Studies on the Metabolic and Functional Consequences of Ischaemia in the Mammalian Myocardium

The metabolic and functional effects of hypoxia, low-flow and no-flow ischaemia were studied and compared in the isolated perfused guinea-pig heart. The low-flow ischaemia model was identified as a suitable experimental system for investigating the role of glucose and fatty acids as metabolic substrates during ischaemia. Hypoxia and ischaemia caused a reduction in high energy phosphate and glycogen in the perfused heart. These conditions also resulted in a rapid loss of contractile force and changes to diastolic tension (contracture development). Substrate availability, heart rate, and the degree of ischaemia affected the metabolic and contractile responses. The effects of impaired glucose metabolism were demonstrated by perfusing the heart in the absence of exogenous glucose. Contracture development was characteristic of conditions in which the glycolytic capacity of the ischaemic heart was shown to be reduced (e.g. under glucose-free conditions and in no-flow ischaemia). Palmitate in the presence of glucose caused contracture developement in the low-flow ischaemic heart. Palmitate also increased the myocardial long-chain acylcamitine content which may increase ischaemic cell damage. The inhibitory effects of etomoxir on palmitoyl carnitine transferase-I activity were demonstrated in isolated mitochondria and the perfused heart. Albumin binding prevented further investigadons into the beneficial effects of reducing fatty acid oxidation by this mechanism. ATP-dependent potassium channel activation was investigated as a possible mechanism of early contractile failure (ECF). The effects of cromakalim in the guinea-pig papillary muscle preparation were inhibited by glibenclamide. Glibenclamide did not prevent ECF during hypoxia in this preparation. The effects of the novel anti-ischaemic agent, ranolazine (Syntex), were investigated in the low-flow ischaemia model. Ranolazine preserved the myocardial ATP content and reduced lactate and creatine kinase release during the ischaemic period. These protective effects were associated with an increased level of active pyruvate dehydrogenase. The studies presented in this thesis have examined some of the potential mechanisms underlying the responses to hypoxia and ischaemia in the isolated perfused guinea-pig heart and papillary muscle. These results indicate that stimulation of glucose metabolism may be an important intervention in reducing ischaemic damage in the myocardium. Therapeutic strategies to achieve this are discussed