Summary
In order to define the role of angiotensin II (AngII) receptor subtypes, AT1 and AT2,
in platelet activation, we examined the effects of AngII and receptor antagonists
on both aggregability and phosphorylation status of protein kinase C (PKC) isoforms
in human platelets obtained from 56 healthy volunteers. AngII promoted both spontaneous
and agonist (collagen and ADP) stimulated platelet aggregation at concentrations of
10 nM or less, but the promotion effects were lost at 100 nM. Antagonism of AT1 receptor
inhibited the promotion effects of AngII at 10 nM or less. On the other hand, antagonism
of AT2 receptor enhanced platelet aggregability modestly with AngII at 10 nM or less,
and markedly with 100 nM AngII. Furthermore, with 10 nM AngII, phospho-PKCα/βII expression
in platelets was increased after collagen stimulation and was inhibited by antagonism
of AT1 receptor. With 100 nM AngII, expression levels of phospho-PKCα/ βII remained
low even after collagen stimulation but were markedly enhanced by antagonism of AT2
receptor. These findings suggest that at 10 nM or below, AngII promotes aggregability
and PKC phosphorylation in human platelets through the AT1 receptor, which can be
inhibited by AT1 receptor antagonists, but at higher concentrations, the promotion
effects were lost through the opposing action of the AT2 receptor. The present study
may provide an additional mechanism for AT1 receptor antagonism, which would provide
clinical benefit to patients with stroke or cardiovascular disease accompanied by
hypertension.
Keywords
Angiotensin II - AT1 receptor - platelet aggregation - protein kinase C - sartan