Abstract and Introduction
Abstract
Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat medically despite advances in pharmacotherapeutic approaches in the field. This unmet need has resulted in a recent re-focus on the pathophysiology, in order to understand the cellular and molecular mechanisms leading to ED in diabetes. Diabetes-induced ED is often resistant to PDE5 inhibitor treatment, thus there is a need to discover targets that may lead to novel approaches for a successful treatment. The aim of this brief review is to update the reader in some of the latest development on that front, with a particular focus on the role of impaired neuronal blood flow and the formation of advanced glycation endproducts.
Introduction
Penile erection is the result of relaxation of smooth muscle in the cavernous body and associated blood vessels. Smooth muscle relaxation is mediated primarily by nitric oxide (NO), which is a gaseous and labile mediator, yet one of the most potent endogenous smooth muscle relaxants. NO is synthesised by neuronal NO synthase (nNOS) in the autonomic postganglionic parasympathetic nerves (nitrergic nerves) and by endothelial nitric oxide synthase in the endothelium lining the blood vessels and cavernosal sinusoids. Nerve impulses in response to sexual stimulus are carried from the spinal cord to the hypogastric plexus where the cell bodies of the nitrergic nerves are located. Once activated, the nitrergic neurones within the hypogastric plexus transmit action potential through their axons to the penile vasculature. These nitrergic axons then release high quantities of NO on to the nearby smooth muscle cells. NO diffuses rapidly into the smooth muscle cells, causing relaxation by increasing the intracellular concentrations of cGMP. The relaxation of the cavernosal and arterial smooth muscle results in an increase in blood flow into the penis. In turn, this causes shear stress on the endothelial lining, which promotes phosphorylation and prolonged activation of endothelial nitric oxide synthase leading to long-lasting release of NO from the endothelium to maintain the smooth muscle relaxation. As the intracavernosal pressure reaches the level of the systemic arterial blood pressure, the subtunical venules are compressed, which results in a rigid erection.
Diabetes mellitus is one of the predominant risk factors of erectile dysfunction (ED) and also one of the most difficult to treat. Approximately 50% of diabetic men will suffer from ED within 10 years of the diagnosis. ED presenting in these men is widely regarded as a manifestation of more systemic vascular disease and is likely to precede a coronary event by 5 years. Combined with the prevalence of obesity and metabolic syndrome in these men, it is apparent that disease progression is likely to reduce the efficacy of conventional pharmacotherapeutic options for the treatment of ED in diabetic men. This has meant that diabetic men form a large group of patients undergoing end-stage treatment in the form of penile prosthesis surgery.
Our knowledge regarding the pathophysiology of ED in diabetes has gradually increased since the 1990s. As NO is the main erectile mediator, the field has focussed on how diabetes alters the nitrergic and endothelial NO function. The aim of this paper is to update the reader with some of the latest development on that front, with a particular focus on the role of impaired neuronal blood flow, and the formation of advanced glycation end products.