The central hypothesis of this project is that chronic endothelin (ET) receptor activation directly contributes to the initiation, progression and severity of the left ventricular (LV) dysfunction and hemodynamic instability which occurs with CHF. Using an animal model of CHF, an isolated myocyte system, and signal transduction experiments, this project has the following specific aims: (1) identify how ET receptor activation during the progression of CHF influences systemic and coronary vascular resistance at rest and with exercise; (2) determine the direct effects of chronic ET receptor activation on myocyte contractile processes and the changes in ET signaling which occur during the progression of CHF; (3) determine the specificity and selectivity of the effects of ET receptor activity on LV and myocyte function during the progression of the CHF process through a series of studies in which neurohormonal modulation and systemic hemodynamics will be controlled by angiotensin converting enzyme inhibition, selective ET receptor blockade, or a combination of both. Through a stepwise and integrative approach, this project will define how the ET receptor signaling mechanism coordinates and contributes to the transition to severe CHF as well as to the identification of a novel therapeutic target to slow the progression of this disease process.
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