Myocardial depression remains a major cause of morbidity and mortality following cardiopulmonary bypass (CPB). Mechanisms contributing to this myocardial depression are ill-defined, but appear to involve an inflammatory component. The acute inflammatory response to injury results in the synthesis and release of cytokines by a variety of immune and non- immune cells. The P.I., Co-P.I. and Consultant were the first to propose the hypothesis that cytokine-stimulated production of nitric oxide (NO) contributed to post-CPB myocardial depression. They provided support for this hypothesis by demonstrating for the first time that: (l) cytokines depressed myocardial contractility in isolated hamster papillary muscles. (2) a specific cytokine (IL-6) was elevated in patients following CPB. (3) IL-6 depressed myocardial contractility in humans. (4) L-NMMA (known inhibitor of NO synthesis) blocked the negative inotropic effects of cytokines on the heart. (5) Myocardial NO synthesis increased in patients following CPB. Considerably more work needs to be done to definitely confirm or refute this hypothesis. However, it is clear that IL-6 and NO have the potential to modulate myocardial contractility in animals and humans. The mechanisms of action of these newly described endogenous regulators of myocardial contractility have yet to be fully elucidated.
The specific aims for this project are: I. Identify the mechanism(s) responsible for the negative inotropic effect of IL-6 and NO on isolated hamster papillary muscles and human atrial pectinate muscles. II. Identify stimuli for myocardial NO production in isolated hamster papillary muscles and human atrial pectinate muscles. The results of these studies will provide important new insights into the mechanism of action of these newly identified endogenous regulators (IL-6; NO) of myocardial contractility.
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