Scholars@Duke

RESEARCH ABSTRACT of Robert B Jennings.

Our main research effort is aimed at learning the molecular event or series
of events that causes myocytes exposed to ischemia to die. We have established that sarcolemmal disruption is the event that causes myocyte death and are in the process or trying to learn the cause of sarcolemmal disruption. Our current studies are aimed chiefly at understanding the metabolic changes developing in ischemic myocardium during the phase of reversible injury.

Our chief accomplishment in the last few years has been the discovery of a
new phenomenon termed ischemic preconditioning. We have shown that myocardium exposed to a brief episode of ischemia and reperfusion will tolerate a much longer episode of sustained ischemia than virgin myocardium. This is a very striking protective effect and has become the subject of intense investigation throughout the world. At the November 1996 American Heart meeting, there were several hundred abstracts on this topic. This is surprising since we first described it in 1986.

At the present time, we are concentrating on learning the mechanism
underlying preconditioning. Our current working hypothesis is that preconditioning is due to a reduction in energy demand occurring during the sustained episode of ischemia. We propose that the reduced demand results from stimulation of A1 receptors by adenosine released into the interstitial space during the preconditioning episode of ischemia. These receptors, via Gi protein, activate protein kinase C to phosphorylate an unknown protein or proteins and thereby reduce energy consumption. We think that the protein phosphorylated is the KATP channel which opens when the level of cellular ATP declines. In the phosphorylated state, we propose that it stays open. The result is increased exit of K+ during ischemia, in effect local cardioplegia and improved tolerance to ischemia.

Using the pig heart we also are investigating the mechanism underlying the cardiotoxicity of diasporin cross-linked human hemoglobin. Vasospasm appears to be the most likely cause of the cardiac necrosis but O(2) derived free radicals also are possible.