Abstract
Objective: β-adrenoreceptor overstimulation with isoproterenol (ISO) induces endothelial dysfunction and hyperreactivity to phenylephrine (PHE). Statins, HMG-CoA reductase inhibitors, has pleiotropic effects that improve endothelial function. The aim of this study is to evaluate the effect of pretreatment with simvastatin (SIMV) on the hyperreactivity to PHE in the aorta of ISO-treated mice. Design and method: C57BL6/J mice were treated with SIMV (5 μg/g/day; gavage) or vehicle (VHC). From day 7, both groups received VHC (soybean oil; sc) or ISO (15 μg/g/kg; sc) for more 7 days. After treatment, the experimental groups (CT, ISO, SIMV and SIMV + ISO) were killed and heart, tibia and thoracic aorta were collected. The analysis of cardiac hypertrophy (CH) was performed using the ratio of heart weight / length of the tibia. PHE-induced contraction (10–10–10–5 M) in the presence or absence of non-selective nitric oxide (NO) synthase inhibitor (L-NAME, 100 μM) were evaluated in aortic rings. The fluorescent dye hydroethidine was used to evaluate the in situ production of reactive oxygen species (ROS) and endothelial NO synthase (eNOS) dimerization by Western Blot. Results are analyzed by Two-way ANOVA; p < 0.05 *vs CT, #vs. SINV. Results: ISO (26 ± 3% *) and SIMV + ISO (20 ± 2% #) presented CH when compared to controls. The maximum response (Rmax) to PHE was reduced in SIMV aortas when compared to CT. However, this response was higher in ISO and SIMV + ISO compared to their respective control. L-NAME increased Rmax to PHE in all groups. The magnitude of this response was greater in SIMV and reduced in ISO and SIMV + ISO. ROS bioavailability increased in ISO and SIMV + ISO, while did not change in SIMV. The ratio of eNOS dimer to monomer was significantly lower in aortas from ISO and SIMV + ISO groups. Conclusions: SIMV, despite increasing the NO bioavailability, was not able to reverse the reduction of nitrergic modulation, oxidative stress and eNOS uncoupled, which result in PHE hyperreactivity in aortas from ISO-treated mice.
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