Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 2

degrade extracellular ATP into ADP, AMP and adenosine [30,83]. Experimental
studies on the vascular effects of purines have been of crucial importance for reveal-
ing the complexities of this system and for the classification of the receptors [18, 20,
27, 49, 51]. Purines and pyrimidines stimulate vasoconstriction and vasodilatation,
are involved in blood pressure regulation, development of myocardial infarction,
heart failure, blood flow regulation during exercise and hypoxia, pulmonary hyper-
tension and regulation of blood flow in most organs of the body. This chapter
is an attempt to summarize the endothelium-mediated effects of purinergic and
pyriminergic regulation on tissue perfusion.
1.2 Regulation of Vascular Tone: Balance Between Contractile
and Dilatory Effects
The net effect on tissue perfusion is a balance between contractile and dilatory
responses. Vasoconstriction produced by ATP released as a cotransmitter with nora-
drenaline from perivascular sympathetic nerves was recognised early [10, 14].
However, following the seminal discovery of endothelium dependent vasodilatation
by Furchgott in the early 1980s, it was shown that ATP acted on endothelial cells
(EC) to cause endothelial dependent vasodilatation [12] and dual purinergic neu-
ral and endothelial control of vascular tone was established [13, 15]. Extracellular
nucleotides (ATP, ADP, UTP and UDP) cause endothelial-dependent relaxation,
while adenosine dilates blood vessels by direct action on vascular smooth muscle
cells (VSMC), mainly via A 2a receptors [51] (Fig. 1.1).
In some situations, adenosine does not solely dilate via direct action on the
VSMC, but may in part activate the endothelium and release nitric oxide (NO).
Fig. 1.1 Purines and pyrimidines regulate vascular tone via endothelial cells. ATP, ADP, UTP and
UDP dilate via release of NO and endothelium derived hyperpolarising factor (EDHF). Adenosine
acts mainly via direct effect on the vascular smooth muscle cells (VSMC), but may also in some
situations cause dilatation via NO-release. The endothelium can release the contractile nucleotides
UP 4 AandAP 4 A, which cause contraction of the VSMC