CLINICS 2010;65(12):1311-1314 Effects of PDE5 inhibitors on vasculogenic ED Savas M et al. Table 2 - Mean serum total antioxidant status, total oxidant status and prolidase enzyme activities of the patients (before and after tadalafil citrate) and control cases. TOS (mmol H2O2 Eq/L) TAS (mmol Trolox Eq/L) Prolidase (U/L) Control (n = 30) 4.37¡ 0.9 1.83¡0.2 218.09¡17.5 Patient (n = 36) BTC 10.3¡1.1 1.1¡0.0 236.4¡19.5 ATC 6.9¡1.2 1.6¡0.0 228.2¡19.2 p1 ,0.0001 ,0.0001 ,0.0001 p Value p2 ,0.0001 ,0.0001 ,0.0001 p3 ,0.0001 ,0.0001 ,0.0001 ATC, after tadalafil citrate administration; BTC, before tadalafil citrate administration; TAS, total antioxidant status; TOS, total oxidant status. p1, independent samples t-test for control and patient before tadalafil citrate; p2, independent samples t-test for control and patient after tadalafil citrate; p3; paired samples t-test for patient before and after tadalafil citrate. inhibitors, making it an ideal candidate when switching from on-demand use to its use as a prophylactic drug for any indication in the future. The safety of the drug will be important for regular long-term users. It has been suggested that oral vasoactive pharmacother- apy, such as PDE5 inhibitor drugs, may provide vasculo- protective benefits for cardiovascular disease as well as for vasculogenic ED.18 Reduced serum oxidative stress is thought to be the foundation of this mechanism. More- over, in support of this theory from the opposite side, oxidative stress has been shown to have a role in the development and progression of atherosclerosis.19 It was claimed, in a placebo-controlled study, that 100 mg silde- nafil improved the serum oxidative status of subjects without any health problems;8 this effect lasted for 1 day. A further study reached the same conclusion in an animal model of second-hand smoke-induced ED.9 Our results for the oxidative status of the patients with ED support these findings for tadalafil citrate and, additionally, we think that the reduced serum oxidative stress may last for more than a day because tadalafil citrate has a longer serum half-life than sildenafil. On the contrary, in a recent study, Burnett et al. found no effect of sildenafil on serum oxidative status in diabetic patients with ED receiving short-term treatment.18 It should be remembered that all three PDE5 inhibitors have similar oxidative activity.19 However, to our knowledge, this is the first clinical study that has evaluated the relation between tadalafil citrate and serum oxidative–antioxidative status, showing decreasing TOS and increasing TAS values with treatment. Prolidase is a highly specific peptidase that has an important functional role in all human tissues and cells. High prolidase activity has been reported in the brain, heart, liver, muscle and, especially, in the kidney. Hereditary prolidase deficiency—a multisystemic disorder—is charac- terized by a wide spectrum of clinical manifestations, including skin ulcers, mental retardation, and susceptibility to infections. Oxidative stress results in collagen degrada- tion and this process is mediated by prolidase.12 Moreover, the degree of severity of oxidative stress is directly related to the inhibition of collagen production, and prolidase is thought to be the target enzyme of this process.20 Our study showed that tadalafil citrate significantly reduced prolidase activity at the peak serum level. This might be due to reduced degradation activity, possibly caused by reduced serum oxidative stress. In addition, reduced prolidase activity also confirms the reduced oxidative stress under the action of tadalafil citrate—a topic still debated in the literature. Fibrosis of the corpora cavernosa and the media of penile arteries, involving loss of smooth muscle cells, is a common 1313 process that underlies most cases of vasculogenic ED.21 The concept that progressive fibrosis of the smooth muscle tissue within the penile corpora cavernosa is responsible for the vasculogenic ED associated with diabetes, ageing, heavy smoking, and pelvic surgery, has gained support over the past decade.22 From a functional perspective, this fibrotic process leads to a decrease in the compliance of the corporal tissue after stimulation by the nitric oxide/cyclic guanosine monophosphate system. This inability of the corporal tissue to relax sufficiently to occlude the regressing subtunical veins occurs in most patients with ED23-26 and is termed venous leakage or corporal veno-occlusive dysfunction. Therefore, the study of fibrosis may provide a unifying view of the vasculogenic disorders affecting the penis. Profibrotic factors, the excessive deposit of collagen fibers and other extracellular matrix, the appearance of a synthetic cell pheno- type in smooth muscle cells or the onset of a fibroblast– myofibroblast transition, and in the case of the corporal or penile arterial tissue, the reduction of the smooth muscle cellular compartment underlies vasculogenic ED. This histopathology leads either to localized plaques or nodules in penile tissue, or to the diffuse fibrosis causing impairment of tissue compliance that underlies corporal veno-occlusive dysfunction and arteriogenic ED. The antifibrotic role of the sustained stimulation of the nitric oxide/cyclic guanosine monophosphate pathway in the penis and its possible relevance to exogenous and endogenous stem cell differ- entiation may explain the collagen biosynthesis. The relation- ship between collagen and prolidase activity was observed during fibrotic processes, where an increase in prolidase activity was accompanied by increase in tissue collagen deposition.27 The negative effect of free radicals is mediated by degradative agents such as proteolytic enzymes and the last step of collagen degradation is mediated by prolidase.12 Surazynski et al. pointed out that prolidase may also have a role in angiogenesis as prolidase deficiency is associated with angiopathy.13 Oxidative stress resulted in collagen degradation and this process is mediated by prolidase.12 Moreover the degree of severity of oxidative stress is directly related to the inhibition of collagen production, and proli- dase is thought to be the target enzyme of this process.28 Yildiz et al. showed that increased serum prolidase activity was significantly associated with the presence and severity of coronary artery disease.29 In accordance with their study we have shown that serum prolidase activity is significantly associated with the presence and severity of vasculogenic ED, and elevated serum prolidase activity may be an indepen- dent predictor of ED.10 In addition, it was suggested that hypertension and its duration is associated with increased serum prolidase activity and might be useful as a marker for the follow-up of hypertensive patients.11