What is the role of the nitric oxide pathway in the pathophysiology of erectile dysfunction (ED)?

Updated: Aug 08, 2018
  • Author: Edward David Kim, MD, FACS; Chief Editor: Edward David Kim, MD, FACS  more...
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Answer

The NO pathway is of critical importance in the physiologic induction of erections. The drugs currently used to treat ED were developed as a result of experimental and clinical work showing that NO released from nerve endings relaxes the vascular and corporal smooth muscle cells of the penile arteries and trabeculae, resulting in an erection.

NO is produced by the enzyme NO synthase (NOS). [13] NOS plays many roles, ranging from homeostasis to immune system regulation. To date, 3 subtypes have been identified: nNOS, iNOS, and eNOS, which are produced by the genes NOS1, NOS2, and NOS3, respectively. This nomenclature is derived from the sources of the original isolates: neuronal tissue (nNOS), immunoactivated macrophage cell lines (iNOS), and vascular endothelium (eNOS). The subtypes are not, however, limited to the tissues from which they were first isolated.

All NOS subtypes produce NO, but each may play a different biologic role in various tissues. nNOS and eNOS are considered constitutive forms because they share biochemical features: They are calcium-dependent, they require calmodulin and reduced nicotinamide adenine dinucleotide phosphate for catalytic activity, and they are competitively inhibited by arginine derivatives. nNOS is involved in the regulation of neurotransmission, and eNOS is involved in the regulation of blood flow.

iNOS is considered an inducible form because it is calcium-independent. iNOS is induced by the inflammatory process, in which it participates in the production of nitrogenous amines. This subtype has been shown to be involved in carcinogenesis, leading to transitional cell carcinoma.

Inside the cell, NOS catalyzes the oxidation of L-arginine to NO and L-citrulline. Endogenous blockers of this pathway have been identified. The gaseous NO that is produced acts as a neurotransmitter or paracrine messenger. Its biologic half-life is only 5 seconds. NO may act within the cell or diffuse and interact with nearby target cells. In the corpora cavernosa, NO activates guanylate cyclase, which in turn increases cyclic guanosine monophosphate (cGMP). Relaxation of vascular smooth muscles by cGMP leads to vasodilation and increased blood flow.

Alteration of NO levels is the focus of several approaches to the treatment of ED. Inhibitors of phosphodiesterase, which primarily hydrolyze cGMP type 5, provided the basis for the development of the PDE5 inhibitors. Chen et al administered oral L-arginine and reported subjective improvement in 50 men with ED. [14] These supplements are readily available commercially. Reported adverse effects include nausea, diarrhea, headache, flushing, numbness, and hypotension.

Increasing evidence indicates that NO acts centrally to modulate sexual behavior and to exert its effects on the penis. NO is thought to act in the medial preoptic area and the paraventricular nucleus. Injection of NOS inhibitors prevents the erectile response in rats that have been given erectogenic agents.


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