Browsing by Subject "isoproterenol"
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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 Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed(2000-08-01) Pearlman, Eric Brian; Barbara Barron; Patricia A. Gwirtz; Michael L. SmithPearlman, Eric B., Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed. Master of Science (Biomedical Science), August, 2000, 37 pp., 3 tables, 11 figures, references, 20 titles. Methionine enkephalin arginine phenylalanine (MERF) has been shown to be co-stored with catecholamines in vesicles. The catecholamines appear to decrease the degradation rate of 3H-MERF in vitro. The aim of this study is to investigate the spillover and metabolism of MERF across the canine heart vascular bed. I hypothesize that 3H-MERF is either degraded in the plasma or taken up and degraded by the heart. I further hypothesize that the exogenous catecholamine, isoproterenol, inhibits or reduces the rate of MERF degradation. Mongrel dogs were anesthetized and instrumented to record cardiovascular parameters, infuse 3H-MERF, and obtain blood samples across the heart. Blood samples were taken before and after stopping 3H-MERF infusion to evaluate kinetics, show steady state, and test the effect of treatments. Steady state concentration of 3H-MERF was observed after 30 min of infusion. Chromatography separated intact from degraded 3H-MERF. Three experimental groups were used: control, propranolol plus isoproterenol, and propranolol only. Blockade of β-receptors was necessary to prevent changes in coronary blood flow. Propranolol bolus (0.2 mg/kg) was administered IV at 50 min. 3 μg/min isoproterenol or 0.5 ml/min normal saline was infused starting at 70 min until the end of sample collection. The 3H-MERF venous-arterial (V-A) difference prior to treatment was negative, indicating degradation in the plasma or uptake and degradation by the heart. The 75 min V-A difference was used to calculate the effect of the infusions on the degradation or uptake of the 3H-MERF; this value was unchanged by any treatment. Spillover of 3H-MERF was significantly lower in the propranolol + isoproterenol dogs (p [less than] 0.05) compared to propranolol only treatment at 75 min. Heart rate was significantly lower for the propranolol only group compared to control. Blood pressure and change in coronary flow were unchanged. In conclusion, isoproterenol does not affect the metabolism of 3H-MERF across the canine heart vascular bed. Propranolol, however, does increase the intact 3H-MERF in the plasma, but additional β adrenergic blockade agents need to be investigated to determine the mechanism by which this takes place.