Chih-Ching Yang1,2,3, Pin-Hao Liao1, Yu-Hsiuan Cheng1, Chen-Yen Chien4,5,6, Kuo-Hsin Cheng7,8, Chiang-Ting Chien1. 1. Department of Life Science, School of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan, ROC. 2. Office of Public Relation of Ministry of Health and Welfare, Taipei, Taiwan, ROC. 3. Center for General Education, Mackay College of Medicine, Nursing and Management, New Taipei City, Taiwan, ROC. 4. Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, ROC. 5. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC. 6. Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan, ROC. 7. Division of General Surgery, Department of Surgery, Far-Eastern Memorial Hospital, New Taipei City, Taiwan, ROC. 8. Department of Electrical Engineering, Yuan Ze University, Taoyuan, Taiwan, ROC.
Abstract
BACKGROUND: Diabetes or hypertension contributes to erectile dysfunction (ED). We hypothesized that excess reactive oxygen species (ROS) production evoked by diabetes combined with hypertension may further suppress endothelial nitric oxide (NO) expression/activity and promote oxidative stress in the ED penis. METHODS: Twenty-four adult male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were divided into four groups: normal WKY, diabetic WKY, normal SHR and diabetic SHR. Intraperitoneal streptozotocin (65 mg/kg) was applied to induce type I diabetes. After 4-week diabetes and/or hypertension induction, we determined the intra-cavernous pressure (ICP) using electrical stimulation of cavernous nerves, intra-cavernosum NO amount using an electrochemical NO probe, and blood ROS using an ultrasensitive chemiluminescence-amplified analyzer. Western blot analysis and immunohistochemistry were used to explore the pathophysiologic mechanisms of inflammation, apoptosis and autophagy in the penis. A novel NO donor, CysaCysd Lu-5 (CCL5, (RCH2CH2S)(R'R"CHCH2S)Fe(NO)2, 1-4 µg), was intravenously administered to these ED rats for evaluating their ICP responses. RESULTS: In the baseline status, the lucigenin- and luminol-amplified blood ROS were significantly enhanced in the diabetic SHR rats vs normal WKY rats. Significantly decreased ICP, eNOS expression and NO amount were found in the normal SHR, diabetic WKY, and diabetic SHR vs normal WKY rats. Intravenous NO donor L-Arginine markedly increased ICP and NO amount, whereas eNOS inhibitor, Nω-Nitro-L-Arginine methyl ester hydrochloride depressed ICP in all four groups. Diabetes and/or hypertension alone increased fibrosis, proinflammatory NF-kB/ICAM-1 expression, mast cell numbers, CD68 expression and infiltration, Caspase 3-mediated apoptosis, Beclin-1/LC3-II-mediated autophagy and mild Nrf-2/HO-1 expression and depressed eNOS expression in the ED penis. The novel NO donor, CCL5, was more efficient than L-arginine to improve diabetes and/or hypertension-induced ED by the significant increase of ICP. CONCLUSION: Diabetes combined with hypertension synergistically exacerbated ED through enhanced oxidative stress, inflammation, apoptosis and autophagy and depressed eNOS activity and NO production.
BACKGROUND: Diabetes or hypertension contributes to erectile dysfunction (ED). We hypothesized that excess reactive oxygen species (ROS) production evoked by diabetes combined with hypertension may further suppress endothelial nitric oxide (NO) expression/activity and promote oxidative stress in the ED penis. METHODS: Twenty-four adult male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were divided into four groups: normal WKY, diabetic WKY, normal SHR and diabetic SHR. Intraperitoneal streptozotocin (65 mg/kg) was applied to induce type I diabetes. After 4-week diabetes and/or hypertension induction, we determined the intra-cavernous pressure (ICP) using electrical stimulation of cavernous nerves, intra-cavernosum NO amount using an electrochemical NO probe, and blood ROS using an ultrasensitive chemiluminescence-amplified analyzer. Western blot analysis and immunohistochemistry were used to explore the pathophysiologic mechanisms of inflammation, apoptosis and autophagy in the penis. A novel NO donor, CysaCysd Lu-5 (CCL5, (RCH2CH2S)(R'R"CHCH2S)Fe(NO)2, 1-4 µg), was intravenously administered to these ED rats for evaluating their ICP responses. RESULTS: In the baseline status, the lucigenin- and luminol-amplified blood ROS were significantly enhanced in the diabetic SHR rats vs normal WKY rats. Significantly decreased ICP, eNOS expression and NO amount were found in the normal SHR, diabetic WKY, and diabetic SHR vs normal WKY rats. Intravenous NO donor L-Arginine markedly increased ICP and NO amount, whereas eNOS inhibitor, Nω-Nitro-L-Arginine methyl ester hydrochloride depressed ICP in all four groups. Diabetes and/or hypertension alone increased fibrosis, proinflammatory NF-kB/ICAM-1 expression, mast cell numbers, CD68 expression and infiltration, Caspase 3-mediated apoptosis, Beclin-1/LC3-II-mediated autophagy and mild Nrf-2/HO-1 expression and depressed eNOS expression in the ED penis. The novel NO donor, CCL5, was more efficient than L-arginine to improve diabetes and/or hypertension-induced ED by the significant increase of ICP. CONCLUSION: Diabetes combined with hypertension synergistically exacerbated ED through enhanced oxidative stress, inflammation, apoptosis and autophagy and depressed eNOS activity and NO production.
Authors: Szu-Ting Yang; Chia-Hao Liu; Sheng-Hsiang Ma; Wen-Hsun Chang; Yi-Jen Chen; Wen-Ling Lee; Peng-Hui Wang Journal: Int J Environ Res Public Health Date: 2022-07-26 Impact factor: 4.614