Sildenafil and tadalafil reduce the risk of contrast-induced nephropathy by modulating the oxidant/antioxidant balance in a murine model

https://doi.org/10.1016/j.fct.2019.111038Get rights and content

Highlights

  • Contrast-induced nephropathy is determined by disturbances in oxidant/antioxidant balance.

  • TAC, GSH and CAT levels decrease while TABRS and PROTC levels increase in CIN.

  • Sildenafil and tadalafil reduce CIN risk.

  • Sildenafil and tadalafil increase TAC, GSH and CAT levels.

  • Sildenafil and tadalafil decrease TBARS and PROTC levels.

Abstract

The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.

Introduction

Contrast-induced nephropathy (CIN), is a serious iatrogenic form of acute kidney injury, occurring 24–72 h after the administration of iodinated contrast media (CM) during angiographic or other radiological procedures (Mamoulakis et al., 2017; Tsarouhas et al., 2018). In the last years, due to the increasing use of CM, CIN has become a big concern due to its high morbidity, hospital stay and mortality (Parfrey, 2005). CIN is an acute manifestation that appears two to three days after CM administration, lasts up to seven days and is not attributed to other causes of renal failure. Usually, the serum creatinine (CRE) levels return to normal within 14 days (Iordache et al., 2019).

CIN incidence is low (0.6–2.0%) in the general population (Caixeta et al., 2009) but it increases up to almost 15–24% in high risk patients such as older patients, and those suffering from chronic renal insufficiency, diabetes mellitus, and cardiovascular conditions (heart failure, hypertension, myocardial infarction) (Faucon et al., 2019; Lameire and Kellum, 2013; Mamoulakis et al., 2017). The route of administration and the type of procedure for which CM is used can influence CIN risk. CIN rate is increased after arterial CM administration compared to intravenous administration (Morabito et al., 2012).

There is no consensus on CIN definition, prevention, and treatment. Data are conflicting, depending on the definition used, on the biomarkers used for the evaluation of renal function, and on the timing of measurements. Consequently, the reported incidence of the condition varies among studies (Mamoulakis et al., 2017). CRE has been widely used for CIN diagnosis, either as 25%–50% increase of the baseline levels and/or an absolute elevation of 0.5–2.0 mg/dL from baseline (ACR Committee on Drugs and Contrast Media, 2016). According to the criteria developed by the Acute Kidney Network consensus group (Mehta et al., 2007), acute kidney injury is diagnosed if within 48 h after a nephrotoxic event (e.g., intravascular iodinated CM exposure), one of the following is observed: i) absolute CRE increase ≥0.3 mg/dL (26.4 μmol/L); ii) % increase in CRE ≥ 50% (≥1.5-fold above baseline); iii) urine output reduced to ≤0.5 mL/kg/h for at least 6 h.

The exact pathophysiology of CIN is not fully elucidated, and the identification of novel biomarkers that may more accurately detect renal function changes; reflect kidney damage; assist monitoring; and elucidate pathophysiology have attracted considerable scientific attention nowadays (Mamoulakis et al., 2019). Different theories and multiple mechanisms appear to be involved (Mamoulakis et al., 2017). The nephrotoxic potential of CM differs among various agent classes and is influenced by their osmolality, molecular structure and viscosity (Barrett and Carlisle, 1993; Tungjai et al., 2018). CM may exert a direct cytotoxic effect on the proximal tubular renal cells characterized by vacuolization, interstitial inflammation, and apoptosis due to the production of reactive oxygen species (ROS) and increase outflow resistance. Another mechanism is related to the ability of CM to increase renal vasoconstriction.

Hydration remains at present the first choice in preventing CIN (Mamoulakis et al., 2017; Pattharanitima and Tasanarong, 2014). Intravenous volume expansion using isotonic fluids prior to CM administration is the intervention proven most effective. The value of using compounds with antioxidant properties other than sodium bicarbonate remains controversial, warranting further clinical investigation (Dutta et al., 2018; Mamoulakis et al., 2017).

Phosphodiesterase 5 (PDE5) inhibitors (PDE5Is) are currently recommended as first-line therapy of erectile dysfunction (ED) in humans by enhancing the vasodilatory effects of nitric oxide (NO) (Hatzimouratidis et al., 2019). Acting via the selective inhibition of cyclic guanosine monophosphate (cGMP)-specific PDE5 that metabolizes cGMP, the principal mediator of NO-induced smooth muscle relaxation, PDE5Is cause vasodilatation in the corpora cavernosa promoting erection. Recently, research has been focused on the preventive and therapeutic use of these agents that are supposed to have a favorable effect on renal hemodynamics, given that the endogenous vasodilator NO is crucial for medullary oxygenation as well by enhancing regional blood flow (Morcos, 2014). Sildenafil's first official use was in 1998 as a pioneer medication for the treatment of ED at 25–100 mg on-demand use. Its onset of action is estimated after 30–60 min, with a duration of up to 12 h and pharmacokinetics affected by fatty food (Goldstein et al., 1998; Moncada et al., 2004). Apart from ED (Hatzimouratidis et al., 2019), sildenafil has been used for treating pulmonary hypertension (Ramani and Park, 2010) and as an off-label medication with unclear role for vasospasm related to other pathologies such as recurrent priapism (Tzortzis et al., 2009), and Raynaud's syndrome (Roustit et al., 2018). Tadalafil was launched in 2003 with a similar onset of action but the prolonged duration of effects lasting up to 36 h. The dose is 10–20 mg for ED (on-demand use); a dose of 5 mg/day has also been approved for treating ED (Hatzimouratidis et al., 2019), and lower urinary tract symptoms secondary to benign prostatic obstruction (Gravas et al., 2019; Oelke et al., 2014; Sakalis et al., 2017). Tadalafil has been approved at a dose of 40 mg for pulmonary arterial hypertension as it promotes vasodilation/inhibits vascular remodeling, resulting in lower pulmonary pressures (Curran (Curran and Keating, 2003; Gacci et al., 2016; Roehrborn et al., 2016; Ventimiglia et al., 2016). Additionally, it has been used as an off-label medication with an unclear role for the vasospasm related to other pathologies such as recurrent priapism (Tzortzis et al., 2009). The protective effect of sildenafil in CIN has been evaluated in some animal studies (Altintop et al., 2018; Lauver et al., 2014), only one study investigated till now the efficacy of tadalafil in the prevention of experimentally induced CIN (Özbek et al., 2015), but no study evaluated the difference and the efficacy of these two agents in the prevention of CIN. Tadalafil can have some advantages over sildenafil regarding the longer duration of action determined by a half-life of 17.5 h compared to only 4–5 h for sildenafil (Forgue et al., 2006; Nichols et al., 2002). The aim of the present study was to evaluate the protective role of sildenafil and tadalafil on a CIN rat model and to evaluate whether this potential effect is associated with oxidative stress modulation.

Section snippets

Reagents

All oxidative stress markers reagents, as well as sildenafil, tadalafil, Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, and N-acetyl cysteine (NAC) were purchased from Sigma-Aldrich (USA). The CM used was iopromide (Ultravist 300 mg iodine per mL, Bayer Pharma AG, Germany). The stock solution of sildenafil, tadalafil, and N-acetyl cysteine were made in dimethyl sulfoxide (DMSO) in a final dose of 0.5% DMSO (v/v) and dissolved in phosphate-buffered saline (PBS). DMSO is a good solvent

Increase of CRE levels at 24 h after CIN compared to baseline

The validity of our CIN model was documented by the fact that all animals in the CIN group presented an increase of CRE levels >25% compared to baseline at 24 h after CM administration. The percentage of CRE increase at 24 h after CIN induction compared to baseline in all groups is presented in Fig. 1.

TAC levels

TAC levels decreased in all groups, compared to sham group reaching the statistical significance only for CIN and CIN + SIL groups (Table 1). TAC levels increased in CIN + SIL, CIN + TAD and

Discussion

CIN represents a severe complication of CM use, especially in patients with risk for renal injury (Mamoulakis et al., 2017). A patient who develops CIN is at higher risk for worse clinical outcomes and complications, presents more extended hospital stay, and higher mortality. CM administration results in vasoconstriction with decreased local prostaglandin synthesis and vasodilatation mediated by NO and also a direct cytotoxic effect on tubular cells determined by increasing oxidative stress.

Conclusions

Induction of CIN in a murine model leads to disturbances in redox status translated by a decrease of TAC, GSH, and CAT levels and an increase of TBARS and PROTC levels. Pre-treatment with sildenafil and tadalafil reduce the incidence of CIN by modulating the oxidant/antioxidant balance in a rat model of CIN. Their effects are superior compared to NAC, even if they did not reach statistical significance, making them good candidates for future studies intending to demonstrate their protective

Author contribution

Andrei Mihai Iordache: conceptualization, methodology, investigation, writing - original draft.

Anca Oana Docea: conceptualization, methodology, investigation, writing - review & editing, supervision.

Ana Maria Buga: conceptualization, methodology, investigation, writing - review & editing, supervision.

Ovidiu Zlatian: methodology, investigation, data curation, writing - original draft.

Marius Eugen Ciurea: conceptualization, methodology, writing - review & editing, supervision.

Otilia Constantina

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This study is part of the PhD theses of Andrei Mihai Iordache from the University of Medicine and Pharmacy of Craiova, Craiova, Romania.

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