The long-term goal of this research program is to elucidate the central neural mechanisms involved in the pathophysiology of hypertension. Accumulating evidence indicates that an increase in sympathetic tone emanating from the brain contributes to hypertension. Under normal conditions a discrete area of the brainstem, the rostral ventrolateral medulla (RVLM), is the primary region of the brain providing tonic stimulation of sympathetic vasomotor activity, and recent studies, including those done in the Pl's laboratory, have indicated that the RVLM is critical for the generation of the increased sympathetic vasomotor activity in experimental models of hypertension, including that in Spontaneously Hypertensive rats (SHR) and Dahl salt-sensitive rats. In particular, blockade of AT1 angiotensin receptors in the RLVM decreases blood l pressure in SHR and Dahl salt-sensitive rats but not in normotensive rats. In hypertensive rats, evidence suggests that increased stimulation of RVLM AT1 receptors is driven by input from the hypothalamic paraventricular nucleus (PVN) and is specifically due to an action on Ct neurons. Therefore, we propose 4 specific aims to test the hypothesis that activity of C1 RVLM neurons, particularly that due to AT1 receptor stimulation driven from the PVN, is important in maintaining increased sympathetic vasomotor tone provided by the RVLM in hypertension. [1] To determine the effect of selective destruction of C1 RVLM neurons on hypertension in SHR and Dahl salt-sensitive rats. Experiments will test the hypothesis that C1 neurons contribute to the maintenance of hypertension in these models. [2] To determine the role of C1 RVLM neurons in the actions of Angll in the RVLM. Experiments will test the hypothesis that the primary sympathoexcitatory action of Angll In the RVLM is on C1 neurons and that this input to C1 RVLM neurons is important in maintaining hypertension. [3] To determine whether C1 RVLM neurons are important for the antihypertensive actions of AT1 receptor antagonists. [4] To determine the role of C1 RVLM neurons in the cardiovascular responses elicited from the PVN in normotensive and hypertensive rats. It is expected that these studies will increase our understanding of the role of the brain in the pathophysiology of hypertension, and may provide new insight to the treatment and prevention of hypertension. ? ?
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