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 AngII (angiotensin II)-induced vascular functional changes by blockade of P2Y12 receptors in the vasculature. Male Sprague–Dawley rats were infused with AngII (60 ng/min) or vehicle for 14 days. The animals were treated with clopidogrel (10 mg·kg−1 of body weight·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 versus control-clopidogrel, 125±4.2; AngII–vehicle, 197±10.7 versus AngII–clopidogrel, 198±5.2], but it normalized increased phenylephrine-induced vascular contractions [(%KCl) vehicle-treated, 182.2±18% versus clopidogrel, 133±14%), as well as impaired vasodilation to acetylcholine [(%) vehicle-treated, 71.7±2.2 versus clopidogrel, 85.3±2.8) in AngII-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 [2-(methylthio) adenosine 5′-trihydrogen diphosphate trisodium]. Although 2-MeS-ADP 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 AngII 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 nitric oxide bioavailability.
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Research Article|
January 12 2010
Clopidogrel, independent of the vascular P2Y12 receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats
Fernanda R. C. Giachini;
Fernanda R. C. Giachini
1
*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
Correspondence: Dr Fernanda R. C. Giachini (email [email protected]).
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David A. Osmond;
David A. Osmond
1
*Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.
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Shali Zhang;
Shali Zhang
*Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.
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Fernando S. Carneiro;
Fernando S. Carneiro
*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
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Victor V. Lima;
Victor V. Lima
*Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.
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Edward W. Inscho;
Edward W. Inscho
*Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.
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R. Clinton Webb;
R. Clinton Webb
*Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A.
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Rita C. Tostes
Rita C. Tostes
*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
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Publisher: Portland Press Ltd
Received:
July 20 2009
Revision Received:
September 08 2009
Accepted:
October 07 2009
Accepted Manuscript online:
October 07 2009
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 118 (7): 463–471.
Article history
Received:
July 20 2009
Revision Received:
September 08 2009
Accepted:
October 07 2009
Accepted Manuscript online:
October 07 2009
Citation
Fernanda R. C. Giachini, David A. Osmond, Shali Zhang, Fernando S. Carneiro, Victor V. Lima, Edward W. Inscho, R. Clinton Webb, Rita C. Tostes; Clopidogrel, independent of the vascular P2Y12 receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats. Clin Sci (Lond) 1 April 2010; 118 (7): 463–471. doi: https://doi.org/10.1042/CS20090392
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