Selective nitrergic neurodegeneration in diabetes mellitus–a nitric oxide-dependent phenomenon


The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6AU, UK. E-mail:


  • In vitro and in vivo studies have demonstrated a dysfunctional nitrergic system in diabetes mellitus, thus explaining the origin of diabetic impotence. However, the mechanism of this nitrergic defect is not understood.

  • In the penises of streptozotocin (STZ)-induced diabetic rats, here, we show by immunohistochemistry that nitrergic nerves undergo selective degeneration since the noradrenergic nerves which have an anti-erectile function in the penis remained intact.

  • Nitrergic relaxation responses in vitro and erectile responses to cavernous nerve stimulation in vivo were attenuated in these animals, whereas noradrenergic responses were enhanced.

  • Activity and protein amount of neuronal nitric oxide synthase (nNOS) were also reduced in the penile tissue of diabetic rats.

  • We, thus, hypothesized that NO in the nitrergic nerves may be involved in the nitrergic nerve damage, since only the nerves which contain neuronal NO synthase underwent degeneration.

  • We administered an inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), in the drinking water of rats for up to 12 weeks following the establishment of diabetes with STZ.

  • Here we demonstrate that this compound protected the nitrergic nerves from morphological and functional impairment. Our results show that selective nitrergic degeneration in diabetes is NO-dependent and suggest that inhibition of NO synthase is neuroprotective in this condition.

British Journal of Pharmacology (1999) 128, 1804–1812; doi:10.1038/sj.bjp.0702981