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Calcium-dependent effects of cadmium on energy metabolism and function of perfused rat heart
Insights
Cadmium exposure negatively impacts heart function and metabolism by interfering with calcium-dependent processes. Lower calcium levels exacerbate cadmium
Area of Science:
- Cardiovascular Physiology
- Environmental Toxicology
- Biochemistry
Background:
- Calcium ions are critical for mammalian heart function, regulating contractility and electrophysiology.
- Cadmium is a toxic heavy metal with known detrimental effects on cellular processes.
- The interaction between cadmium and calcium in cardiac tissue requires further elucidation.
Purpose of the Study:
- To investigate the effects of varying perfusate calcium concentrations on isolated rat heart function and metabolism.
- To determine how cadmium exposure modulates these calcium-dependent cardiac processes.
- To elucidate the mechanism of cadmium toxicity in the mammalian heart.
Main Methods:
- Isolated rat hearts were perfused with solutions containing different calcium concentrations (0.9-5.0 mM) and varying doses of cadmium (0.03-3.0 microM).
- Cardiac function (contractility, heart rate, conduction) and coronary flow were measured.
- Cardiac metabolites, including phosphatic compounds and glycerol 3-phosphorylcholine (GPC), were analyzed.
Main Results:
- Increased calcium concentration (0.9-5.0 mM) enhanced cardiac contractility (positive inotropy) and increased GPC levels.
- Cadmium (3.0 microM) significantly impaired cardiac function and altered energy phosphate levels, with effects inversely proportional to calcium concentration.
- Low-dose cadmium (0.03 microM) induced changes only at the lowest calcium concentration (0.9 mM), and cadmium inhibited calcium-stimulated GPC increase.
Conclusions:
- Cadmium interferes with calcium-mediated physiological and biochemical processes in the mammalian heart.
- Cadmium toxicity likely involves competition with calcium for membrane and intracellular binding sites.
- The severity of cadmium's adverse effects is dependent on the extracellular calcium concentration.
Abstract:
Postequilibrated isolated rat hearts were perfused for 60 min with a standard supporting electrolyte buffer containing one of the following calcium concentrations: 0.9, 1.8, 3.5, or 5.0 mM, either with or without added cadmium. Doses of cadmium which proved to be minimally (0.03 microM Cd)--and maximally (3.0 microM Cd)--effective at 0.9 mM Ca were studied at all other calcium concentrations. A dose-dependent positive inotropy that persisted throughout the 60-min perfusion period was induced by the graded increases in the perfusate calcium concentration throughout the range from 0.9 to 5.0 mM. Atrioventricular node conductivity was prolonged significantly in hearts perfused with 0.9 mM Ca as compared to hearts perfused with higher calcium concentrations. Increasing the perfusate calcium concentration caused a dose-dependent increase in heart glycerol 3-phosphorylcholine (GPC) content. The other measured phosphatic metabolites of the heart were not altered significantly by varying the perfusate calcium level. In contrast, cadmium (3.0 microM Cd) induced extensive functional and metabolic aberrations which varied in magnitude as an inverse function of the perfusate calcium concentration. Contractile tension, rate of tension development (dT/dt), heart rate, coronary flow rate, and atrioventricular node conductivity were decreased significantly in response to cadmium perfusion. Moreover, these hearts characteristically had significantly elevated low energy phosphate (inosine monophosphate and inorganic phosphate) and decreased high energy phosphate (ATP, PCr) levels relative to their respective calcium controls. Furthermore, various phosphorylated intermediates of glycolysis (glucose 6-phosphate, fructose 6-phosphate, glucose 1-phosphate), as well as glycerol 3-phosphate, and uridine diphosphoglucose accumulated significantly in hearts perfused with cadmium at certain calcium concentrations below 5.0 mM. The calcium-activated increase in heart GPC was inhibited completely by 3 microM cadmium. At the minimally effective dose of cadmium (0.03 microM), demonstrable changes were apparent only at the lowest perfusate calcium concentration examined (0.9 mM). These findings are consistent with the hypothesis that cadmium interferes with calcium-activated and calcium-mediated physiologic and biochemical processes of the mammalian heart. The primary mechanistic basis for the action of cadmium appears to be linked to a competition with calcium for membrane and possibly intracellular binding and activation sites.