NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.
OBJECTIVE
Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system. We employed this tissue model to explore mechanisms involved in AngII-mediated superoxide production.


METHODS
Platelet suspensions from hypertensive patients' blood were activated with AngII or phorbol 12-myristate 13-acetate (PMA). Inhibitors of NAD(P)H oxidase, PKC, and the AT1 receptor were employed to study their effects on superoxide production.


RESULTS
Superoxide production was stimulated by AngII and PMA and attenuated by AT1 receptor antagonists (mean percentage reduction 80.2%, P<0.01) and inhibitors of PKC (mean reduction 94.8%, P<0.001) and NAD(P)H oxidase (mean reduction 100%, P< 0.001).


CONCLUSIONS
AngII stimulates platelet superoxide production through activation of vascular NAD(P)H oxidase via the AT1 receptor and PKC.
Plumb
Richard D
RD
Department of Therapeutics and Pharmacology, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.
El-Sherbeeny
Naglaa A
NA
Dixon
Lana J
LJ
Hughes
Sinead M T
SM
Devine
Adrian B
AB
Leahey
William J
WJ
McVeigh
Gary E
GE
D000368:Aged; D000470:Alkaloids; D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D053119:Benzophenanthridines; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D009247:NADH, NADPH Oxidoreductases / Q000097:blood*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000097:blood; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013481:Superoxides / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D000470:Alkaloids; D057911:Angiotensin Receptor Antagonists; D053119:Benzophenanthridines; D008562:Membrane Glycoproteins; D010617:Phenanthridines; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D000068756:Valsartan; C016299:chelerythrine; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011493:Protein Kinase C; D014633:Valine; D013755:Tetradecanoylphorbol Acetate