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Calcium inhibition of glycolysis contributes to ischaemic injury
1Cardiovascular Research Institute, University of California San Francisco 94143.
Insights
Hypertension and thyrotoxicosis affect intracellular calcium and pH during ischemia differently. Maintaining calcium homeostasis is key for post-ischemic recovery in hypertensive hearts.
Area of Science:
- Cardiovascular Physiology
- Cellular Metabolism
- Ischemic Heart Disease Research
Background:
- Hypertension and thyrotoxicosis alter cardiac function.
- Ischemia-induced changes in intracellular calcium ([Ca2+]i) and pH ([H+]i) impact myocardial energy metabolism.
- Understanding these changes is crucial for improving post-ischemic recovery.
Purpose of the Study:
- To investigate the differential effects of hypertension and thyrotoxicosis on [Ca2+]i and [H+]i during ischemia.
- To determine how alterations in [Ca2+]i and [H+]i influence glycolysis and phosphomonoester sugar levels.
- To correlate these metabolic changes with post-ischemic recovery outcomes.
Main Methods:
- Utilized a rat model with induced hypertension (aortic banding) and thyrotoxicosis (L-thyroxine injection).
- Measured [Ca2+]i using INDO-1 fluorescence and [H+]i and phosphomonoester sugars via 31P nuclear magnetic resonance (NMR).
- Subjected isolated hearts to 30 minutes of global ischemia followed by 30 minutes of reperfusion.
Main Results:
- Hypertensive hearts showed a greater rise in [Ca2+]i and phosphomonoester sugars during ischemia compared to thyrotoxic hearts.
- Verapamil treatment in hypertensive rats attenuated the rise in [Ca2+]i and phosphomonoester sugars.
- Post-ischemic recovery was complete in thyrotoxic and verapamil-treated hypertensive hearts, inversely related to ischemic [Ca2+]i and phosphomonoester levels.
Conclusions:
- The ability to maintain calcium homeostasis during ischemia is critical for myocardial function.
- Thyrotoxicosis and verapamil treatment protect the heart by preserving calcium balance.
- Post-ischemic recovery is linked to the control of intracellular calcium and mitochondrial activity.
Study Objective:
The purpose of the study was to confirm that [Ca2+]i and .[H+]i increase during ischaemia in hypertensive hearts but not in thyrotoxic hearts, and that the rise in [Ca2+]i and [H+]i inhibits glycolysis, causing a rise in phosphomonoester sugars and thereby influencing postischaemic recovery.
Design:
Rats were made hypertensive by aortic banding and thyrotoxic by injection of L-thyroxine. [Ca2+]i was studied in isolated hearts by surface fluorometry assessing calcium dependent changes in the fluorescent dye INDO-1, while [pH]i and phosphomonoester sugars were studied by 31P nuclear magnetic resonance (NMR). Global ischaemia was carried out by turning off all flow to the heart for 30 min. Hearts were then reperfused for 30 min.
Subjects:
72 Sprague-Dawley rats, weight 500-600 g, were used. Left ventricular hypertrophy was generated by aortic banding in 36, half of which were treated with verapamil. Eighteen were injected with L-thyroxine and there were 18 controls.
Measurements And Results:
With all groups, developed pressure immediately declined after the onset of global ischaemia. During ischaemia the phosphomonoester sugars rose less in the hearts of thyrotoxic rats and the verapamil treated aortic constricted rats than in those of untreated aortic constricted and normal rats. During ischaemia there was no significant difference in [pH]i among the four groups. During ischaemia intracellular calcium rose least in thyrotoxic and verapamil treated aortic constricted rats, and most in untreated aortic constricted and normal rats. Intracellular calcium rose 10-15 min after the onset of ischaemia in verapamil treated pressure overload and control hearts; calcium rose immediately after the onset of ischaemia in the untreated aortic constricted hearts, but negligibly in hearts from thyroxine treated animals. Verapamil treatment of the aortic constricted hearts prevented the rise in intracellular calcium, and attenuated phosphomonoester sugar accumulation. Postischaemic recovery was complete in hearts in thyroxine treated and verapamil treated aortic constricted rats, but not in hearts from untreated aortic constricted and normal rats. Postischaemic recovery was inversely related to ischaemic diastolic [Ca2+]i and phosphomonoester sugar levels, but was not related to ischaemic values for [pH]i.
Conclusions:
Postischaemic recovery may depend on the ability of the cell to maintain mitochondrial activity as evidenced by oxygen consumption, thereby controlling the voltage of the cell, and influencing the ability of the myocardium to maintain its calcium homeostasis.