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Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

International Journal of Impotence Research volume 16, pages 21–29 (2004)Cite this article

Abstract

Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats + sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVβgal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS +sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1–2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3′,5′-guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. STZ-diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve; AUC) after CNS when compared to control rats. STZ-diabetic rats+AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVβgal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.

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Acknowledgements

We thank Drs Donald D Heistad and Beverley Davidson and the University of Iowa Vector Core Laboratory for preparation of the virus. This work was supported in part by a Young Investigator Award from the International Society of Impotence Research and Pfizer Inc. and the American Medical Association to TJ Bivalacqua.

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Authors and Affiliations

  1. Department of Urology, Tulane University School of Medicine, New Orleans, Louisana, USA

    T J Bivalacqua, M F Usta, S Leungwattanakij & W J G Hellstrom

  2. Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisana, USA

    T J Bivalacqua, P A Dabisch, D B McNamara & P J Kadowitz

  3. Departtment of Internal Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA

    H C Champion

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  1. T J Bivalacqua
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  2. M F Usta
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Correspondence to W J G Hellstrom.

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Bivalacqua, T., Usta, M., Champion, H. et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 16, 21–29 (2004). https://doi.org/10.1038/sj.ijir.3901054

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