Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction

Abstract

Background: Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED). Aim: To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP). Methods: Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9−10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation-and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22 phox , interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student's t-test. Outcomes: The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels. Clinical Translation: The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors. Strengths and limitations: Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence. Conclusions: L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction.

Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats

“… 20 In this study, the expression of eNOS did not change in the L-OHP group; moreover, GJG administration did not affect NOS expression ( Figure 3 B). In our previous study, L-OHP significantly decreased the eNOS protein levels, 3 but in this study, the eNOS expression remained unchanged in the L-OHP group. After 2-3 days of receiving oxaliplatin, the food intake also decreased.…”

“…Intracavernos pressure (ICP) was measured by electrical stimulation as previously reported. 3 , 10 , 11 , 12 , 13 , 14 Rats from each group were briefly anesthetized using isoflurane (Mylan, Canonsburg, PA, USA) using inhalation anesthesia apparatus (Nakazawa Seisaku-sho, Funabashi, Japan). The carotid artery was cannulated for continuous monitoring of the mean arterial pressure (MAP), and the left crus of the corpus cavernosum was cannulated using a 23-G needle for continuous ICP monitoring.…”

“…Western blot analysis was performed as previously reported. 3 , 15 , 16 We extracted protein from the corpus cavernosum using Cell Culture Lysis Reagent (Promega Corp., Madison, WI, USA) in accordance with the manufacturer's instructions. Total protein concentration was quantified using BCA Protein Assay Reagent (Pierce Biotechnology, Rockford, IL, USA).…”

“…Oxaliplatin (L-OHP), a third-generation platinum-containing anti-cancer drug, is widely used for colorectal cancer, and colorectal cancer is the third most common type of cancer among adults in the Western world. 1 , 2 We previously reported that L-OHP caused erectile dysfunction (ED) in rats, 3 while neuropathy is a common adverse effect of the platinum agent. 4 The development of neuropathy is a major concern that may negatively influence a patient's quality of life.…”

Evaluating the Effects of Low Carbohydrate and High Protein Diet on Erectile Function in Rats

“…Blood pressure was measured as per methods previously reported. 9 , 10 Systemic and diastolic arterial blood pressures of the rats were measured at 0, 2, and 4 weeks, using a noninvasive automatic device (BP-98A-L, Softron, Tokyo, Japan). Mean arterial pressure was automatically calculated by the device.…”