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1.5 Receptor Subtypes Involved in Endothelial Relaxation
The prototypical endothelial receptor, since the definition of the P2Y and P2X recep-
tor subclasses, is the P2Y 1 receptor, and still, even after cloning of eight different
P2Y receptors, it seems to be of main importance in most vascular beds [51].
Pharmacology of vasodilatation and mRNA quantification in man indicates that
P2Y 1 , P2Y 2 and P2Y 6 are the most important endothelial P2Y-receptors [72, 74].
Knockout mice experiments recently confirmed this picture and demonstrated that
the P2Y 4 receptor does not mediate dilatation [33]. Knockout of the P2Y 2 and
P2Y 6 receptor reveals that a major part of the UTP mediated dilatation is in fact
mediated by the UDP receptor P2Y 6 [1, 33], after degradation of UTP to UDP by
ectonucleotidases.
The ATP receptor P2Y 11 is one of the transcriptionally highest expressed P2Y
receptors in the endothelium, but it does not seem to be involved in dilatory
mechanisms [72]. Instead, it could stimulate proinflammatory responses.
The P2X 1 receptor is not expressed on the human endothelium and the evi-
dence for other P2X receptors have been scarce, except for the P2X 4 receptor
which is the highest expressed P2 receptor in endothelium [72, 77]. Using anti-
sense oligonucleotides the P2X 4 receptor was shown to be important for shear
stress dependent Ca 2+ -influx via an ATP dependent mechanism [76]. This indicates
that ATP and P2 receptors may be of importance for shear stress mediated effects
which is in agreement with the well established release of ATP from endothelial
cells during shear stress [3]. Vessel dilation induced by acute increases in blood
flow is markedly suppressed in P2X 4 -/-mice. Thus, endothelial P2X 4 channels
are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular
remodeling [79].
The importance of the presence of ATP for flow-induced vasodilation has been
confirmed rat mesenteric arteries [41]. If ATP was not present in the lumen, the flow-
induced vasodilation was reduced by half. Interestingly, the effect of ATP could be
mimicked by UTP, indicating that P2Y receptors could be of similar importance as
the P2X 4 receptor for shear induced vasodilatation.
In summary, endothelium dependent dilatation is stimulated directly by ATP,
ADP, UTP and UDP by activation of P2Y 1 , P2Y 2 and P2Y 6 receptors and shear
stress mediated vasodilatation is dependent on ATP activation of P2X 4 receptors,
but also by UTP.
1.6 Mediators of Endothelial Dependent Vasodilation: NO,
EDHF and PGI 2
ATP and ADP release prostacyclin (PGI 2 ) from endothelial cells [6]. PGI 2 is a
dilator in some blood vessel but usually its contribution to endothelial dependent
dilatation is small or absent. It may have a more important role as a potent platelet
inhibitor, preventing thrombus formation in the microcirculation.
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