Mechanism of protective action of adenosine in cardioplegic solutions
Principal Investigator: William R. Law, Ph.D.
Co-Investigators:  Dorie Schwertz, BSN, PhD

Funding:   VA Merit Review

Project Summary:  Clinical and Animal Lab Studies-There is an inverse correlation between time on bypass and myocardial functional recovery after surgical procedures requiring cardioplegia.  Evidence indicates that calcium dyshomeostasis, once believed to be the culprit of injury, is not the primary problem in these hearts.  Likely mediators are the generation of oxygen free-radicals upon reperfusion, altered function of contractile proteins, and protein degradation.  Adenosine added to cardioplegic solutions has been shown to reduce the cardiac injury and improve functional recovery upon re-oxygenation, but the mechanisms of its actions are not known.  Adenosine can have a variety of effects on cardiac function.   The overall goal of this long-term program is to determine the mechanisms of adenosine's protective effects in order to formulate an additive to cardioplegic solutions that will optimize beneficial actions of adenosine, while minimizing deleterious affects.  The short-term goals of this program are to determine how adenosine in cardioplegic solution affects superoxide radical formation, protein kinase C activation (and subsequent phosphorylation) and glycolysis, and the effects of these mechanisms on global cardiac performance and, at the molecular level, on contractile protein status and function.

Funding Source: National Institutes of Health R41-GM065593

This is a small business grant to test the feasibility of using pentostatin, an adenosine deaminase (ADA) inhibitor, to treat systemic inflammatory response syndrome. The goals are to: 1. determine how long macrophage ADA activity remains suppressed after treatment with pentostatin, and 2. determine if pentostatin causes overt vascular collapse during frank sepsis (measurements of cardiac output and calculation of total systemic vascular resistance).