Depressed myocardial performance has been implicated as a key factor in the pathophysiology of shock of varying etiologies. Animals studies have indicated that this reduced myocardial performance is linked to modifications in the beta-adrenergic receptor adenylate cyclase complex during injury-induced infections. Beta-adrenergic receptor mediated function is attenuated by the persistent exposure to catecholamine and results in a reduction in affinity of the beta receptor in its target cell for catecholamines. The long-term objective of the proposed studies is to clarify the pathophysiology of myocardial dysfunction in sepsis and following endotoxemia, by investigating the myocardial alterations in isolated perfused hearts, in isolated cardiocytes, and in ventricular membrane preparations. The proposed work is based on the premise that myocardial dysfunction, demonstrated in hearts during hyperdynamic sepsis, or following endotoxin treatment, is due to altered beta-adrenergic receptor adenylate cyclase coupling. We will use the isolated heart preparation as a standard for determining myocardial dysfunction, then use myocytes to study cyclic AMP metabolism prior to preparing ventricular membranes to probe beta-adrenergic receptor regulation and adenylate cyclase activity in both septic and endotoxemic animals. The proposed investigations will test whether beta-adrenergic receptor and/or post receptor functions are altered in the hearts of septic and endotoxemic animals in response to the elevated plasma catecholamine concentrations found in sepsis. We further hypothesize that the decreased myocardial function is not specific to sepsis, but that it represents a general reaction to trauma. Our model of chronic endotoxin treatment demonstrates similar alterations as sepsis at similar times after insult. Itt is hoped that investigating the myocardial functional derangements in isolated perfused hearts, cardiocytes, and ventricular membranes in sepsis and following chronic endotoxin administration will provide us with a better understanding of the pathophysiologic mechanisms of decreased myocardial performance in a wide variety of clinical conditions.
| DeBlieux, P M; McDonough, K H; Barbee, R W et al. (1989) Exercise training attenuates the myocardial dysfunction induced by endotoxin. J Appl Physiol 66:2805-10 |
