Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Congestive heart failure is a major health problem which has reached pandemic proportions in the Western world. It is now known that heart failure is associated with elevated plasma levels of several hormones, which produce harmful effects and result in the inability of the heart to pump sufficient blood to meet the needs of the body. Although several drugs, based on blocking the effects of these hormones, are now available for the treatment of heart failure, none of these drugs are satisfactory because these do not improve the survival rate of patients with heart failure. We now wish to investigate if combination therapy with existing drugs for blocking sympathetic nervous system (SNS) and renin-angiotensin system (RAS) will improve heart function by preventing changes in the contractile machinery in the failing heart. For this purpose, we will use a rat model of heart failure induced by occluding the coronary artery. The first series of experiments will test the effect of combination therapy by using carvedilol (for the SNS blockade) and imidapril (for the RAS blockade). Different mechanisms of the beneficial effects of combination therapy in heart failure will be examined. In addition, we will explore the effectiveness of different drugs which block the actions of other hormones, such as vasopressin, endothelin, aldosterone, and serotonin either alone or in conjunction with combination therapy with imidapril plus carvedilol to establish if these agents enhance the benefits. These studies are hoped to provide the experimental basis for the use of combination therapy in the treatment of heart failure.