The broad long-term research objective is to understand the mechanisms underlying endothelial dysfunction and vascular alterations in heart failure. The contribution of angiotensin II to the genesis of endothelial dysfunction is of particular interest. Heart failure is one of the leading causes of cardiac death world wide. The presence of a dysfunctional is of particular interest. Heart failure is one of the leading causes of cardiac death worldwide. The presence of a dysfunctional endothelium and alterations in the renin-angiotensin system have been postulated to be involved in the etiology of this complication. Precise mechanisms leading to these alterations, however, are still unknown. This research proposal focuses on the effect of inhibition of the renin-angiotensin system on endothelial dysfunction and vascular alterations in heart failure. Two- month old Syrian cardiomyopathic hamsters will serve as the model because endothelial dysfunction is already present by this age in these animals. After 4 weeks of treatment with a combination of enalapril (50 mg/kg/day) and losartan (10 mg/kg/day) to completely block the synthesis and effects of angiotensin II, aortic rings will be used to investigate the following the following specific aims: 1) to evaluate if suppression of the renin-angiotensin system improves endothelial dysfunction, and to investigate the status of the signaling pathway of nitric oxide (NO) production; 2) to determine if suppression of the renin- angiotensin system modifies the contribution of contractile prostaglandins to endothelial dysfunction; 3) to determine the effect of the blockade of the renin-angiotensin system on vasoconstrictor prostaglandins administered exogenously; 4) to evaluate if this therapy modifies the enhanced contractile vascular response to angiotensin II, and to supraphysiological norepinephrine concentrations; 5) to determine the effect of chronic suppression of the renin-angiotensin system on the activity of vascular and cardiac angiotensin-converting enzyme; and 6) to determine the effect of chronic inhibition of the renin-angiotensin system on myolysis/necrosis present in cardiac and vascular smooth muscle cells. To evaluate endothelial function, dose-response curves for acetylcholine- induced relaxation will be generate using aortic rings pre-contracted with norepinephrine. These curves will be performed in the presence and absence of L-arginine, Pertussis toxin, and GTP-gamma-S. Pre-contracted aortic rings will also be treated with A23187 to stimulate NO-synthase directly by increasing the intracellular calcium, concentration. The possibility that an increased production of contractile prostaglandins is involved in the genesis of heart failure will be evaluated by comparing acetylcholine dose-response curves generated before and after tissue incubation with 1muM indomethacin. This study will contribute to the elucidation of the role of angiotensin II in the genesis of endothelial dysfunction and vascular alterations, and of the mechanisms underlying endothelial dysfunction in heart failure. The proposed studies should provide the rationale for the development of new therapeutic strategies.
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