Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

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.

Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

“…Interestingly, although some recent studies demonstrated that association with antioxidants (e.g., polyphenols or vitamin E) potentiates vascular protection [213,214], sildenafil may also provide intrinsic antioxidant effects through NADPH oxidase activity inhibition [215]. This evidence was complemented by our research in various models of hypertension, nephropathy or atherosclerosis and demonstrated protective effects for endothelial, cardiac and kidney functions in physiological parameters, such as morphological analyses (Figure 1) [209,212,216,217,218,219]. Therefore, our studies and other experimental evidence support the clinical findings of improvement in endothelial function, reduction of markers of vascular inflammation, and beneficial effects for conditions beyond erectile dysfunction [220,221,222,223,224].…”

Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells

“…To our knowledge, we are the first to use flow cytometry to show that chronic sildenafil treatment by oral gavage, in addition to its vasoactivity, indirectly prevents damage to bone marrow cells by reducing ROS production and genomic instability which, consequently, preserves cell cycle kinetics in different cell types from atherosclerotic and hypertensive mice [7,10,[12][13][14]. Considering that the bone marrow is the primary stem cell source in adults and that autologous transplantation is the preferred therapy in clinical applications, our data provide insights into therapeutic potential of bone marrow stem cells from patients with cardiovascular disease.…”

“…To understand the mechanisms underlying atherosclerosis development and progression and how it impacts cell function, we use apolipoprotein E deficient (apoE −/− ) mice [1][2][3]11], which show high levels of plasma cholesterol and develop atherosclerotic lesions that resemble human disease. Emerging evidence suggests the beneficial effects of phosphodiesterase 5 (PDE5) inhibition with sildenafil on cardiovascular diseases and other target organs [6,7,10,[12][13][14]. However, the effects of sildenafil on oxidative DNA damage in bone marrow cells from apoE −/− mice have yet to be characterized.…”

Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling

“…Importantly, recombinant human ACE2 treatment was able to rescue Ang II-mediated pathological actions in the ApoEKO mice with improvement of renal inflammation, oxidative stress and ultrastructure injury. ACE2 has local physiological effects, especially in the kidney, turning the balance within the RAS cascade from pro-inflammatory and pro-oxidant effects to anti-inflammatory and anti-oxidant effects [ 23 – 25 ]. Our data showed that downregulation of renal ACE2 levels was observed in the ApoEKO mice with no changes in SBP and renal Ang II levels.…”