Browsing by Subject "contractile function"
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Item Mechanisms of Pyruvate Potentiation of β-adrenergic Inotropism in Stunned Myocardium(1999-05-01) Tejero DelRio, Maria Isabel; Mallet, Robert T.; Downey, H. Fred; Caffrey, James L.Tejero DelRio, M. Isabel. Mechanisms of Pyruvate Potentiation of β-adrenergic inotropism in stunned myocardium. Doctor of Philosophy (Biomedical Sciences), May, 1999; pp. 158; tables 6; illustrations 18; bibliography, 104 titles. This study tests three hypotheses: 1) the sensitivity of stunned myocardium to β-adrenergic stimulation is diminished; 2) the decreased β-adrenergic responsiveness of stunned myocardium is due in part to adenylate cyclase inactivation by oxidative stress; and 3), pyruvate could augment post-ischemic β-adrenergic responsiveness by ameliorating oxidative stress. These hypotheses were tested in isolated working guinea pig hearts perfused with Krebs-Henseleit butter fortified with 10 mM glucose. Myocardial stunning and pyruvate effects on myocardium are reviewed in the Introduction. In Chapter I, contractile function, β-adrenergic stimulation, and energy metabolism of stunned myocardium treated with pyruvate are examined. The effect of stunning, β-adrenergic stimulation, and pyruvate treatment on cellular and antioxidant defenses are examined in Chapter II. Conclusions and suggestions for future studies complete this dissertation. Results: the dose:power response curve to 0.1-100 nM isoproterenol was significantly shifted to the right in stunned hearts: EC50 (nM) increased from 0.3 ± 0.06 to 5.2 ± 1.86. Pyruvate (5 mM) and N-acetylcysteine (5 mM) restored responsiveness to isoproterenol, lowering EC50 to 1.1 ± 0.34 and 1.56 ± 0.43 nM, respectively. Cardiac power of stunned hearts treated with 2 nM isoproterenol was increased four-fold during combined treatment with pyruvate or N-acetylcysteine. Myocardium cyclic AMP content, unchanged by single treatments, increased when isoproterenol (2 nM) was combined with pyruvate by 41%, and N-acetylcysteine by 100%. Reduced antioxidant GSH/GSSG and NADPH/NADP+ ratios in stunning were restored to pre-ischemic levels with pyruvate plus isoproterenol treatment. Pyruvate did not augment power or cyclic AMP content in hearts stimulated with 30 nM isoproterenol, but lessened the decline in cytosolic phosphorylation potential. Conclusions: Both β-adrenergic inotropism and cellular antioxidant power were attenuated in the stunned myocardium. Pyruvate potentiated the effects of sub-maximal doses of attenuated energy depletion by high doses of isoproterenol. Pyruvate may allow restoration of contractile performance with lower, energetically less costly doses of β-adrenergic agents.Item The Effects of Insulin on Myocardial Glucose Metabolism and Contractile Function During Moderate Coronary Hypoperfusion(1997-08-01) Tune, Johnathan D.; Downey, H. Fred; Mallet, Robert T.; Caffrey, James L.Tune, Jonathan David, The Effects on Insulin on Myocardial Glucose Metabolism and Contractile Function during Moderate Coronary Hypoperfusion Doctor of Philosophy (Biomedical Sciences), August, 1997, 98 pp, 3 tables, 11 figures, references, 117 titles. This study was designed to determine the effects of insulin on myocardial metabolism and contractile function during moderate coronary hypoperfusion. Coronary perfusion pressure (CPP) was lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery of anesthetized, open chest dogs. Regional glucose uptake, lactate uptake, oxygen consumption (MVO2), and percent segment shortening were determined without (n=12) or with either intravenous insulin (4 U/min, n=12) or intracoronary insulin (4 U/min, n=6). Glucose metabolites, high energy phosphates, and the phosphorylation state of creatine phosphate were determine in freeze clamped biopsies of control (n=6), and of intravenous insulin (n=6) treated hearts at the completion of the protocol (CPP = 40 mmHg). Glucose uptake increased with both intravenous and intracoronary insulin treatments (P0.05). Thus, insulin treatment improved contractile function while myocardial oxygen demand was unchanged, i.e. oxygen utilization efficiency increased. Myocardial glycogen, alanine, lactate, and pyruvate contents were not significantly different in untreated and intravenous insulin treated hearts. Reducing CPP to 40 mmHg produced similar changes in both untreated and insulin treated hearts: ATP content was unchanged, creatine phosphate content decreased 17%, creatine content and inorganic phosphate concentration increased 27% and 124%, respectively, and the phosphorylation potential decreased 80%. We conclude that 1) when the potentially detrimental effects on insulin stimulated glucose metabolism are avoided during moderate ischemia, insulin treatment increases contractile function without significantly elevating myocardial oxygen demand; 2) during moderate ischemia, insulin stimulated glucose metabolism increases oxygen utilization efficiency and prevents a further decline in the energy state of the myocardium.