Nonadrenergic, noncholinergic (NANC) neurons are widely distributed in peripheral tissues, especially the gastrointestinal and reproductive tracts (see Chapter 6). Considerable evidence implicates NO as a mediator of certain NANC actions, and some NANC neurons appear to release NO. Penile erection is thought to be caused by the release of NO from NANC neurons; NO promotes relaxation of the smooth muscle in the corpora cavernosa—the initiating factor in penile erection—and inhibitors of NOS have been shown to prevent erection caused by pelvic nerve stimulation in the rat. An established approach in treating erectile dysfunction is to enhance the effect of NO signaling by inhibiting the breakdown of cGMP by the phosphodiesterase (PDE isoform 5) present in the smooth muscle of the corpora cavernosa with drugs such as sildenafil, tadalafil, and vardenafil (see Chapter 12).
NO is administered by inhalation to newborns with hypoxic respiratory failure associated with pulmonary hypertension. The current treatment for severely defective gas exchange in the newborn is with extracorporeal membrane oxygenation (ECMO), which does not directly affect pulmonary vascular pressures. NO inhalation dilates pulmonary vessels, resulting in decreased pulmonary vascular resistance and reduced pulmonary artery pressure. Inhaled NO also improves oxygenation by reducing mismatch of ventilation and perfusion in the lung. Inhalation of NO results in dilation of pulmonary vessels in areas of the lung with better ventilation, thereby redistributing pulmonary blood flow away from poorly ventilated areas. NO inhalation does not typically exert pronounced effects on the systemic circulation. Inhaled NO has also been shown to improve cardiopulmonary function in adult patients with pulmonary artery hypertension.
An additional approach for treating pulmonary hypertension is to potentiate the actions of NO in pulmonary vascular beds. Due to the enrichment of PDE-5 in pulmonary vascular beds, PDE-5 inhibitors such as sildenafil and tadalafil induce vasodilation and marked reductions in pulmonary hypertension (see also Chapters 12 and 17).
Chen Z, Stamler JS: Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase. Trends Cardiovasc Med 2006;16:259.
Griffiths MJ, Evans TW: Inhaled nitric oxide therapy in adults. N Engl J Med 2005;353:2683.
Guix FX et al: The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005;76:126.
McMillan K et al: Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc Nat Acad Sci USA 2000;97:1506.
Moncada S, Higgs EA: The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006;147:S193.
Napoli C, Ignarro LJ: Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 2003;43:97.
Paige JS, Jaffrey, SR: Pharmacologic manipulation of nitric oxide signaling: Targeting NOS dimerization and protein-protein interactions. Curr Topics Med Chem 2007;7:97.
Wimalawansa SJ: Nitric oxide: New evidence for novel therapeutic indications. Expert Opin Pharmacother 2008;9:1935.