Abstract
BackgroundThe clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).ResultsThe 2K1C mice exhibited normal plasma levels of Ang I, II and 1–7, whereas the intrarenal Ang I and II were increased (~35% and ~140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (~45%) and intrarenal (+15%) Ang 1–7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.ConclusionThese data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.
Highlights
High blood pressure (BP) has become a health issue, with a projected prevalence of about one third of the global population worldwide by 2025 [1], and endothelial dysfunction is the hallmark of this condition [2]
Animals were divided into two groups (8 to 10 animals per group): renovascular hypertensive mice treated with vehicle (2K1C) and hypertensive mice treated with 40 mg/kg/day of the phosphodiesterase 5 (PDE5)-inhibitor sildenafil (Viagra®, Pfizer) for 2 weeks by oral gavage (2K1C-sildenafil)
As previously reported by our laboratory [21], sildenafil reduced tendency of increased levels of Ang II (14%, p > 0.05) and normal levels of Ang 1–7 in the hypertensive 2K1C mice compared to the Sham mice (Figure 2A, C and E)
Summary
High blood pressure (BP) has become a health issue, with a projected prevalence of about one third of the global population worldwide by 2025 [1], and endothelial dysfunction is the hallmark of this condition [2]. It is well known that unilateral renal artery stenosis reduces renal perfusion, which activates the RAS [5] This system has been extended by the addition of a novel axis consisting of the angiotensin-converting enzyme 2 (ACE2), the heptapeptide angiotensin (Ang) 1–7, and the G protein-coupled receptor Mas [16]. Our laboratory analyzed some RAS peptides during the development phase of 2K1C hypertension in a murine model [3,20,21], in the present study, we extended the analysis of the Ang I, II and 1–7 levels in both plasma and the stenotic kidney during the established phase of renovascular hypertension. The clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. In the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance
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