title: Biphasic effects of angiotensin II and receptor antagonism on aggregability and protein kinase C phosphorylation in human platelets.
abstract: 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-PKCalpha/betaII expression in platelets was increased after collagen stimulation and was inhibited by antagonism of AT1 receptor. With 100 nM AngII, expression levels of phospho-PKCalpha/ betaII 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.
authors.affiliation: Department of Neurology, Iwate Medical University, 19-1 Uchimaru, Morioka/020-8505, Japan. kutsugi@iwate-med.ac.jp
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Utsugisawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Kizawa
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nagane
authors.forename: Ryushi
authors.initials: R
authors.lastname: Kondoh
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iwa
authors.forename: Hitomi
authors.initials: H
authors.lastname: Akutsu
authors.forename: Hideo
authors.initials: H
authors.lastname: Tohgi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terayama
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D011493:Protein Kinase C; D014633:Valine; C081643:candesartan