Sympatho-excitation contributes to the progressive deterioration of cardiac function in severe chronic heart failure (CHF). While we have learned much concerning the central mechanisms for this phenomenon there is still no satisfactory treatment for sympatho-excitation in CHF. Beta adrenergic blockade has been successful in targeting cardiac adrenergic stimulation but does little for peripheral sympatho-excitation. The use of current central sympatho-inhibitory agents is fraught with problems including an increased mortality and various intolerable side effects. HMGCoA Reductase inhibitors (statins) have been shown to possess a variety of pleiotropic effects that make them ideal agents for providing sympatho-inhibition in the CHF state (e.g. stimulation of nitric oxide (NO)). Our previous data indicate that chronic statin treatment does indeed result in sympatho-inhibition and an improvement in arterial baroreflex function in rabbits with pacing-induced CHF. Based on our animal studies and on new preliminary data we now hypothesize that statins also act as sympatho-inhibitory agents in patients with CHF. The mechanisms by which statins evoke this effect are unclear. Based on novel preliminary data, we hypothesize that statins reduce sympathetic outflow in CHF by acting centrally on cellular Ang II, NO and reactive oxidant species, in part, via a Rho Kinase mechanism. We have proposed 4 Specific Aims in order to expand our previous work and uncover new therapeutic targets involved in sympatho-excitation.
In Specific Aim 1 we will determine the mechanism by which AT1 receptor protein is down regulated following statin treatment.
Specific Aim 2 will investigate one potential mechanism for the neuronal action of statins. The role of the small GTP binding protein Rho and Rho Kinase and NO synthase will be investigated in intact animals and in isolated neuronal cell cultures.
Specific Aim 3 will examine the relationship between statins and NO release in isolated cells and in specific central nuclei.
This aim will further evaluate the role of ROS in determining the bioavailability of NO with and without chronic statn treatment.
Specific Aim 4 will determine the effects of statin treatment on muscle sympathetic nerve activity in patients with CHF and the relationship to changes in NO and ROS. We believe that these studies will provide important new information concerning mechanisms of cellular and integrative sympathetic function in the CHF state and provide novel targets for modulation of sympathetic outflow and neuroprotection.
These studies will help define mechanisms related to the course of heart failure and identify new targets in the brain for therapy in the heart failure state. We will determine if a class of drugs called statins has the potential for reducing some of the deleterious consequences of compensatory mechanisms in the heart failure state.
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