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Effects of carbon monoxide on isolated heart muscle cells
B A Wittenberg1, J B Wittenberg
1Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461.
Insights
Carbon monoxide impairs heart cell function by binding to myoglobin, reducing oxygen use and energy production. This cellular effect may contribute to exercise-induced cardiotoxicity.
Area of Science:
- Cardiovascular Physiology
- Cellular Respiration
- Toxicology
Background:
- Carbon monoxide (CO) is known to cause cardiotoxicity, especially during exercise.
- Intracellular myoglobin in cardiac cells plays a role in oxygen transport and utilization.
- CO binding to myoglobin forms carboxymyoglobin, potentially disrupting normal cellular functions.
Purpose of the Study:
- To investigate the hypothesis that CO blockade of myoglobin function contributes to exercise-induced cardiotoxicity at the cellular level.
- To determine the impact of carboxymyoglobin formation on oxygen uptake and oxidative phosphorylation in isolated cardiac myocytes.
Main Methods:
- Isolated rat cardiac myocytes were exposed to varying partial pressures of CO under physiological oxygen conditions.
- Spectrophotometry was used to quantify the fraction of intracellular myoglobin bound to CO (carboxymyoglobin).
- Oxygen consumption and the ratio of phosphocreatine to adenosine triphosphate were measured to assess cellular energy metabolism.
Main Results:
- The fraction of carboxymyoglobin correlated with CO partial pressure, matching predictions.
- At low oxygen pressures (≤5 torr) and ~50% myoglobin binding, oxygen uptake significantly decreased.
- A carboxymyoglobin fraction of at least 40% led to a significant decrease in the phosphocreatine to adenosine triphosphate ratio, indicating reduced oxidative phosphorylation.
Conclusions:
- Sequestering intracellular myoglobin as carboxymyoglobin significantly reduces the rate of oxidative phosphorylation in cardiac myocytes.
- This cellular mechanism of impaired myoglobin function likely contributes to carbon monoxide's cardiotoxicity during exercise.
- In vivo inhibition of myoglobin-dependent oxidative phosphorylation is estimated to occur when 20-40% of arterial hemoglobin is carboxyhemoglobin.
Abstract:
By sequestering intracellular myoglobin of cardiac muscle cells in the nonfunctioning carboxymyoglobin form, carbon monoxide blocks myoglobin-facilitated diffusion of oxygen, as well as myoglobin-mediated oxidative phosphorylation. Here, we explore the hypothesis that the carbon monoxide blockade of myoglobin function may be responsible at the cellular level for a component of the cardiotoxicity of carbon monoxide observed during exercise. Suspensions of isolated rat cardiac myocytes were held in near steady states of oxygen pressure near the intracellular partial pressure of oxygen of the working heart (2 to 5 torr) and near the end-venous partial pressure of oxygen (20 torr). These suspensions were exposed to CO at low pressure (0.07 to 70 torr; 90 to 90,000 parts per million). The fraction of intracellular carboxymyoglobin, determined spectrophotometrically, was in good agreement with the fraction predicted from the ratio of carbon monoxide partial pressure to oxygen partial pressure. The effects observed were related to the fraction of intracellular myoglobin bound to CO. At physiological oxygen pressures no greater than 5 torr, after sequestration of approximately 50% of the myoglobin, steady-state oxygen uptake decreased significantly and was significantly less than the respiration of cell groups for which the fraction of carboxymyoglobin was 0% to 40%. When respiration is diminished, the rate of aerobic adenosine triphosphate synthesis (oxidative phosphorylation) also decreases. As in the whole heart, cytoplasmic adenosine triphosphate concentration in isolated heart cells is controlled at a constant level by the creatine phosphokinase equilibrium. When adenosine triphosphate utilization is unchanged, a sensitive monitor of the decreased adenosine triphosphate synthesis is the ratio of phophocreatine to adenosine triphosphate. When carboxymyoglobin was at least 40% of the total intracellular myoglobin, we found that the ratio of phosphocreatine to adenosine triphosphate in carbon monoxide-treated heart cells was significantly lower than that in control cells from the same preparation. Thus, we concluded that sequestering intracellular myoglobin as carboxymyoglobin significantly decreased the rate of oxidative phosphorylation of isolated cardiac myocytes. We estimate that intracellular myoglobin-dependent oxidative phosphorylation will be inhibited when approximately 20% to 40% of the arterial hemoglobin in the whole animal is carboxyhemoglobin.