Miller, Marek Antoni Witold; (1997) Cyclic nucleotide metabolism in the streptozotocin diabetic rat corpus cavernosum; Relevance to human diabetic erectile dysfunction. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Diabetes mellitus is an important risk factor for the development of male erectile dysfunction. Notwithstanding the effects of diabetes in terms of angiopathy and neuropathy which have been thought to be the principal causes for erectile dysfunction there are well described alterations in the transduction mechanisms that are responsible for normal penile erection. Much attention has focused recently on the role of nitric oxide as the main neurotransmitter responsible for the mediation of penile erection. Using the streptozotocin rat model of diabetes mellitus the effects of diabetes upon nitric oxide mediated transduction mechanisms was studied using a variety of experimental techniques. Nitric oxide synthase autoradiography demonstrated that at two and six months duration of diabetes there was an increased nitric oxide synthase binding compared to control rats. Further investigations demonstrated the effects of experimental diabetes in the same model upon guanylate and adenylate cyclase, the enzymes responsible for the synthesis of 3'5' cyclic guanosine monophosphate and 3'5' adenosine monophosphate respectively. These two important second messengers are crucial for the control of smooth muscle relaxation and hence penile erection. It was found that the activity of these cyclases as measured by generation of the cyclic nucleotides determined by radioimmunoassay were significantly increased in the diabetic model. Further experiments were performed to elucidate changes in the activity of the phosphodiesterase enzymes which act specifically to hydrolyse the cyclic nucleotides, it was found that diabetes resulted in a reduction of phosphodiesterase activity. Taken together, these findings would seem to support the hypothesis that penile tissues adapt to the diabetic environment in a manner which attempts to maintain cyclic nucleotide bioavailability. Further studies were carried out to examine the effects of various vascular risk factors on cyclic nucleotide metabolism in an acute experimental setting. A clinical study was also undertaken to examine the possible role of fibrinogen as a risk factor in the development of erectile dysfunction, it is our impression from this preliminary study that fibrinogen is indeed a novel risk factor for erectile dysfunction. The relevance of our findings in the streptozotocin diabetic rat model to human erectile dysfunction are discussed, as is the validity of the model, possibilities for future investigations and areas for novel drug interventions.

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