Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 8

catalytic capacity of ectonucleotidases and, could in fact, stimulate ATP release by
increasing permeability of the RBC [69], probably via P2X 7 receptors [60]. ATP
can also release ATP from endothelial cells [4]. At high concentrations of ATP, a
self sustaining process may thus be instigated which may contribute to the irre-
versible stage of circulatory shock that can develop rapidly in severely ill patients.
Similar mechanisms may be of importance in malaria because induction of the
osmolyte permeability in Plasmodium-infected erythrocytes involves purinoceptor
signalling [65].
Recently, a role for P2X 7 receptors in alpha-hemolysin induced hemolysis was
suggested. The pore formation triggers purinergic receptor activation to medi-
ate the full hemolytic action. These findings potentially have clinical perspec-
tives as P2 antagonists may ameliorate symptoms during sepsis with hemolytic
bacteria [59].
1.8.5 Hypertension
Purinergic blood pressure regulation is the net result of the balancing contractile and
dilatory effects described above. ATP and UTP released on the luminal side from
endothelial cells and erythrocytes stimulates vasodilatation in contrast to release
from nerves on the adventitial side which results in vasoconstriction.
In spontaneously hypertensive rats (SHR), the importance of ATP as a sympa-
thetic cotransmitter is increased [7, 71]. The renal vasculature shows an enhanced
responsiveness to ab-meATP in perfused rat kidneys from SHR [28], while mesen-
teric vascular contractile reactivity to ATP via P2X 1 and P2Y 2 receptors is not
altered in DOCA-salt hypertension [29], and in the aorta of SHR, the endothelium-
dependent relaxation to ATP is impaired because of the simultaneous generation
of an endothelium-derived contracting factor (EDCF). Vasoconstriction to ATP is
potentiated in SHR aorta [80].
Diadenosine polyphosphates such as AP 4 A, AP 5 A and AP 6 A are combinations
of two adenosine molecules connected with 4-6 phosphate groups. They have been
identified as vasocontractile agents [58], via actions on P2X 1 and P2Y 2 receptors.
AP 5 A and AP 6 A are stored at higher levels in platelets from patients with hyperten-
sion and may contribute to their increased peripheral vascular resistance [34]. UP 4 A
is a novel endothelium derived vasoconstrictive factor more potent than endothelin
in renal vasoconstriction [37]. It is released upon stimulation of the endothelium
by acetylcholine, thrombin and mechanical stress and can be cleaved into either
ATP or UTP to stimulate both P2X 1 and P2Y 2 receptors on VSMC resulting in
increased blood pressure [37]. P2X 4 -/- mice demonstrated a higher blood pressure
and excrete smaller amounts of NO products in their urine than do wild-type mice
[79]. P2X 4 receptor protein is up-regulated in the placenta in preeclampsia [53].
Interestingly, some of the most commonly used medicines to lower blood pressure,
beta-blockers, may in part mediate their dilatory effects via release of ATP from
endothelial cells [39].