Name: MARCOS ANDRÉ SOARES LEAL
Publication date: 21/06/2019
Advisor:
Name |
Role |
|---|---|
| ELISARDO CORRAL VASQUEZ | Advisor * |
Examining board:
| Name |
Role |
|---|---|
| BRENO VALENTIM NOGUEIRA | External Examiner * |
| CAMILLE DE MOURA BALARINI | External Examiner * |
| ELISARDO CORRAL VASQUEZ | Advisor * |
| NAZARE SOUZA BISSOLI | Internal Examiner * |
| VALERIO GARRONE BARAUNA | Internal Examiner * |
Summary: Arterial hypertension is a condition associated with endothelial dysfunction of small and large vessels, accompanied by an imbalance in the production of reactive oxygen species (ROS), vasodilators and vasoconstrictors prostanoids and NO. The aim of this study was to investigate the effects of sildenafil, a selective phosphodiesterase-5 inhibitor that increase NO pathway, on endothelial function in aortas from Spontaneously Hypertensive Rats (SHR).
EXPERIMENTAL APPROACH: SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar control rats. Vascular reactivity was measured in isolated rat aortic rings. Circulating endothelial progenitor cells and superoxide anions were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Picrosirius staining and scanning electron microscopy was used for vascular morphology and structural analysis of the endothelial surface.
KEY RESULTS: Sildenafil partially restored the vasodilator response to acetylcholine in SHR aorta and normalized the vasoconstrictor response to phenylephrine. Our experiments with a NO synthase blocker revealed an augmented participation of NO, decreased participation of oxidative stress, prostanoids Cox-1-derived in the vascular dilation and contration, respectively, in sildenafil-treated SHR and improvement in prostacyclin thromboxane balance. The improved vascular function in sildenafil-treated SHR was unaffected by SC-560 and apocynin.The relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR. Sildenafil restored the prooxidant/antioxidant balance and the vascular morphology and endothelial architecture.
CONCLUSIONS AND IMPLICATIONS: Sildenafil reverses endothelial dysfunction in SHR by improving vascular contraction and relaxation to phenylephrine and acetylcholine, respectively. The mains mechanism behinde sildenafil effects are reduction of the oxidative stress and cyclooxygenase-1 prostanoids, improvement in prostacyclin thromboxane balance, with an augmentation of NO bioavailability and improvement in the cGMP/PKG signaling. Also, sildenafil improves structural damage in the vascular and endothelium surface.
