Effects of carbon monoxide on the brain may be mediated by nitric oxide

Abstract

Carbon monoxide (CO) is known to be a toxic molecule due to the high affinity of hemoglobin for it. However, it has recently been shown that low doses of CO may play a physiological role. The aim of the present study was to examine processes occurring in the brain during exposure to 1,000 parts per million CO that result in an increase in cerebral blood flow (CBF) but are not accompanied by changes in oxidation metabolism. This study was carried out in awake rats with the multiprobe assembly developed in this laboratory for the simultaneous continuous measurement of CBF, intramitochondrial NADH redox levels, direct current potential, and extracellular concentrations of K+, Ca2+, and H+ as well as the electrocorticogram. Exposure to 1,000 parts per million CO in air resulted in an increased CBF without any concomitant changes in any of the other metabolic or ionic parameters measured. This indicates that tissue hypoxia was not the trigger for this vasodilation. Injection of N omega-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, before exposure to CO effectively blocked the increase in CBF that was observed when the animal was exposed to CO without prior injection of L-NNA. Furthermore, electrocorticographic depression was observed after the combined treatment of L-NNA and CO. In conclusion, exposure to relatively low doses of CO apparently does not have a deleterious effect on oxidative metabolism because the increase in CBF after this exposure is sufficient to prevent changes in oxidative metabolism, as indicated by the fact that NADH levels remained constant. This protective autoregulatory effect may be mediated by nitric oxide.

Carbon monoxide poisoning

“…Exchange transfusion with blood containing 80% CO-Hgb to otherwise healthy dogs resulted in no toxic effects, however, despite resultant CO-Hgb levels of 57% to 64%, suggesting that CO toxicity is not dependent on CO-Hgb formation. Other studies have corroborated the findings of morbidity and mortality due to CO poisoning independent of hypoxia or CO-Hgb formation [45][46][47][48][49].…”

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

“…Preconditioning of K Ca channels by NO may blunt the responses of these channels to CO (Wu et al, 2002). Some physiological effects of CO, such as cerebral vasodilation in adult rats, may even be directly mediated by NO (Meilin et al, 1996). Furthermore, NO has been reported to increased HO-2 activity and CO production in a cGMP-dependent manner in cerebral microvascular tissues (Leffler et al, 2005).…”

Kinetics of CO Ligation with Nitric-oxide Synthase by Flash Photolysis and Stopped-flow Spectrophotometry

“…For CO, Y is no more than about 5% in Mb, 20 -50% in various Hb R , depending on pH, and somewhat less in Hb under conditions that favor T-like structures (42). In P450 cam , Y is reported to be as large as 90% in the absence of substrate, reduced to only 2% with camphor bound (41). NOS is like P450 in having very small Y with substrate bound.…”

“…The equilibrium constant reported here suggests that their value is too high, but we concur with the conclusion that CO inhibition is unlikely. In fact, a recent study suggests just the opposite; far from being an inhibitor, small amounts of CO, 1000 ppm, may increase NO production (41). If that observation is confirmed, it will have important implications for the mechanism of NOS action.…”