Endothelins & erectile dysfunction

Erectile dysfunction (ED) is common and a significant contributor to poor quality of life and psychosocial morbidity in men. Normal erectile function requires effective co-ordination between a number of complex neural pathways. Penile tumescence occurs in response to rapid arterial inflow to the corpora cavernosa with simultaneous venous outflow restriction due to expansion of the lacunar spaces. This process is under both central and local neuromediation. Endothelins are potent vasoconstrictor peptides that cause strong, slowly developing but sustained contraction of trabecular smooth muscles cells of the corpora cavernosa. Multiple mechanisms of action are proposed, including transmembrane calcium flux, mobilisation of inositol triphosphate sensitive intracellular calcium stores and calcium sensitisation through the Rho-Rho kinase pathway. The exact role of endothelins in the pathogenesis of ED currently remains unclear. Elevated endothelin-1 levels are found in patients with diabetes mellitus and this alone may be sufficient to cause ED. However, this is not borne out in clinical studies. The resultant elevated intracellular calcium may, however, modulate gene expression sufficiently to cause smooth muscle proliferation. Alternatively, alterations in endothelin receptor sensitivity in conditions such as diabetes and hypertension may enhance vasoconstrictor processes. Currently there is contradictory evidence for the role of endothelin receptor antagonists in ED. Animals studies suggest they inhibit corporal vasoconstriction, improve erectile function and protect against diabetes-induced smooth muscle apoptosis. However, the results of clinical studies in ED have been less promising. Uncertainty regarding the exact role of endothelin in penile erection hampers progress in this area. It is possible that the endothelin system may only be relevant to ED in certain conditions where global endothelial dysfunction exists (e.g. diabetes mellitus, systemic sclerosis) and the use of endothelin antagonists in these patient groups may yield improved outcomes.