Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 6

Vasodilatation and decreased blood pressure by release of NO has been demon-
strated in several studies [24, 52]. NO is especially important in the regulation of
medium to large arteries. In smaller arteries and vascular beds the dilatory response
has not been possible to block with NO-inhibitors. This has led to the definition of
a third endothelial dilatory factory called endothelium derived hyperpolarizing fac-
tor (EDHF). The exact chemical entity is not fully understood but EDHF is defined
as resistant to NO and prostaglandin inhibitors, it hyperpolarises VSMC and it is
blocked by potassium channel blockers.
Extracellular nucleotides acting on P2Y receptors have been shown to mediate a
major part of the dilatation via endothelium derived hyperpolarizing factor (EDHF)
[44, 45, 47]. This has been confirmed in human blood vessels examined in vitro
[74]. The importance of EDHF becomes even more pronounced in vivo, e.g. in the
mesenteric vascular bed were NO played a minor role and EDHF was the dominat-
ing factor mediating ATP, ADP and UTP induced dilatations [43]. This was even
more pronounced in man where both UTP and ATP reduced forearm vascular resis-
tance in a prostaglandin and NO independent way [35], indicating an important role
for EDHF in P2 receptor mediated vasodilatation [35].
1.7 Mediators of Endothelial Dependent Vasoconstriction:
AP 4 A, UP 4 A
The endothelial can also release substances that stimulate vasoconstriction, as
exemplified by the peptide endothelin which play an important role in pulmonary
hypertension. Recently, the two tetraphosphate nucleotides AP 4 A, UP 4 A have been
shown to be released from the endothelium and to mediate potent contractile effects
by activation of P2X 1 and P2Y receptors [37, 67]. They seem to be especially impor-
tant in the renal vascular regulation and infusion of AP 4 A results in nanomolar
concentration results in mean arterial pressure.
1.8 Extracellular Nucleotides in Physiological Vascular
Regulation
1.8.1 Retrograde Spreading Dilatation
Blood flow to a tissue is a complex process designed to provide adequate amounts
of oxygen to meet the changing metabolic needs of the tissue. Hypoxia and acidosis
that causes release of dilatory ATP, occurs on the venular side of the capillary bed,
but to increase blood flow to the tissue the arterioles upstream need to be dilated.
Ellsworth have demonstrated that addition of ATP to the venular side binds to
purinergic receptors located on the vascular endothelium and induces a vasodilation
that is conducted upstream increasing oxygen supply to the region of tissue supplied
by the vessel [21].