Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now,
we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile
hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil.
The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and
compared with apoE and wild-type (WT) mice administered with vehicle (veh). The apoE-veh mice exhibited an imbalance
of nitric oxide and reactive oxygen species (NO/ROS) levels and an increased maximum response (Rmax, 20%) and
sensitivity (7%) to PE, which were not modified by endothelial removal. Under the prostanoids blockade, vasocontraction
was decreased more in apoE-veh (-37%) than in WT (-27%) and apoE-sil (-30%) mice. NADPH-oxidase blockade abolished
the enhanced contractile responsiveness in apoE-veh (-33%), without effects in WT and apoE-sil groups. The atherosclerotic
lesions and the imbalance of NO/ROS were reduced (40%) in apoE-sil mice. In conclusion, ED in apoE mice
was characterized by decreased NO-bioavailability and contractile hyperresponsiveness, due to thromboxane and oxidative
stress, and was normalized by sildenafil. The beneficial effects of this phosphodiesterase-5 inhibitor on ED and lipid
deposition provide new insights for its use as adjuvant in the treatment of atherosclerosis.
Keywords: ApoE knockout mice, atherosclerosis, endothelial dysfunction, nitric oxide, oxidative stress, sildenafil.
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