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Published on: December 23, 2014
Clopidogrel improves endothelial function and NO bioavailability by sensitizing adenylyl cyclase in rats with
Andreas Schäfer1, Daniela Fraccarollo, Stephanie Pförtsch
1Klinik für Kardiologie und Angiologie, Zentrum Innere Medizin, Medizinische Hochschule Hannover, Germany. schaefer.andreas@mh-hannover.de
Insights
Clopidogrel treatment improved endothelial function in rats with heart failure by enhancing nitric oxide (NO) bioavailability and signaling pathways. This study shows clopidogrel
Area of Science:
- Cardiovascular Research
- Pharmacology
- Endothelial Function
Background:
- Congestive heart failure (CHF) is linked to endothelial dysfunction and heightened platelet activation.
- Clopidogrel, an antiplatelet medication, is known to improve endothelial function and nitric oxide (NO) bioavailability in coronary artery disease.
Purpose of the Study:
- To investigate the effects of clopidogrel on endothelial function in a rat model of congestive heart failure (CHF) induced by myocardial infarction (MI).
Main Methods:
- Rats with CHF were treated with either clopidogrel or placebo for two weeks.
- Endothelial function was assessed using isolated aortic rings in organ bath experiments, measuring vasorelaxation and vasoconstriction responses.
- Key signaling molecules, including AKT and endothelial nitric oxide synthase (eNOS), were analyzed for phosphorylation levels.
Main Results:
- Clopidogrel treatment significantly improved acetylcholine-induced, NO-mediated vasorelaxation in CHF rats.
- The drug also enhanced adenosine-induced vasorelaxation, indicating improved adenylyl cyclase signaling.
- Clopidogrel prevented increased vasoconstriction and normalized P2Y(12) signaling, alongside increasing AKT and eNOS phosphorylation.
Conclusions:
- Clopidogrel effectively improves endothelial function and nitric oxide bioavailability in a rat model of heart failure.
- The study suggests that P2Y(12) blockade with clopidogrel can ameliorate impaired signaling pathways in CHF, contributing to improved vascular health.
Abstract:
Clopidogrel treatment in patients with coronary artery disease not only inhibits platelet activation but also improves endothelial function and nitric oxide (NO) bioavailability. Congestive heart failure (CHF) is associated with endothelial dysfunction and increased platelet activation. In rats with CHF following myocardial infarction (MI), we investigated whether treatment with clopidogrel modifies endothelial function. Eight weeks after coronary artery ligation, rats with CHF were randomized to placebo or the P2Y(12) receptor antagonist clopidogrel (5 mg/kg twice daily, given by gavage) for another 2 weeks. Afterwards, endothelial function was assessed in isolated aortic rings in organ bath experiments. Acetylcholine-induced, endothelium-dependent, nitric oxide-mediated vasorelaxation was significantly attenuated in CHF rats compared to sham-operated animals, and was significantly improved by treatment with clopidogrel. Adenosine-induced vasorelaxation via adenylyl cyclase stimulation was attenuated in CHF and significantly improved by clopidogrel. Increased vasoconstriction to phenylephrine was observed in CHF, particularly evident under cyclooxygenase inhibition, but prevented by clopidogrel treatment. Vasoconstriction by the P2Y(12) activator 2MeS-ADP was increased in CHF. Clopidogrel-treated CHF animals displayed enhanced phosphorylation of AKT and eNOS. In conclusion, clopidogrel improved endothelial function and NO bioavailability in heart failure. During CHF, sensitivity to P2Y(12) signaling was increased leading to impaired adenylyl cyclase-mediated signaling. Chronic P2Y(12)-blockade with clopidogrel improved adenylyl cyclase-mediated signaling including increased AKT- and eNOS-phosphorylation contributing to improved NO-mediated vasorelaxation.
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