Potassium channels and erectile dysfunction.
The incidence of erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, increases with age and with risk factors for vascular disease, including smoking, diabetes and hypertension. Penile erection results from an arousal-induced synthesis of nitric oxide (NO) in nonadrenergic-noncholinergic nerves (NANC), endothelial cells and cavernosal smooth muscle cells (SMCs). Vasodilation and relaxation of cavernosal SMCs engorges the corpora cavernosa with blood at arterial pressure. The subcellular mechanism by which tumescence occurs involves NO-induced activation of soluble guanylate cyclase, increased cyclic guanosine monophosphate (cGMP) levels and activation of cGMP-dependent protein kinase (PKG). PKG phosphorylates numerous ion channels and pumps, each promoting a reduction in cytosolic calcium. In particular, PKG activates high-conductance Ca2+(-)sensitive K+ (BKCa) channels, which hyperpolarize the arterial and cavernosal SMC membranes, causing relaxation. This mechanism appears to be compromised with age and with vascular disease, leading to ED. Thus, increasing cavernosal nitric oxide synthase (NOS) expression, cGMP levels and/or BKCa channel expression is an effective therapy for experimental ED. Future therapies may involve augmenting K+ channel expression by gene transfer or increasing channel function through the use of Type 5 phosphodiesterase (Type 5 PDE) inhibitors or phosphatase inhibitors.
Archer
Stephen L
SL
2C2.36 Walter Mackenzie Health Sciences Centre, Department of Medicine (Cardiology), Vascular Biology Group, University of Alberta, Edmonton, AB, Canada T6G 2B7. sarcher@cha.ab.ca
D000375:Aging / Q000378:metabolism; D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D007172:Erectile Dysfunction / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009130:Muscle, Smooth / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000201:enzymology / Q000378:metabolism; D015221:Potassium Channels / Q000096:biosynthesis*
D015221:Potassium Channels; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases