Alpha2-adrenergic receptor (alpha2-AR) have been implicated in the development or maintenance of hypertension. It is our hypothesis that alterations in the function or expression of alpha2-AR contribute to the development of hypertension by increasing the sympathetic outflow and/or by affecting kidney function and vascular responsiveness. However, it is not clear which alpha2-AR subtype contributes to the control of the sympathetic outflow or kidney function. It is our goal to study (a) the role of each alpha2-AR subtype in blood pressure regulation and (b)to determine the mechanisms that control the levels of alpha2-AR expression.
Our specific aims are: (1) To determine the role of each alpha2-AR in normal cardiovascular regulation by utilizing knockout mice that are missing either the alphaA2-, alpha2B- or alpha2C-AR gene and analyzing the effects on blood pressure, levels of neurohumoral factors and pattern of expression of the remaining alpha2-AR genes. In addition, we will measure the effects of sodium loading on kidney function, blood pressure and heart rate, and will test whether elimination of a particular alpha2-AR subtype affects vascular reactivity to norepinephrine. (2) To evaluate the role of each alpha2-AR subtype in the development and maintenance of hypertension by utilizing the knockout mice in experimental protocols that produce hypertension in wild type mice. Blood pressure, heart rate and leyels of neurohumoral factors will be measured to test whether elimination of a particular subtype of alpha2-AR alters the course of developing hypertension. (3) To determine the influence of neurohumoral factors on the expression of alpha2-AR by studying the effects of insulin, norepinephrine, vasopressin and angiotensin II on alpha2-AR mRNA levels in cultured vascular smooth muscle cells. The effects of cellular proliferation on alpha2-AR expression will also be examined. (4) To determine nuclear factors affecting the transcription of the alpha2-AR gene, especially in response to the substances used in specific aim 3, and to study the distribution of these nuclear factors in normotensive and hypertensive animal models. We believe these studies will allow us to determine which alpha2-AR subtype(s) is (are) key to blood pressure control and will help us to develop future strategies to up and down regulate alpha2-AR gene expression in vivo, in order to influence alpha2- AR function with a long-term goal of developing more specific treatments to control blood pressure.
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