Sildenafil Inhibits Superoxide Formation and Prevents Endothelial Dysfunction in a Mouse Model of Secondhand Smoke Induced Erectile Dysfunction

Abstract

Purpose We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy. Materials and Methods Four groups of mice were used, including group 1—controls, group 2—mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3—control plus sildenafil (100 mg/kg per day) and group 4—smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed. Results Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine. Conclusions Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative stress. Sildenafil therapy restored nitric oxide synthase activity and decreased reactive oxygen species signaling, resulting in improved erectile function.

Assessment of the acute effects of tadalafil on the cardiovascular system based on examination of serum oxidative status and paraoxonase activity in men with erectile dysfunction: a preliminary study

“…11 Another study reported the same conclusion in an animal model of passive-smoking-induced ED. 12 Our results on the oxidative status of patients with ED support these findings for tadalafil citrate; additionally, although we did not measure data more than 2 h after drug administration, we propose that the reduction in serum oxidative stress may last more than a day, given that tadalafil citrate has a longer serum half-life than sildenafil citrate. This beneficial effect of PD5 on serum oxidative status may also be supported empirically by the finding that the antioxidant vitamin E enhances levels of circulating NO and thus may improve erectile function, with potential for a synergistic effect with PDE5 inhibitors.…”

“…Studies on the beneficial effects of PDE5 inhibitors on endothelial functions and their contribution to vascular repair have provided justification for the expansion of the indication spectrum. 11,12,20,21 Paradoxically, the associations of PDE5 inhibitors usage and some life-threatening events, such as acute MI and stroke, in connection with some disorders, such as cardiac arrhythmias, hypo/hypertension, are related to the cardiac and neurovascular systems. 7,8 Nevertheless, recent reports strongly suggest that there is no increase in the incidence of acute MI or death rates during sexual activity while using PDE5 inhibitors.…”

“…10 In some of these studies, sildenafil citrate was shown to have protective effects on oxidative stress by inhibiting free radical formation and supporting antioxidant redox systems; this reduction in oxidative stress is the supposed reason behind the improvement in endothelial function. 11,12 However, to the best of our knowledge, the effect of PDE5 inhibitors on paraoxonase, which is closely related to serum oxidative status and cardiovascular and endothelial functions, has not yet been reported.…”

Fundamental role of Warburg effect in various pathophysiological processes

“…Statins (121,122) 765 13. Sildenafil : Sildenafil has been used in PAH, erectile dysfunction (ED) and it has been shown to 766 restore eNOS ,prevented endothelial dysfunction and decreased iNOS in the ED animal model 767 (227). Sildenafil can be given in later stages of septic shock, whereas in the initial state ( Figure 3), 768…”

Mountainside to bedside: reality or fiction?

“…While this Editorial might be intuitively explained by the direct effect of sildenafil as a pulmonary dilator, the improvement in exercise capacity at altitude occurred in the absence of pulmonary hemodynamic changes [24]. Alternative mechanisms may therefore be responsible, including alterations in ROS metabolism and nitric oxide synthase activity, which may in part explain some of the benefits of sildenafil in patients at sea level [25].…”