Sildenafil reduces aortic endothelial dysfunction and structural damage in spontaneously hypertensive rats: Role of
Marcos A S Leal1, Rafaela Aires1, Thamirys Pandolfi1
1Laboratory of Translational Physiology, Federal University of Espirito Santo, Vitoria, ES, Brazil.
Abstract:
Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.
Insights
Sildenafil treatment improved endothelial function in hypertensive rats by increasing nitric oxide availability and reducing oxidative stress. This suggests sildenafil
Area of Science:
- Pharmacology
- Cardiovascular Research
- Endothelial Function
Background:
- Arterial hypertension is linked to endothelial dysfunction, characterized by an imbalance in reactive oxygen species (ROS) and nitric oxide (NO) production.
- Understanding the mechanisms of drugs affecting endothelial function is crucial for treating hypertension-related cardiovascular diseases.
Purpose of the Study:
- To investigate the mechanisms by which sildenafil, a phosphodiesterase-5 inhibitor, improves endothelial function in spontaneously hypertensive rats (SHR).
- To evaluate sildenafil's effects on blood pressure, vascular reactivity, oxidative stress, and endothelial structure in SHR.
Main Methods:
- Spontaneously hypertensive rats (SHR) were treated with sildenafil (40 mg/kg/day) for 3 weeks.
- Measurements included systolic blood pressure, vascular reactivity in aortic rings, circulating endothelial progenitor cells, systemic ROS, antioxidant capacity, NO production, lipid peroxidation, and endothelial structure via scanning electron microscopy.
- Selective inhibitors were used to elucidate the pathways involved in endothelium-dependent vasodilation.
Main Results:
- Sildenafil treatment reduced systolic blood pressure and partially restored vasodilation responses to acetylcholine and sodium nitroprusside in SHR.
- Sildenafil increased NO bioavailability, decreased oxidative stress and cyclooxygenase-1 (COX-1)-derived prostanoids, and improved endothelial architecture.
- Relaxant responses to sildenafil and 8-Br-cGMP were normalized, indicating improved cGMP/PKG signaling.
Conclusions:
- Sildenafil reverses endothelial dysfunction in hypertensive rats by enhancing NO-mediated vasodilation, reducing oxidative stress and COX-1 activity, and improving cGMP/PKG signaling.
- Sildenafil also mitigates structural endothelial damage, highlighting its potential as an adjuvant therapy for cardiovascular diseases associated with hypertension.
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