Carbon monoxide is the leading cause of fatal poisoning in many countries. At least two mechanisms of CO toxicity are currently recognized: carboxyhemoglobin formation and CO binding to haeme proteins such as mitochondrial cytochrome C oxidase and myoglobin. However, a growing body of evidence also suggests interference with NO pathways such as nitrosative stress and peroxynitrite formation. Cardiac manifestations of CO poisoning include myocardial ischemia, cardiogenic pulmonary edema, and arrhythmias. Their pathophysiology is unclear, and conflicting observations have been made in animal models, with either an improvement or a deterioration of cardiac function. We therefore explored the functional effects of CO on isolated perfused rat hearts.
Materials and methods: Conscious adult rats were intoxicated with various concentrations of CO in a closed chamber for 90 minutes. Cardiac function was assessed on isolated perfused hearts, along with dose-response, calcium sensitivity and pharmacological studies. Simultaneous biological studies included iNOS Western blot, plasma nitrate assay and high-resolution respirometry.
Results: cardiac function was improved by CO exposure, as shown by the dP/dtmax ratio, reflecting a rise in coronary perfusion pressure, at concentrations as low as 100 ppm; these effects plateaued after 250 ppm and lasted for 96 hours. No change in mean arterial pressure or cardiac frequency occurred. Cardiac rhythm disturbances occurred immediately and lasted until 3 hours of reoxygenation. Calcium sensitivity was increased Vasoreactivity was also modified, with a decreased response to acetylcholine and to an NO donor. Beta-blockade and NO synthase inhibition with L-NAME had no preventive effect. In contrast, N-acetylcysteine and FeTPPS, a peroxynitrite decomposition catalyst, partially prevented the increase in contractility, without affecting coronary pressure. Interestingly, ODQ, a guanylate cyclase inhibitor, had no preventive effect, but when given alone it led to an increase in contractility and coronary pressure. Protein expression of iNOS increased as early as 24 hours and peaked at 96 hours. Plasma nitrate levels were slightly increased High-resolution respirometry showed marked inhibition of cytochrome C oxidase at H3 but not at later times.
Discussion: mechanism of cardiac toxicity could be explained as follows:--Nitrosative stress, due to peroxynitrite formation but without NO formation may occur as in cerebral CO toxicity. That could explain in part the increase in contractility in this model. It may act by increasing cardiac fiber calcium sensitivity.--Considering the vasoreactivity partial loss, CO may act as a partial guanylate cyclase agonist, that may explain disequilibrium in GMPc/AMPc pathway, leading to an increase in AMPc levels and therefore in enhanced contractility.--For the first time in the heart, NO related endothelium dysfunction has been proved in a CO poisoning animal model. NO pathways are incriminated Endothelium dysfunction seems to trigger coronary vasoconstriction and increase of cardiac function. In the context of cellular hypoxia as demonstrated here, it could explain ischemic situation in vivo and all its detrimental consequences.