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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

effective and preferential pulmonary vasodilator in children with
pulmonary hypertension secondary to congenital heart defects; it
has also been used for treating pulmonary hypertension after cardiac
surgery. EPA, one of the active components in fish oil that has
antihypertensive effects, increases the release of ATP from vascular
endothelial cells leading to reduction of the blood pressure rise
characteristic of ageing.

Varicose veins are characterised by hypoxia, inflammation
and cell death, all likely to lead to increases in extracellular ATP.
P2X1 and P2X7 receptors are expressed by saphenous vein smooth
muscle and it has been suggested that resultant P2X7 receptor
activation contributes to the decrease in contractile myocytes and
resulting disorganisation of the vessel wall. P2 receptors have been
proposed as potential new players in atherosclerosis (7). Large
clinical trials with clopidogrel and ticlodipine (P2Y12 receptor
antagonists) in patients with atherosclerotic disease have shown
significant benefit compared with aspirin.

Saphenous vein, internal mammary and radial arteries have been
used as grafts for coronary bypass surgery; the level of endothelial
P2Y2 receptors is comparable in all three vessels, but endothelial P2X4
receptors vary from high in saphenous vein to significantly lower
in the other two vessels. It has been suggested that P2X4 receptors play
a more significant role in intense proliferation in arteriosclerosis and
restenosis in the P2Y2 receptors reflected by susceptibility of
saphenous vein grafts to atherosclerosis compared to internal
mammary arteries. In another study, P2X1 and P2Y6 receptors mediate
more prominent contractions in the saphenous vein compared to the
internal mammary artery; it has been suggested that selective
antagonists to these receptors may prevent vasospasm and restenosis
in the saphenous vein during and after revascularisation surgery. A
novel role for the P2Y2 receptors has been suggested whereby UTP
induces vascular cell adhesion molecule-1 expression in coronary
artery endothelial cells that mediates the recruitment of monocytes;
this may be associated with the development of atherosclerosis. The
long-term (trophic) roles of purinergic signalling in vascular smooth
muscle and endothelial cell proliferation and death, have been
implicated in atherosclerosis and restenosis and suggest the
exploration of therapeutic strategies in relation to these events (5).

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