs as P2 receptor stimulants and as substrates for the nucleotidases.In summary, vascular endothelial and smooth muscle cells respond to extracellularATP and ADP, and can also metabolise thesenucleotides extracellularly by ectonucleotidases. In addition, ATP and ADP can be selectively released from the cells of the vessel wall and from activated platelets. Thus, the endothelial pericellular environment can be the site of complex interactions by which vascular tone is regulated through the release, actions and metabolism ofextracellular nucleotides.
Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells
