title: Clopidogrel, independent of the vascular P2Y12 receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats.
abstract: The P2Y12 receptor antagonist clopidogrel blocks platelet aggregation, improves systemic endothelial nitric oxide bioavailability, and has anti-inflammatory effects. Since P2Y12 receptors have been identified in the vasculature, we hypothesized that clopidogrel ameliorates angiotensin II (Ang II) -induced vascular functional changes by blockade of P2Y12 receptors in the vasculature. Male Sprague Dawley rats were infused with Ang II (60 ng.min-1) or vehicle for 14 days. The animals were treated with clopidogrel (10mg*kg-1*day-1) or vehicle. Vascular reactivity was evaluated in second-order mesenteric arteries. Clopidogrel treatment did not change systolic blood pressure [(mmHg) control-vehicle, 117+/-7.1 vs. control- Clopidogrel, 125+/-4.2; AngII-vehicle, 197+/-10.7 vs. AngII-Clopidogrel, 198+/-5.2], but it normalized increased phenylephrine-induced vascular contractions [(%KCl) vehicle-treated, 182.2+/-18 vs. Clopidogrel, 133+/-14%), as well as impaired vasodilation to acetylcholine [(%) vehicle-treated, 71.7+/-2.2 vs. Clopidogrel, 85.3+/-2.8) in Ang II-treated animals. Vascular expression of P2Y12 receptor was determined by western blot. Pharmacological characterization of vascular P2Y12 was performed with the P2Y12 agonist 2-MeS-ADP. Although 2-MeSADP induced endothelium-dependent relaxation [(Emax %) = 71%+/-12), as well as contractile vascular responses (Emax %= 83+/-12) these actions are not mediated by P2Y12 receptor activation. 2-MeS-ADP produced similar vascular responses in control and Ang II rats. These results indicate potential effects of Clopidogrel, such as improvement of hypertension-related vascular functional changes that are not associated with direct actions of clopidogrel in the vasculature, supporting the concept that activated platelets contribute to endothelial dysfunction, possibly via impaired NO bioavailability.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.; Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo SP 05508-900, Brazil.
authors.forename: Fernanca R C
authors.initials: FR
authors.lastname: Giachini
authors.forename: David A
authors.initials: DA
authors.lastname: Osmond
authors.forename: Shali
authors.initials: S
authors.lastname: Zhang
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Carneiro
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lima
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II; D000818:Animals; D015153:Blotting, Western; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D013873:Thionucleotides / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C553058:P2ry12 protein, rat; D058921:Purinergic P2Y Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013873:Thionucleotides; D014665:Vasodilator Agents; D000804:Angiotensin II; C002480:methylthio-ADP; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000109:Acetylcholine; D013988:Ticlopidine; D019331:NG-Nitroarginine Methyl Ester