Platelet activation in hypertension associated with hypercholesterolemia: effects of irbesartan.
OBJECTIVE
The aim of this study was to determine the effect of simultaneous hypertension and hypercholesterolemia on platelet activation, nitric oxide (NO) production and oxidative stress, and to evaluate the role of irbesartan, an angiotensin II type 1 receptor antagonist.


METHODS
Golden Syrian hamsters were divided into three groups: controls, C (fed a standard diet); hypertensive-hypercholesterolemic, HH (fed a diet enriched in 3% cholesterol, 15% butter and 8% NaCl, for 4 months); and hypertensive-hypercholesterolemic treated with irbesartan, HHI (fed as HH group, plus irbesartan 10 mg kg(-1) per day, for 4 months).


RESULTS
Compared with the C group, platelets isolated from the HH group showed: morphological modifications; increased integrin β3 exposure and protein expression of P-selectin, FAK, PI3K, Akt and Src; reduced eNOS protein expression and NO production; higher generation of ROS, mostly produced by NADPH-oxidase, cyclooxygenase-1 (COX-1) and 12-lipoxygenase; and enhanced NAD(P)H oxidase activity and protein expression of gp91phox and p22phox subunits, 12-lipoxygenase, COX-1, cPLA(2) and PKC. Compared with the HH group, the treatment with irbesartan (HHI group) significantly attenuates the changes in all the molecules tested, reduces platelet aggregation, and improves intraplatelet redox balance.


CONCLUSIONS
Experimental hypertension associated with hypercholesterolemia produces major changes in morphology, signaling mechanisms and oxidative stress in blood platelets. These changes were significantly diminished by irbesartan administration, which functions as an antioxidant on platelets.
Alexandru
N
N
Petru Poni Institute of Macromolecular Chemistry, Iasi Institute of Cellular Biology and Pathology- Nicolae Simionescu, Bucharest, Romania. nicoleta.alexandru@icbp.ro
Popov
D
D
Dragan
E
E
Andrei
E
E
Georgescu
A
A
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D006224:Cricetinae; D051545:Cyclooxygenase 1 / Q000097:blood; D004195:Disease Models, Animal; D054513:Group IV Phospholipases A2 / Q000097:blood; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D039661:Integrin beta3 / Q000097:blood; D000077405:Irbesartan; D008055:Lipids / Q000097:blood; D008647:Mesocricetus; D019255:NADPH Oxidases / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000097:blood; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D019007:P-Selectin / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D051745:Protein Kinase C-delta / Q000097:blood; D017382:Reactive Oxygen Species / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000975:Antioxidants; D001713:Biphenyl Compounds; D039661:Integrin beta3; D008055:Lipids; D019007:P-Selectin; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D019255:NADPH Oxidases; D051745:Protein Kinase C-delta; D054513:Group IV Phospholipases A2; D000077405:Irbesartan