Research Papers:

Long-term administration of ketamine induces erectile dysfunction by decreasing neuronal nitric oxide synthase on cavernous nerve and increasing corporal smooth muscle cell apoptosis in rats

Hung-Sheng Shang, Yi-No Wu, Chun-Hou Liao, Tzong-Shi Chiueh, Yuh-Feng Lin and Han-Sun Chiang _

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Oncotarget. 2017; 8:73670-73683. https://doi.org/10.18632/oncotarget.10727

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Hung-Sheng Shang1,2,*, Yi-No Wu3,*, Chun-Hou Liao4,5, Tzong-Shi Chiueh2, Yuh-Feng Lin1,7,8 and Han-Sun Chiang3,4,6

1Graduate Institute of Clinical of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

2Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

3Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

4Division of Urology, Department of Surgery, Cardinal Tien Hospital, Taipei City, Taiwan

5College of Medicine, Fu Jen Catholic University, Taipei City, Taiwan

6Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan

7Division of Nephrology, Department of Medicine, Shuang Ho Hospital, School of Medicine, College of Medicine, Taipei Medical University, New Taipei City, Taiwan

8Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Han-Sun Chiang, email: [email protected]

Yuh-Feng Lin, email: [email protected]

Keywords: apoptosis, corporal smooth muscle, erectile dysfunction, ketamine, nitric oxide synthase

Received: November 09, 2015    Accepted: June 01, 2016    Published: July 20, 2016


We investigated and evaluated the mechanisms of erectile dysfunction (ED) in a rat model of long-term ketamine administration.

Adult male Sprague-Dawley rats (n = 32) were divided into four groups: namely the control group receiving intraperitoneal injection of saline, 1-month, 2-month and 3-month groups receiving daily intraperitoneal injection of ketamine (100 mg/kg/day) for 1, 2, and 3 month respectively. After treatment, animals underwent an erectile response protocol to assess intracavernosal pressure (ICP). Smooth muscle content was evaluated. Neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression were assessed using immunostaining assay. Ketamine-induced apoptosis was analyzed using TUNEL assay.

Long-term ketamine administration caused significantly decreased erectile responses as measured by ICP. Smooth muscle content was significantly decreased in the ketamine-treated rats for 3 months. In the erectile tissue, ketamine administration significantly reduced nNOS expression and increased iNOS content compared with controls, whereas eNOS expression was not altered. Ketamine induced apoptosis in corpus cavernosum.

The present study demonstrates that long-term ketamine administration led to erectile dysfunction in rat. The molecular mechanisms of ketamine-induced ED involved the increased apoptosis and up-regulated iNOS expression incorporating with loss of corporal smooth muscle content and reduced nNOS expression in cavernous nerve.

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