Nrf2 activation improves both hyperpolarization- and NO-mediated responses in penile vasculature from patients with erectile dysfunction
Angulo, J1; El Assar, M2; Martínez-Salamanca, JI3; La Fuente, JM4; Fernández, A1; Sánchez-Ferrer, A2; Pepe-Cardoso, AJ5; Louro, N4; Rodríguez-Mañas, L6
1: Hospital Universitario Ramón y Cajal, Spain; 2: FIBio Hospital Universitario de Getafe, Spain; 3: Hospital Universitario Puerta de Hierro, Spain; 4: Hospital Santo Antonio, Portugal; 5: Hospital Fernando da Fonseca, Portugal; 6: Hospital Universitario de Getafe, Spain
Objective: Oxidative stress has been proposed to be related to erectile dysfunction (ED) pathophysiology. Nrf2 is a master regulator of antioxidant defense. We have previously reported an improvement of endothelium-dependent relaxation by Nrf2 activator, sulforaphane, in rat corpus cavernosum (RCC) from aged rats and in penile resistance arteries (HPRA) and corpus cavernosum (HCC) from patients with ED. The aim of this work was to characterize the effects of Nrf2 activation in human penile tissue function.
Methods: HPRA and HCC were dissected from cavernosal specimens from 17 patients (64.3±2.4 years old) undergoing penile prosthesis insertion, who gave informed consent, and functionally evaluated in wire myographs and organ chambers, respectively. Six patients had diabetes, 11 hypertension, 7 dyslipidemia, 2 obesity and 4 established cardiovascular disease. All patients had one or more cardiovascular risk factors (CVRFs).
Results: Two different Nrf2 activators, sulforaphane (10 µM) and oltipraz (30 µM) were able to improve endothelial relaxation in HCC, contributed by NO, and in HPRA, contributed by NO and endothelium-derived hyperpolarizing factor (EDHF). In fact, sulforaphane markedly improved EDHF-mediated vasodilation (after NO synthesis and cyclooxygenase inhibition) in HPRA (Emax 47.0±10.7% vs. 77.1±3.9%, p < 0.05). Small- and intermediate-conductance calcium-activated potassium channels (SK and IK) are involved in EDHF-mediated vasodilation. In this sense, sulforaphane enhanced the relaxation induced by the SK and IK activator, NS309, in HPRA. However, the very limited endothelial vasodilation (10.2±4.9%) remaining after blocking hyperpolarization with KCl in HPRA was also significantly potentiated by sulforaphane (24.7±4.7%, p < 0.05), suggesting that Nrf2 activation potentiates NO-dependent vasodilation. In this sense, treatment of HPRA from ED patients with sulforaphane resulted in an improvement of vasodilation driven by the PDE5 inhibitor, tadalafil (pD2 6.24±0.51 vs. 7.55±0.55, p < 0.05).
Conclusions: Thus, Nrf2 activation results in improved EDHF- and NO-mediated responses in human penile vasculature from patients with ED and CVRFs and would potentially increase therapeutic activity of PDE5 inhibitors in these men.
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