Diabetes Exacerbates the Functional Deficiency of NO/cGMP Pathway Associated with Erectile Dysfunction in Human Corpus Cavernosum and Penile Arteries

Abstract

Introduction Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. Aim The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. Methods Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. Main Outcome Measures Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. Results The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (Emax 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. Conclusions ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

“…The efficacy of PDE5 inhibitors for treating ED is lower in diabetic patients (Vickers and Satyanarayana, 2002;El-Sakka, 2004). It has been recently demonstrated that capacity of sildenafil to relax HPRA is reduced in diabetic patients with ED (Angulo et al, 2010a). In addition to confirm the impaired vasodilatory capacity of sildenafil in HPRA from diabetic patients, the present results show that the activation of KCa with NS-8 potentiates the relaxant responses to PDE5 inhibition on HPRA from both diabetic and non-diabetic men.…”

“…The ability of PDE5 inhibitors to relax isolated horse and human penile arteries and, rabbit and HCC, has been previously observed (Taher et al, 1997;Kalsi et al, 2004;Ruiz-Rubio et al, 2004;Angulo et al, 2010a). Relaxation of contracted HPRA and HCC caused by PDE5 inhibition is sensitive to blockade of NO synthesis or inhibition of soluble guanylyl cyclase, confirming the involvement of the NO/cGMP pathway in these responses.…”

“…Sildenafil was a gift from Nitromed (Bedford, MA, USA) while tadalafil was provided by ICOS Corporation (Seattle, WA, USA). For in vitro experiments, all drugs were dissolved in deionized water, except for NS-8, NS1619 (Malysz et al, 2004), sildenafil (Angulo et al, 2010a) and tadalafil (Angulo et al, 2012), which were dissolved at 10 mM concentration in dimethylsulfoxide (DMSO). The subsequent dilutions were made in deionized water.…”

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

“…The severity of endothelial dysfunction and peripheral neuropathy are mainly responsible for the poor responsiveness of diabetic patients to PDE5 inhibitors (8,9). Because the effects of PDE5 inhibitors depend on endogenous NO formation, PDE5 inhibitors fail to increase the cGMP level above the threshold required for penile erection if bioavailable NO is insufficient as the result of severe endothelial dysfunction or peripheral neuropathy (9). Therefore, a new treatment strategy that corrects both endothelial dysfunction and peripheral neuropathy is required for men with diabetic ED.…”

“…The multiple factors causing diabetic ED contribute to reduced responsiveness to currently available oral phosphodiesterase-5 (PDE5) inhibitors, which enhance the nitric oxide (NO)-cGMP pathway by inhibiting the breakdown of cGMP (7). The severity of endothelial dysfunction and peripheral neuropathy are mainly responsible for the poor responsiveness of diabetic patients to PDE5 inhibitors (8,9). Because the effects of PDE5 inhibitors depend on endogenous NO formation, PDE5 inhibitors fail to increase the cGMP level above the threshold required for penile erection if bioavailable NO is insufficient as the result of severe endothelial dysfunction or peripheral neuropathy (9).…”