The central nervous system coordinates effector systems that control blood pressure. Structures of the lamina terminalis (LT) receive and process information about of the status of the cardiovascular system and body fluid balance. Processed output from the LT is projected into a neural network that regulates blood pressure over the long term. Therefore the LT is a pivotal neural node for determining cardiovascular homeostasis. In recent studies, we have discovered that antagonism of brain mineralocorticoid receptors (MR), angiotensin Type 1 receptors (ATrR), or transient receptor potential, vanilloid Type 1 (TRPV1) channel or increased scavenging of central reactive oxygen species (ROS) block the development of mineralocorticoid (MC)-induced hypertension (HT). The primary hypothesis to be tested in this proposal is that neurons in structures of the LT use MR, AT^R, ROS, and TRPV1 channels in information processing that is essential for maintaining normal blood pressure and body fluid homeostasis. To test this hypothesis, both in vivo and in vitro experiments will be conducted in which MR, ATrR, ROS, and TRPV1 proteins are manipulated within structures of the LT. The experiments will address the following four specific aims:
Aim 1. determine if components of the LT are critical for the roles of MR, AT^R, ROS and TRPV1 channels in aldosterone (ALDO)-induced HT;
Aim 2. determine the effects of ALDO pretreatment on angiotensin II (ANG II), hypertonic saline (HTS) or acetylcholine (ACh) activation of cells in the LT;
Aim 3. determine the effects of ALDO pretreatment on ROS generation and on ANG IIinduced release of intracellular ROS ([ROS]() in the LT;
and Aim 4. determine the effects of ALDO pretreatment on expression of ATrR, superoxide dismutase (SOD) and NADPH oxidase in the LT. Techniques to be applied include chronic telemetric measurements of blood pressure and heart rate, in vitro imaging in living brain slices to determine induced changes in intracellular calcium ([Ca2+]j) and [ROS]j, and quantitative determination of the expression of key signaling molecules that have been implicated in MC-induced HT. New knowledge derived from studies on the mechanisms of LT neuronal function in reception and processing of information is highly relevant to understanding the pathophysiology associated with disordered fluid and cardiovascular regulation. This new information will be critical for a fuller understanding of the etiology and treatment of diseases such as hypertension and heart failure.
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