Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 7

In an elegant experiment, Winter and Dora, used triple cannulation of isolated
arteries to enable focal application of purine and pyrimidine nucleotides to the
endothelium, avoiding potential complicating actions of these agents on the smooth
muscle [75]. Nucleotides were locally infused through one branch of a bifurcation,
causing near maximal local dilatation attributable to EDHF. Dilatation then spread
rapidly backwards to the adjacent feed artery and upstream against the direction of
luminal flow, and increases flow into the feed artery. The data demonstrate that direct
luminal stimulation of P2Y receptor on the endothelium of rat mesenteric arteries
leads to marked spreading retrograde dilatation and thus suggests that circulating
purines and pyrimidines may act as important regulators of blood flow [75]. In sum-
mary, ATP and UTP are released by endothelial and red blood cells in tissues in need
of increased blood flow and stimulate an EDHF-dependent dilatation that spreads in
a retrograde direction to the supplying artery to increase blood flow (Fig. 1.2).

1.8.2 Sympathicolytic Effects Mediated Via Endothelial Activation

Sympathetic nerves express inhibitory P2Y and P1 (A1) receptors indicating a
P2-receptor mediated negative feedback loop both directly by ATP and its degra-
dation product adenosine [5, 23]. An important balancing mechanism is the
endothelium dependent sympathicolytic effect seen in exercising skeletal mus-
cle. This mechanism is mimicked by injection in the arterial lumen of ATP and
UTP, inducing a vasodilatation that overrides sympathetic vasoconstrictor activity
in human skeletal muscle, an effect not obtained by injection of adenosine, indicat-
ing involvement of P2Y 2 receptors [55, 56]. Thus, endothelial P2 receptors mediate
increases in skeletal blood flow during exercise both via direct dilatory effects, but
also via a sympathicolytic effect.

1.8.3 Reactive Hyperemia

Reactive hyperemia is the massive increase in blood flow that starts when a blood
vessel is opened after a period of ischemia. It is well known that ATP is released
during ischemia [30, 70] and ADP has been shown to mediate the midportion and
peak of hyperemia via endothelial P2Y 1 receptors [48]. ADP is then degraded to
adenosine mediating the late phase hyperemia via A 2A receptors on SMC [57]. It is
possible that ATP mediates dilatation during the first phase.

1.8.4 The Role of P2 Receptors in Circulatory Shock and Sepsis

It is possible that in extreme conditions such as circulatory or septic shock with
acidosis and hypoxia, high ATP levels could be deleterious, leading to a drop in
blood pressure [69]. At levels above 100 μ M, ATP concentrations may exceed the