title: Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats.
abstract: The aim was to investigate the beneficial effects of clopidogrel in thoracic aorta function and structure and to characterize if P2Y12 receptors contribute to these effects. Male Sprague Dawley rats were infused with angiotensin II [(Ang II) 60 ng x min(-1), 14 days] or saline (control rats) and were simultaneously treated with clopidogrel (10 mg x kg(-1) x day(-1)) or vehicle. After 14 days, systolic blood pressure (mmHg) was similar in Ang II-hypertensive rats treated with clopidogrel or vehicle (199±9 vs. 190±11, respectively). Systolic blood pressure in control rats was not altered by clopidogrel treatment (128±1 vs. vehicle, 134±2). Endothelium-dependent relaxation induced by 2-MeS-ADP was decreased in aortas from vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. This response was elicited via activation of P2Y1 and P2Y12 receptors. In the presence of L-NAME and indomethacin, 2-MeS-ADP induced contraction and this response was augmented in vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. The contraction to 2-MeS-ADP was evoked by P2Y13 and P2Y12 receptor activation. Clopidogrel-treatment did not normalize relaxation or contractile responses induced by 2-MeS-ADP in aortas from Ang II-hypertensive rats. P2Y1 and P2Y12 protein expression was increased, whereas P2Y13 receptor expression was reduced in aorta from vehicle-treated Ang II-hypertensive rats. Endothelium-dependent relaxation upon acetylcholine-stimulation was reduced in vehicle-treated Ang II-hypertensive rats, and clopidogrel treatment was effective in improving endothelial function. Clopidogrel also prevented vascular remodeling, evidenced by augmented media thickness in aortas from Ang II-hypertensive rats. Clopidogrel has beneficial effects on the aortic endothelium of Ang II-hypertensive rats, but its effects do not seem to be directly related to the presence of P2Y12 receptors in this vessel.
authors.affiliation: Institute of Biological Sciences and Health, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
authors.forename: Fernanda R
authors.initials: FR
authors.lastname: Giachini
authors.affiliation: School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, MG, Brazil.
authors.forename: Romulo
authors.initials: R
authors.lastname: Leite
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Osmond
authors.affiliation: Institute of Biological Sciences and Health, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D000077144:Clopidogrel; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D015870:Gene Expression; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058470:Receptors, Purinergic P2Y; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine