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Previously, we have shown that potassium and magnesium (K-Mg, 20 mM each) cardioplegia ameliorated cytosolic calcium ([Ca2+]i) accumulation and was associated with enhanced functional recovery after surgically induced global ischemia in the aged heart. K-Mg cardioplegia was also shown to enhance cytosolic cytochrome oxidase I activity and mRNA levels, suggesting that enhanced functional recovery may involve the preservation of high-energy phosphates. To investigate this hypothesis, 31P nuclear magnetic resonance was used to measure serial alterations in phosphocreatine (PCr), inorganic phosphate, nucleoside triphosphate (NTP), intracellular free magnesium (Mgf), and intracellular pH (pHi) in Langendorff-perfused, aged (135 wk) rabbit hearts during preischemia, global ischemia (30 min), and reperfusion (30 min). K-Mg cardioplegia retarded PCr depletion (P < 0.05) and significantly enhanced NTP preservation (P < 0.05) during ischemia and reperfusion. K-Mg cardioplegia also attenuated the increase in Mgf during ischemia (P < 0.05). These results were correlated with amelioration of [Ca2+]i accumulation during ischemia and preservation of left ventricular function after reperfusion and suggest that optimal functional recovery from surgically induced ischemia is provided by K-Mg cardioplegia in the aged myocardium.

Objective: The effect of cardioplegic solutions with high concentrations of potassium or magnesium (or both) on cytosolic calcium accumulation was investigated with fura-2 in isolated perfused mature (n = 24) and aged (n = 24) rabbit hearts., Methods: We compared cytosolic calcium accumulation before ischemia (control), during 30 minutes of ischemia and 30 minutes of reperfusion under global ischemia, or after treatment with potassium (20 mmol/L), magnesium (20 mmol/L), or both., Results: Cytosolic calcium accumulation was increased during global ischemia in the mature heart (from 178.7 +/- 24.2 in the control group to 393.6 +/- 25.5 nmol/L; p < 0.005) and in the aged heart (from 187.4 +/- 18.7 in the control group to 501.0 +/- 46.1 nmol/L; p < 0.005). Potassium reduced cytosolic calcium accumulation during ischemia in both the mature and aged hearts (300.9 +/- 23.2 and 365.2 +/- 27.7 nmol/L, respectively; p < 0.05 vs global ischemia). Magnesium and potassium/magnesium completely controlled cytosolic calcium accumulation in the mature heart (198.7 +/- 27.5 nmol/L; p < 0.01 vs global ischemia and p < 0.05 vs potassium: 182.3 +/- 22.7 nmol/L; p < 0.05 vs global ischemia and potassium, respectively). Magnesium and potassium/magnesium attenuated cytosolic calcium accumulation in the aged heart (261.3 +/- 26.7, 262.3 +/- 25.2 nmol/L, respectively; p < 0.01 vs global ischemia). These changes in cytosolic calcium accumulation correlated with improved post-ischemic ventricular function. To investigate the mechanism(s) of magnesium-supplemented cardioplegic inhibition of cytosolic calcium accumulation, we performed parallel studies (n = 43) using nifedipine, ryanodine, and dimethylthiourea. Nifedipine with or without ryanodine reduced cytosolic calcium accumulation. Dimethylthiourea did not alter cytosolic calcium accumulation during global ischemia. Our results suggest that cytosolic calcium accumulation during global ischemia was mainly increased via the sarcolemmal 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel. The modulating action of potassium/magnesium cardioplegia on cytosolic calcium accumulation during ischemia would appear to act through the inhibition of the myocardial 1-type calcium channel and the sarcoplasmic reticulum calcium-release channel., Conclusion: Senescent cardiac dysfunction correlates with increased ischemia-induced cytosolic calcium accumulation. Magnesium-supplemented potassium cardioplegia ameliorates this age-related phenomenon at normothermia and may have important implications in myocardial protection in the elderly population.

Background: The aged myocardium accumulates significantly more cytosolic calcium [Ca2+]i during ischemia, and functional recovery is more severely compromised as compared with the mature heart. Cardioplegia ameliorates these phenomena. The mechanism by which increased calcium accumulation reduces functional recovery in the senescent myocardium is unknown, but it has been suggested that futile calcium cycling in the mitochondria leading to depletion of ATP stores during normothermic global ischemia may be involved., Methods and Results: To investigate the effect of cardioplegia on mitochondrial calcium ([Ca2+]mt) accumulation and the expression of cytochrome oxidase I (COX I) during global ischemia, mitochondria were isolated from mature (age, 15 to 20 weeks) and aged (age > 130 weeks) rabbit hearts after Langendorff perfusion. Five perfused heart groups were investigated: 30 minutes of global ischemia without treatment (control), with potassium (K, 20 mmol/L), magnesium (Mg, 20 mmol/L), or potassium and magnesium (K/Mg) cardioplegia. No significant difference in [Ca2+]mt was evident in mature hearts with any protocol. In aged hearts, [Ca2+]mt was increased in global ischemia but was ameliorated with Mg and K/Mg cardioplegia. COX I mRNA levels in aged hearts were lower in both control and global ischemia but were increased with cardioplegia. Maximal velocities for COX I were significantly increased with Mg cardioplegia both in the mature and the aged myocardium., Conclusions: K and/or Mg cardioplegia ameliorates [Ca2+]mt accumulation in aged hearts during normothermic global ischemia and increases COX I mRNA levels to a level not significantly different from that found in mature hearts.

Background: Previously, we have shown that normothermic global ischemia increases cytosolic calcium accumulation in both the mature and aged heart. Increased nuclear and mitochondrial calcium accumulation was shown to occur in the aged but not the mature heart, and these age-related differences were associated with increased DNA fragmentation and decreased cellular viability only in the aged heart., Methods: To investigate the relationship between increased mitochondrial and nuclear calcium and DNA fragmentation, mature and aged rabbit hearts were subjected to normothermic global ischemia with and without the addition of ruthenium red to block mitochondrial calcium influx. Cytosolic calcium accumulation was measured in a parallel experiment using fura-2., Results: Ruthenium red ameliorated mitochondrial calcium accumulation and was associated with both decreased DNA fragmentation and decreased nuclear calcium accumulation., Conclusions: Nuclear calcium accumulation was correlated with increased mitochondrial calcium accumulation but not increased cytosolic calcium accumulation in the aged heart. Modulation of mitochondrion "futile calcium cycling" may be of significance in the modulation of ischemic myocardial injury.

Previous reports have indicated that the senescent myocardium is less tolerant to surgically induced ischemia and that diminished functional recovery is associated with alterations in cytosolic calcium ([Ca2+]i) accumulation. Recently, increased [Ca2+]i has been suggested to alter nuclear calcium ([Ca2+]n) accumulation. To investigate the relation between [Ca2+]i and [Ca2+]n, we subjected mature and aged rabbit hearts to normothermic global ischemia, either without treatment or after treatment with potassium cardioplegia, magnesium cardioplegia, or a combination of potassium and magnesium cardioplegia. The relation between altered [Ca2+]n and DNA fragmentation was also investigated. Our results indicate that [Ca2+]i was increased during 30 minutes of normothermic global ischemia without treatment in both the mature and aged hearts (p < 0.05). Accumulation of [Ca2+]i during global ischemia was reduced with the use of potassium, magnesium, and a combination of potassium and magnesium cardioplegia (p < 0.05 versus untreated ischemia) in both the mature and aged hearts. Levels of [Ca2+]n were unaffected by global ischemia or cardioplegia in the mature myocardium; however, in the aged myocardium, [Ca2+]n was increased during global ischemia and with potassium cardioplegia and was associated with increased nuclear DNA fragmentation (p < 0.05). The use of magnesium and a combination of potassium and magnesium cardioplegia attenuated [Ca2+]n accumulation and nuclear DNA fragmentation (p < 0.05). Control of [Ca2+]i and [Ca2+]n was associated with enhanced functional recovery during reperfusion. These results indicate that during normothermic ischemia, there is increased [Ca2+]i and [Ca2+]n in the aged myocardium, and increased [Ca2+]n is associated with increased nuclear DNA fragmentation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytosolic calcium in the myocardium is rapidly accumulated during ischemia and has been correlated with the attenuation of functional recovery in the myocardium. The aged myocardium is more sensitive to ischemia and accumulates significantly more cytosolic calcium than either the newborn or the mature myocardium. Modification of the age-related propensity to increased cytosolic calcium accumulation may be achieved through the use of magnesium or potassium/magnesium cardioplegia. Improved postischemic ventricular function obtained with magnesium or potassium/magnesium cardioplegia may have important implications in the reduction of myocardial morbidity and mortality.