Sexual MedicineDaily Treatment with Sildenafil Reverses Endothelial Dysfunction and Oxidative Stress in an Animal Model of Insulin Resistance
Introduction
Insulin resistance (IR) has been implicated in the pathogenesis of obesity and the metabolic syndrome (MetS) as defined either by the International Diabetes Federation (IDF), National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATPIII), or European Group for the study of Insulin Resistance (EGIR) criteria [1]. In fact, MetS in both children and adults is a known independent cardiovascular risk factor [1], and patients with MetS exhibit impaired endothelium-dependent vasodilation [2]. It is now recognized that these disturbances in endothelial function are principal players in cardiovascular diseases [3]. It was reported that fructose consumption might be a contributing factor to the development of obesity and the accompanying metabolic abnormalities observed in MetS [4], and fructose has also been associated with angiopathy in patients with diabetes [5]. Interestingly, high fructose consumption by animals leads to impaired glucose tolerance, IR, hyperinsulinemia, and hypertriglyceridemia [6], with even a mild elevation of blood pressure found by some authors [7] but not confirmed by others [8].
In a previous study, we evidenced the beneficial effects of daily sildenafil on erectile function in normal rats and further characterized these effects in vitro to be via improved cavernosal endothelial function [9]. Because previous work had shown the central role of the Akt-dependent phosphorylation of endothelial nitric oxide synthase (eNOS) in mediating penile erection [10], we hypothesized that chronic sildenafil may actually exert a direct or indirect effect beyond phosphodiesterase (type) 5 (PDE5) inhibition and thus modulate the transduction pathway leading to the activation of eNOS. Indeed, the serine/threonine–specific protein kinase Akt could be involved in the upregulation of eNOS activity by a calcium-independent mechanism, resulting in the phosphorylation of eNOS and increase in eNOS activity [11]. Thus, a plausible explanation of the beneficial effects of daily sildenafil on endothelial reactivity may be that it leads to an increased expression of phosphorylated eNOS over total eNOS and active Akt over total Akt, as recently evidenced in cavernosal tissues [12]. Furthermore, it was suggested that daily treatment with PDE5 inhibitors could have additional and prolonged beneficial effects on endothelial function in patients with increased cardiovascular risks [13]. The benefit of this therapy could even be sustained 2 wk after discontinuation of therapy [13].
In this study, we aimed to investigate whether chronic sildenafil could improve systemic endothelium-dependent relaxations in an experimental model of IR by in vitro isometric tension studies on aortic and superior mesenteric arterial (SMA) rings. Moreover, because oxidative stress has been suggested to contribute to IR [14] and associated endothelial dysfunction [15], we sought to determine the effects of chronic sildenafil on a potentially relevant biomarker of endothelial dysfunction, urinary 8-isoprostanes (IPT) content, a direct marker of nonenzymatic in vivo lipid peroxidation and the most reliable and clinically relevant marker of oxidative stress available to date [16].
Section snippets
Chronic treatment of rats and monitoring of endothelial biomarkers
All procedures were performed in accordance with the legislation on the use of laboratory animals (NIH publication No 85-23, revised 2002) and animal care regulations in force in France. Male Wistar rats (Charles River, L’Arbresle, France, 180–220 g) were given standard chow (Reference TD.03102; CONT) or an isocaloric fructose-enriched diet containing 18.3% protein, 60.3% fructose, and 5.2% lard expressed in % diet by weight (Reference TD.89247; fructose-fed rats, FFR) for the following 9 wk
Results
Body weight changes, fasting glycemia, and plasma IL-6 and TNF-α levels remained statistically unchanged in the various treatment groups (Table 1). Conversely, FFR displayed an impaired OGTT as indicated by a greater hyperglycemic response and AUC compared with control rats both at weeks 8 and 9. Strikingly, chronic treatment with sildenafil corrected this hyperglycemic response while treatment lasted (p < 0.05, one-way ANOVA; Fig. 1). This effect, however, wore off 1 wk after cessation of
Discussion
A high-fructose diet in rats leads to impaired glucose tolerance, IR, hyperinsulinemia, and hypertriglyceridemia [6], with even a mild elevation of blood pressure found by some authors [7] but not confirmed by others [8], a set of symptoms that resembles MetS in humans. In humans, each of the above abnormalities is associated with endothelial dysfunction, let alone when all these risk factors are combined. Here, we confirmed the elevation of triglycerides and the lack of fasting hyperglycemia
Conflicts of interest
This work was supported by a restricted grant from Pfizer Ltd.
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