The newborn heart possesses a higher tolerance to ischemia in comparison to adult hearts. Post-ischemic interventions that increase energy production are beneficial for recovery. These data suggest that the newborn heart holds on a very tight energetic plasticity and may not be capable to effectively respond to increases in energetic demand. Congenital heart defects can lead to the development of cardiac hypertrophy and often require surgical intervention. Using an animal model of newborn hypertrophy and biventricular isolated working heart we confirm the metabolic profile of the newborn rabbit heart, in which fatty acid oxidation provides the vast majority of energy to the heart. Our findings show that when right ventricle load is added, the increasing energy requirements are met by increasing glucose oxidation rates. Our data generated by the isolated biventricular working heart model further supports the concept of the newborn heart in a state of deficient energy reserve.

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published_or_final_version / Community Medicine / Doctoral / Doctor of Philosophy

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The cardiac ryanodine receptor (RyR2) is a Ca2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca2+ flux out of the SR, which results in an overload of intracellular Ca2+; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the Beta-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the Beta;-adrenergic receptor, but can also directly inhibit the release of Ca2+ from RyR2.

Chronic ventricular sympathectomy elicits changes in the coronary circulation, myocardial oxygen consumption and size of infarction resulting fromcoronary occlusion. These changes indicate a change occurring in the basic metabolism of the heart in response to the removal of its sympathetic nervous input. This hypothesis was tested using two groups of dogs, a shamoperated control and a ventricular sympathectomized group. The sympathectomy procedure was an intrapericardial surgical technique which selectively removes ventricular sympathetic input. Four weeks after surgery, left ventricular tissue samples were obtained and rapidly frozen to -80°C. Selected metabolic variables were then compared between the two groups.

Opioid/adrenergic interactions were studied to evaluate two hypotheses: (1) naloxone potentiates the effect of epinephrine on cardiac contractility by increasing circulating epinephrine concentrations; and (2) endogenous and exogenous opioids alter left cardiac nerve stimulationinduced norepinephrine release and cardiac function. A canine isolated heart-lung preparation was used for the first study. Plasma epinephrine was determined and myocardial epinephrine uptake was calculated during intravenous epinephrine infusion. Naloxone (4 mg) was given and the epinephrine infusion was repeated. Naloxone increased cardiac contractility, coronary blood flow, and the coronary sinus epinephrine concentration. When coronary blood flow was subsequently held constant (100% above resting), naloxone increased only contractility. This result indicated that the previously observed increase in coronary sinus epinephrine was flow dependent. Corticosterone (an uptake II blocker) was employed as a positive control. Corticosterone increased the contractile response to epinephrine, but unlike naloxone, corticosterone was accompanied by a clear decrease in myocardial epinephrine uptake. The stereospecificity of the response to naloxone was investigated and (+) naloxone equaled or exceeded (-) naloxone in potentiating the inotropic effect of epinephrine. In the second study, the left cardiac nerve was isolated and electrically stimulated in intact dogs. Norepinephrine overflow gradually declined during successive control stimulations. Pretreatment with naloxone (100 Mg/kg) prevented or delayed the decline. An intracoronary dynorphin 1-9 infusion (2 nmol/min/kg for 20 minutes) reduced both norepinephrine overflow and cardiac performance, and both effects were prevented by pretreatment with naloxone (100 /xg/kg) . To summarize, naloxone potentiated the inotropic effect of infused epinephrine without altering circulating epinephrine concentrations or myocardial epinephrine uptake. This effect of naloxone was not stereospecific and probably not mediated through a traditional opiate receptor. Endogenous and exogenous opioids inhibited the left cardiac nerve stimulation-induced norepinephrine overflow, suggesting that opiate receptors may regulate cardiac excitability by modulating norepinephrine release.

Amendments inserted at back. "May 2002" Includes bibliographical references (leaves 237-290) Experiments described in this thesis address the potential role of inducible nitric oxide synthase (iNOS) in hibernating myocardium. Specifically it was sought to establish a cellular model of hibernating myocardium and investigate the expression, regulation and effects of iNOS in this model. Experiments were performed using primary cultures of neonatal rat ventricular myocytes.

Bibliography: leaves 94-106. / v, 106, [33] leaves, [2] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Assessment of myocardial metabolism with radiolabelled substrates and positron emission tomography provides a potentially sensitive technique to investigate physiological and pathological cardiac states "in vitro". Prior studies have indicated that overall metabolic activity cannot be estimated from rates of utilization of any one particular substrate. It was hypothesized that acetate labelled with carbon-11 would provide an index of oxidative metabolism, based on fundamental biochemical principles. The hypothesis is confirmed in studies using isolated perfused rabbit hearts and closed chest canine studies. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1995