Functional and Morphological Improvement in Erectile Tissue of Hypertensive Rats by Long-Term Combined Therapy with Phosphodiesterase Type 5 Inhibitor and Losartan

Abstract

Introduction Erectile dysfunction (ED) is highly associated to cardiovascular disease, especially arterial hypertension. Phosphodiesterase type 5 (PDE5) inhibitors and angiotensin II receptor blockers (ARB) are both common and efficient therapy in patients with ED and arterial hypertension, respectively. Aim To evaluate the effect of PDE5 inhibitor, sildenafil (S), and of ARB Losartan (L) in a continuous combined therapy for a long term on penile structures in a hypertensive rat model. Methods During 6 months, four groups of male spontaneously hypertensive rats (SHR) and one of Wistar-Kyoto (WKY) rats, as control group, were studied: no-treatment SHR, SHR with L, SHR with S, SHR with S+L, and no-treatment WKY. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, collagen type III (COL-III), and endothelial nitric oxide synthase (eNOS) expression in cavernous space were evaluated. Main Outcome Measure Functional and morphological differences between S and L in a continuous combined therapy vs. either drug as monotherapy on penile structures. Results After 6 months, SHR that received L, S, or combined therapy showed a similar reduction in blood pressure compared with untreated SHR. Nevertheless, SHR+L+S and control WKY showed significantly lower values of (i) CSM (P < 0.01), (ii) VSM (P < 0.01), and (iii) COL-III (P < 0.01) when compared with the untreated SHR and also with the SHR with monotherapy. Additionally, SHR+L+S, presented a higher eNOS expression in sinusoidal endothelium in comparison with the untreated SHR and the SHR with monotherapy (P < 0.01). In vitro studies revealed that SHR+L+S displayed a better relaxation response to acetylcholine than the untreated SHR and the SHR with monotherapy (P < 0.01). Conclusions These results suggest that a long-term combined therapy using L and S is a useful tool for functional and structural modification in cavernous tissue from SHR.

Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

“…1), if given for extended periods of time, has sustained beneficial cardiovascular effects. The finding that beneficial effects outlast the increase in circulating levels of the cGMP has also been reported in the remnant kidney model [18] and in the erectile tissue [17]. The potential additional benefits of repeated doses of the drug were not addressed in the present studies.…”

“…2). Concordant with this explanation is the report of Tobili et al [17] who gave the drug for several months in a study intended to examine the effect of therapy on the erectile tissue histology, and found a significant reduction in blood pressure.…”

“…Yet, the potential cardiovascular benefits of chronic sildenafil administration deserve careful evaluation since long-term studies conducted to examine erectile tissue morphology [17] in SHR found a significant reduction in blood pressure. Therefore, the present studies were done to evaluate the long-term (6 months) effects of sildenafil administration on the blood pressure, endothelial dysfunction, and renal oxidative stress and inflammation in SHR.…”

Losartan Preserves Erectile Function by Suppression of Apoptosis and Fibrosis of Corpus Cavernosum and Corporal Veno-Occlusive Dysfunction in Diabetic Rats

“…Treatment with losartan, an antagonist of the Ang II type 1 receptor, suppressed the TGF-β1/Smad pathway and preserved erectile function, suggesting that Ang II type 1 receptor antagonism may counteract structural changes in the corpus cavernosum and preserve erectile function [21]. In addition, recent evidence indicates that blocking of Ang II is more important than inhibition of TGF-β in non-penile tissue fibrosis [22], and combined therapy with sildenafil and losartan presented a better outcome in terms of functional and structural modification in the cavernous tissue of spontaneously hypertensive rats (SHR) as compared with either of the two drugs alone [23]. However, the role of Ang II in apoptosis and fibrosis of the penile corpora cavernosa and CVOD in a diabetic condition has not been investigated until recently.…”

Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis

“…3 These conditions are frequently associated with a reduced endothelium-mediated vasodilation, where nitric oxide (NO) has a critical function. [4][5][6] If the bioactivity of NO is significantly reduced, this could lead to endothelial dysfunction that contributes to ED as a result of the atherosclerotic vascular disease. Therefore, preservation or restoration of NO bioactivity could be a potential target for ED treatment, especially in the presence of systemic atherosclerosis (AS).…”