Sullivan, Mark Edward; (1999) Investigations into the pathogenesis of diabetic erectile dysfunction: An experimental animal model. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Diabetes Mellitus (DM) is a major risk factor for erectile dysfunction (ED) in both human and animal models. The nitric oxide (NO)-guanosine 3'5'cyclic monophosphate (cGMP) axis is an important mediator of cavernosal smooth muscle relaxation, an essential step for penile erection. The prostacyclin (PGl2)-adenosine 3'5' cyclic monophosphate (cAMP) axis also appears to play a role in penile erection. Impairment of endothelium-dependent and neurogenic-mediated relaxation of the cavernosal smooth muscle has been demonstrated in both diabetic patients and rabbit models. The pathogenesis of this endothelial and nerve dysfunction has not been fully elucidated, but the interaction between NO, PGI2 and endothelin-1 (ET-1) is thought to be important. New Zealand White rabbit cavernosal tissue was obtained to investigate these interactions using functional, autoradiographic, immunohistochemical, biochemical and structural analyses. Any changes brought about by experimental DM (alloxan-induced) were also assessed. These studies demonstrate: 1) enhanced relaxation to NO in 6 month diabetic cavernosal strips, which suggests that end-organ response is not impaired 2) a significant increase in endothelin B binding sites in 6 month diabetic cavernosa, which could be a pathophysiological pathway in diabetic ED or a compensatory response to impaired NO and PGI2 synthesis 3) receptor-linked PGI2 and cAMP synthesis is markedly impaired in the diabetic rabbit penis, which may contribute to ED as cAMP mediates cavernosal smooth muscle relaxation 4) endothelial cGMP synthesis is significantly diminished in the diabetic rabbit penis and 5) an increase in NO synthase (NOS) activity on diabetic cavernosal smooth muscle, this may represent an up-regulation of inducible NOS in response to reduced NO bioavailability (eg due to quenching). All these changes predate functional alterations of cavernosal smooth muscle. The findings reported in this thesis support the concept that endothelial dysfunction plays a role in the pathogenesis of diabetic ED. These findings may have therapeutic implications.

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