The broad objective of this revised application is to define humoral mechanisms that participate in the pathophysiology of asymptomatic ventricular dysfunction (ALVD) and it's progression to overt congestive heart failure (CHF). Our focus is upon cardiac cGMP, a ubiquitous intracellular second messenger whose production is regulated by two systems - the natriuretic peptide system (NPS) and the nitric oxide system (NO). The novel aspect of this application lays in the investigation of the NPS and NO together as a complimentary system which regulates a second messenger whose ultimate level of activation will reflect the cumulative activation of these systems as well as the relative potency of their second messenger signaling. We will determine the temporal alterations in these two systems and in their combined impact on cGMP during the progression from ALVD to CHF. We will examine the functional consequences of alterations in these systems in respect to regulation of coronary blood flow and myocardial function. Lastly, we will explore the common and disparate mechanisms whereby these complimentary systems alter left ventricular function. Based on preliminary studies, we advance three hypotheses. First, we hypothesize that the NPS and NO are differentially activated during the progression from ALVD to CHF. Second, we hypothesize that through their common second messenger cGMP, these two systems uniquely preserve myocardial blood flow and diastolic function without adverse effects on systolic function. Third, we propose that unlike the NPS, NO possesses additional actions which are independent of its effects on cGMP and which impair systolic function. These studies will enhance our understanding of how these endogenous biochemical mediators influence myocardial perfusion and ventricular function throughout the progression of ALVD to CHF and provide the basis for therapeutic strategies to delay the transition from ALVD to severe CHF. In order to determine whether these complimentary systems are activated, how they modulate cGMP production and whether they ultimately influence myocardial perfusion and ventricular function, studies in the intact dog and in harvested tissue before and during the progression of asymptomatic LV dysfunction (ALVD) to severe CHF are planned and will address the following Specific Aims;
Aim 1 :Determine if myocardial cGMP and its dual regulators, the NPS and NO systems are activated during the progression from ALVD to severe CHF;
Aim 2 :Determine whether endogenous NPS and NO modulate myocardial cGMP, coronary blood flow and basal and stimulated LV function during the progression from ALVD to severe CHF;
and Aim 3 :Determine if the actions of the NPS and NO on basal LV function and beta-adrenergic responsiveness during the progression to CHF are mediated by CGMP.
