Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism.

Abstract

In this study, we show that oxygen regulates nitric oxide (NO) levels through effects on NO synthase (NOS) enzyme kinetics. Initially, NO synthesis in the static lung was measured in bronchiolar gases during an expiratory breath-hold in normal individuals. NO accumulated exponentially to a plateau, indicating balance between NO production and consumption in the lung. Detection of NO2-, NO3-, and S-nitrosothiols in lung epithelial lining fluids confirmed NO consumption by chemical reactions in the lung. Interestingly, alveolar gas NO (estimated from bronchiolar gases at end-expiration) was near zero, suggesting NO in exhaled gases is not derived from circulatory/systemic sources. Dynamic NO levels during tidal breathing in different airway regions (mouth, trachea, bronchus, and bronchiole) were similar. However, in individuals breathing varying levels of inspired oxygen, dynamic NO levels were notably dependent on O2 concentration in the hypoxic range (KmO2 190 microM). Purified NOS type II enzyme activity in vitro was similarly dependent on molecular oxygen levels (KmO2 135 microM), revealing a means by which oxygen concentration affects NO levels in vivo. Based upon these results, we propose that NOS II is a mediator of the vascular response to oxygen in the lung, because its KmO2 allows generation of NO in proportion to the inspired oxygen concentration throughout the physiologic range.

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation

“…The reported K m of NO synthase for O 2 varies widely, from 6-23 M (37) up to 135-400 M (38). However, in our hands S-EITU was able to inhibit NO release even when given at an [O 2 ] as low as 10 M, indicating that NO synthase remains active in the cells at very low [O 2 ].…”

“…We refer to both these situations, an accumulation of electrons at cytochrome a or an increase in reduced species at the catalytic center, as cytochrome c oxidase becoming more reduced. (37,38,49).…”

Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders

“…1) Exhaled NO does not increase after experimental elevation of cardiac output (12). 2) Exhaled NO is decreased on acute exposure to high altitude, despite elevation of cardiac output (11,23,30).…”

“…Other things being equal, higher cardiac output might even lower NO if it causes recruitment and perfusion of blood vessels in which NO output could be scavenged by circulating hemoglobin, instead of being exhaled. NO delivery from the circulation to the lung is discounted, because hemoglobin inactivates NO (21) and because direct measurement of bronchiolar gases showed that alveolar NO was virtually nil (12,24).…”

Bioanalytical profile of the l-arginine/nitric oxide pathway and its evaluation by capillary electrophoresis

“…[31]). It includes transcriptional [32], translational and posttranslational [33][34][35] regulations of NO-synthesis mechanisms, negative feedback regulation of NOS by NO [36][37][38][39], membrane transport of substrates [40][41][42][43], intracellular metabolic recycling of substrates [43][44][45][46][47][48][49][50][51], availability of molecular oxygen and cell respiration [52][53][54][55][56][57], and intracellular redox state [58][59][60].…”