NEW INOTROPIC AGENTS FOR THE TREATMENT OF HEART FAILURE

DESCRIPTION (provided by applicant): The goal of the project is to develop new positive inotropes, represented by specifically modified AMP molecules. All of the currently available positive inotropic agents have significant adverse effects with digitalis being the only orally available positive inotrope. ATP causes a pronounced positive inotropic effect. Receptors for ATP, known as P2 purinergic receptor, has been shown to mediate its positive inotropic effect. However, agonists acting at this cardiac P2 receptor with enhanced efficacy, potency and selectivity, are lacking. Preliminary data suggest that certain specific modifications of the AMP molecule will confer positive inotropic activity and selectivity vs. the vascular P2 receptor. Adult rat ventricular myocytes and intact heart model have been developed to determine the affinity and efficacy of new agents at the myocyte P2 receptor and their effects on the various functional parameters in the intact heart. The overall objective of the study is to use these cardiac models to test these specifically modified AMP molecules at the cardiac P2 receptor. New chemical structures will be correlated with the affinity and the positive inotropic activity and cardiac vs. vascular P2 receptor selectivity. The effects of these compounds on the heart rate and blood pressure in conscious rats will also be determined. The studies may lead to potentially useful new positive inotropic agents for the treatment of heart failure.