Nitric oxide and airways.

For over 20 yrs it has been recognized that the vasodilator responses to many agents are mediated by the release of a vasodilator substance from endothelial cells [1]. The identity of endothelium-derived relaxant factor (EDRF) remained elusive, largely because of its short half-life, until 1987 when PALMER and eo-workers [2] were able to show that EDRF was likely to be nitric oxide (NO). Many were surprised that such a simple molecule could account for all of the actions of EDRF, but extensive investigations, in many species, have now provided supportive evidence [3]. One of the most important advances has been the discovery of substances which block the production of endogenous NO. Nitric oxide is formed from the semi-essential amino acid L-arginine via the action of an enzyme NO synthase [4]. NO synthase exists in constitutive forms (requiring Ca+ for activation) and inducible forms (which are independent of Ca2+), and several NO synthase genes have recently been cloned [3]. Analogues of L-arginine were found , which acted as false substrates for the enzyme and, therefore, blocked the formation of endogenous NO. This blockade can be overcome by adding back L-arginine, but not by adding D-arginine, which is not a substrate for the enzyme. Several arginine analogues have been developed, including N°-monomethylL-arginine (L-NMMA) and N°-nitro-L-arginine methyl ester (L-NAME), which have proved to be extremely useful in revealing the role of endogenous NO in a whole variety of processes [5]. Nitric oxide relaxes vascular smooth muscle by activation of soluble guanylyl cyclase, with an increase in concentration of cyclic guanosine 3'5'monophosphate (cGMP) . It had long been recognized that directly acting vasodilators, such as glyceryl trinitrate and sodium nitroprusside act as NO donors [6]. The observation that NO is a vasodilator, immediately suggested that it may play a role in the regulation of the pulmonary circulation, and this has been extensively investigated. Nitric oxide mediates the vasodilator action of acetylcholine in animal and human pulmonary vessels [7 , 8], and appears to act as a braking mechanism against pulmonary vasoconstriction [8]. Release of NO from endothelial cells in the pulmonary circulation appears to counteract hypoxic vasoconstriction [9, 10], and NO release is apparently decreased in hypoxia [11] . There is circumstantial evidence that NO release from pulmonary vessels may be impaired in patients with chronic obstructive pulmonary disease (COPD) [12]. Since NO is a potent pulmonary vasodilator, inhalation of NO