The investigation was undertaken to study the effect of tolbutamide on the release of FFA from diabetic and nondiabetic ischaemic perfused rat hearts, in addition lactate production was also investigated. An initial study was undertaken to establish a model for the perfusion of isolated rat hearts under ischaemic conditions. The results demonstrated that the model used throughout the investigation was satisfactory, and gave an adequate representation of ischaemia. Using this model the effects of tolbutamide on both mechanical and metabolic responses of the heart were determined. This was done in conjunction with adrenaline, a known stimulator of myocardial lipolysis. These results demonstrated that both drugs had the ability to cause intracellular lipolysis as measured by FFA release to the same extent, yet only the adrenaline challenged hearts demonstrated any detrimental effect with regard to arrhythmia development. In addition both drugs increased lactate production to the same extent. Insulin was given to examine the effects of this hormone on the release of FFA from the heart. The results showed that insulin had the ability to reduce the levels of FFA in the perfusate, however no increase in overall performance of the heart or reversal of the arrhythmic condition (in the case of the adrenaline stimulated hearts) occurred. Both drugs increased FFA and lactate levels, yet only the adrenaline challenged hearts developed arrhythmias, consequently it was thought that the work load imposed on the heart by adrenaline could be relevant to arrhythmia production. It was therefore decided to administer tolbutamide and increase the work load, using calcium, in order to obtain a situation similar to that seen after adrenaline challenge. The results showed that hearts given tolbutamide in combination with calcium developed arrhythmias to a greater extent than hearts given calcium alone. Further, in an investigation into the role played by cyclic AMP, it was shown that this nucleotide may also be arrhythmogenic.
|Date of Award||1978|