Page 7 - 71_02

VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

aspirin. There are genetic variations in P2Y1 and P2Y12 receptor
gene sequences in healthy subjects that explain variations in the
platelet response to ADP; this may reflect individual variation in
atherothrombotic risk and the efficacy of purinergic antithrombotic
drugs. Postoperative carotid thrombosis is a significant risk for
stroke; it seems likely that clopidogrel or ticlopodine may provide an
avenue for targeted antiplatelet therapy following vascular
intervention. Platelet aggregation in response to ADP is significantly
inhibited in patients with peripheral vascular disease two to four
hours after a loading dose of clopidogrel. There is a synergistic
interaction between ATP and noradrenaline in stimulating platelet
aggregation, which suggests a prothrombotic role for ATP in stress.
Leishmania-infected dogs show changes in haemocoagulative
functions and there is a significant decrease in ADP- and collagen-
induced platelet aggregation. Platelet activation that occurs in human
acute malaria infection is associated with elevated plasma ATP
concentrations.

Upregulation of P2X1 and P2Y2 receptor mRNA in the hearts of
rats with congestive heart failure has been reported. ATP and
adenosine are widely used for the treatment of paroxysmal
supraventricular tachycardia in both infants and adults. The
substantial enhancement of mechanical performance with 2-deoxy-
ATP in cardiac muscle suggests that it may be a better substrate for
contractility than ATP and suggests that ribonucleotide reductase
may be a target for therapy in heart failure. Enhanced adrenergic
activity causes cardiac dysfunction, arrhythmias and sudden cardiac
death in myocardial ischaemia; a novel role for the ectonucleotidase,
E-NTPDase 1 or CD39 (an ectoADPase), at sympathetic nerve
terminals may offer a novel therapeutic approach to hyperadrenergic
states such as myocardial ischaemia and its consequences and since
it also inhibits platelet aggregation, for the treatment of thrombotic
diatheses. ATP was shown to inhibit atrioventricular conduction
rather than the firing rate of sinoatrial nodes in patients with
ischaemic heart disease; injection of ATP is used only when a
transient cardiac standstill was needed, such as for endovascular
grafting surgery. The implantable cardioventer defibrillator reduces
the mortality of patients with ventricular arrhythmias. Employing
transgenic overexpression of human P2X4 receptors, cardiac P2X 4

287