Browsing by Subject "guinea pig"
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Item Acetoacetate: A Cardioprotective Antioxidant(2002-05-01) Squires, Jeffrey E.; Mallet, Robert T.; Caffrey, James L.; Carroll, JoanSquires, Jeffrey E., Acetoacetate: A Cardioprotective Antioxidant. Master of Science, June 2002, 100 pp., 1 table, 18 illustrations, bibliography, 70 titles. The purpose of this study was to test the effectiveness of acetoacetate and β-hydroxybutyrate as myocardial protectants following peroxide injury and to determine acetoacetate’s ability to potentiate β-adrenergic responsiveness following ischemia-reperfusion injury. This study utilized antegradely perfused isolated working hearts exercised from male guinea pigs and sustained with glucose-fortified Krebs-Henseleit. Hearts were challenged by either 10 min perfusion with 100 μM H2O2 or 45 min of low flow ischemia exacerbated by ι-norepinephrine infusion. H2O2-challenged hearts were treated with 5 mM acetoacetate or β-hydroxybutyrate, whereas hearts injured by ischemia/reperfusion were treated with 5 mM acetoacetate. In the case of the ischemically injured hearts, acetoacetate treatment was combined with 2 nM isoproterenol to delineate acetoacetate’s ability to enhance β-andrenergic responsiveness to submaximal inotropic stimulation. Data were compared to non-injured time control hearts and injured untreated hearts to determine the impact of ketone body treatment. Acetoacetate increased citrate and glucose 6-phosphate content, nearly restored power, and increased the glutathione antioxidant redox potential (GSH/GSSG) by 140% in H2O2-injured myocardium. Although β-hydroxybutyrate increased citrate, an activator of NADPH-generating pathways, and glucose 6-phosphate, the substrate for the hexose monophosphate shunt to the same extent as acetoacetate, β-hydroxybutyrate raised GSH/GSSG by only 60% and did not enhance cardiac power. Therefore, acetoacetate enhances contractile function by augmenting the glutathione redox potential, and does so by additional mechanisms independent of the citrate and hexose monophosphate pathway. In hearts stunned by ischemia/reperfusion, acetoacetate and isoproterenol each increased power and glutathione redox potential three-to-fourfold, but phosphocreatine potential was 70% higher in acetoacetate hearts. Combined, acetoacetate + isoproterenol synergistically increased power and GSH/GSSG 16- and 17- fold respectively, doubled {NADPH/NADP+}, and increased cyclic AMP content 30%. These findings support the conclusion that acetoacetate enhances myocardial sensitivity to β-adrenergic stimulation possibly by enhancing GSH/GSSG.Item Role of Adenosine in Acute Hibernation of Guinea-Pig Myocardium(1995-08-01) Gao, Zhi-Ping; H. Fred Downey; James L. Caffrey; Patricia A. GwirtzGao, Zhi-Ping, Role of Adenosine in Acute Hibernation of Guinea-Pig Myocardium Doctor of Philosophy (Biomedical Sciences), August, 1995; 111 pp; 3 tables; 15 figures, bibliography, 158 titles. Myocardial hibernation is a state of depressed contractile function and energy demand during chronic ischemia. When coronary flow is restored, depressed contractile function can partially or completely recover to the pre-ischemic level, and ischemic injury of the myocardium in not evident. This project tested the hypothesis that endogenous adenosine mediates hibernation in guinea-pig myocardium. Isolated working guinea-pig hearts, perfused with glucose fortified Krebs-Henseleit buffer, were subjected to global low-flow ischemia. Left ventricular performance and cytosolic energy level were assessed. Lactate and purine nucleotides were measured in venous effluent. Heart were perfused with [U-14C]glucose to investigate the role of adenosine on glucose metabolism in myocardium. Left ventricular function in untreated hearts decreased by 80% and remained stable during ischemia, and completely recovered upon reperfusion. Neither adenosine receptor blockade with 8-p-sulfophenyl theophylline (8-SPT; 20 μM) nor ecto 5’-nucleotidase inhibitor αβ-methylene adenosine 5’-diphosphonate (AOPCP; 50μM) affected left ventricular function either ischemia or during reperfusion. Cytosolic energy level fell by 67% at 10 min ischemia in untreated hearts, but subsequently recovered to the pre-ischemic level despite continued ischemia. Adenosine receptor blockade increased cytosolic energy level at 10 min ischemia relative to untreated hearts, but blunted the subsequent rebound of phosphorylation potential. Moreover, 8-SPT doubled ischemic lactate release. Adenosine receptor blockade also increased glucose uptake during pre-ischemia and hypoperfusion, but did not stimulate glucose oxidation. Crossover plots of glycolytic intermediates revealed that phosphofructokinase, a key rate-controlling step in glycolysis, was activated by adenosine receptor blockade in both pre-ischemic and hibernating myocardium. We conclude that 1) activation of adenosine receptors results in recovery of cytosolic energy level of moderately ischemic working myocardium, but this energetic recover is not solely responsible for post-ischemic contractile recovery; 2) endogenous adenosine attenuates anaerobic glycolysis during myocardial hibernation by blunting phosphofructokinase activity.