Clopidogrel, independent of the vascular P2Y₁₂ receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats

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.