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Published on: December 5, 2017
How does chronic sildenafil prevent vascular oxidative stress in insulin-resistant rats?
Alexandra Oudot1, Delphine Behr-Roussel, Olivier Le Coz
1Pelvipharm, Orsay, France.
Introduction:
Insulin resistance features both endothelial dysfunction and increased oxidative stress. Both disorders are targeted by a chronic treatment with sildenafil. However, the mechanism of action by which chronic sildenafil exerts its effects on reactive oxygen species sources is still largely unknown.
Aim:
We therefore investigated how chronic sildenafil administration could impact vascular endothelial NO and superoxide release in a rat model of insulin resistance induced by fructose overload.
Methods:
Adult male Wistar rats were fed a fructose-enriched diet (fructose-fed rats [FFR]) for 9 weeks. From weeks 6-8, sildenafil was administered subcutaneously twice daily (20 mg/kg), followed by a 1-week washout.
Main Outcome Measures:
Vascular endothelial NO and superoxide release were monitored in vitro in thoracic aortic segments using oxidative fluorescence. Specific inhibitors were used to distinguish the respective role of the main superoxide-producing systems within the vascular wall (i.e., mitochondrial respiratory chain and NADPH oxidases). The levels of expression of eNOS, Akt, and NADPH oxidase subunits were determined in the abdominal aorta.
Results:
Chronic sildenafil administration corrected hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in FFR. Moreover, after 9 weeks of diet, while global unstimulated aortic endothelial NO and superoxide release were unchanged in FFR, the relative contribution of the mitochondrial respiratory chain and NADPH oxidases was modified. Chronic sildenafil treatment, even after the 1-week washout period, was able to increase endothelial NO release independently of Akt-dependent phosphorylation by up-regulating eNOS expression, and restored the relative contribution of each superoxide-producing system examined, yielding endothelial superoxide release. Finally, in vitro incubation of aortic segments with sildenafil markedly decreased the endothelial aortic superoxide release.
Conclusions:
The present study showed that chronic sildenafil produced sustained vascular antioxidant effects in insulin-resistant rats by increasing NO release and regulating vascular superoxide release, supporting therefore further investigations using chronic sildenafil administration in preventing cardiovascular alterations associated with oxidative stress.
Insights
Chronic sildenafil treatment improved insulin resistance in rats by boosting nitric oxide (NO) and regulating superoxide release, offering potential cardiovascular benefits.
Area of Science:
- Cardiovascular Research
- Metabolic Syndrome
- Pharmacology
Background:
- Insulin resistance is linked to endothelial dysfunction and oxidative stress.
- Sildenafil is known to target these conditions, but its mechanism on reactive oxygen species sources is unclear.
Purpose of the Study:
- To investigate the effects of chronic sildenafil on vascular endothelial nitric oxide (NO) and superoxide release in fructose-induced insulin-resistant rats.
- To elucidate the underlying mechanisms of sildenafil's action on oxidative stress markers.
Main Methods:
- Rats were fed a fructose-enriched diet to induce insulin resistance.
- Sildenafil was administered for a period, followed by a washout phase.
- Vascular NO and superoxide release were measured in aortic segments, with specific inhibitors used to identify superoxide sources (mitochondrial respiratory chain, NADPH oxidases).
- Expression of eNOS, Akt, and NADPH oxidase subunits was analyzed.
Main Results:
- Sildenafil treatment normalized hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in fructose-fed rats.
- Chronic sildenafil increased endothelial NO release by up-regulating eNOS expression, independent of Akt phosphorylation.
- Sildenafil treatment restored the balance of vascular superoxide production and reduced overall superoxide release.
- These effects persisted even after a washout period.
Conclusions:
- Chronic sildenafil administration exerts sustained vascular antioxidant effects in insulin resistance.
- Sildenafil increases NO bioavailability and modulates vascular superoxide release.
- These findings support further research into sildenafil for preventing cardiovascular complications associated with oxidative stress.
