Sympatho-excitation along with general neurohumoral activation is a universal finding in the setting of chronic heart failure (CHF). Interruption of sympathetic nerve activity using beta blockers has been a standard therapeutic regimen for CHF patients for many years. However, the mechanisms responsible for sympatho-excitation in the CHF state are still unclear. Recently, it has been shown that several substances which are either increased or decreased in the CHF state act as modulators of sympathetic outflow. These substances include nitric oxide (NO), angiotensin II (Ang II) and endothelin-1 (ET-1). Recent animal and human studies have shown that the class of compounds known as HMG CoA reductase inhibitors or statins possess a variety of biological effects other than their ability to lower plasma cholesterol. These so called pleiotropic effects include lowering of arterial pressure, increasing production of endothelial NO, reducing Ang II receptors, reducing the production of ET-1 and scavenging of oxygen derived free radicals. Because of these actions we hypothesize that statins participate in sympatho-inhibition in the CHF state by virtue of several of the above effects. Preliminary data suggest that administration of simvastatin to rabbits with experimental CHF reduces resting renal sympathetic nerve activity (RSNA) and enhances baroreflex function. We propose a series of experiments to extend these preliminary studies and investigate the role of statins in sympathetic regulation in conscious rabbits with and without pacing-induced CHF. Rabbits will be treated with either simvastatin or pravastatin. Hemodynamics and RSNA will be measured as well as arterial baroreflex function. The role of NO will be determined by repeating experiments following peripheral and central blockade of nNOS. Central alterations in Ang II receptors and in ET-1 will be determined. Finally, the involvement of the GTP binding proteins of the Rho family will be determined in order to assess the role of these substances in mediating the enhancement of NO production by statins. These experiments will shed new light on central mechanisms of sympatho-excitation in the CHF state. The data accrued will have applicability to our understanding of autonomic regulation and therapeutics in this disease.
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