α _2A -Adrenergic Receptors Mediate Sympathoinhibitory Responses to Atrial Natriuretic Peptide in the Mouse Anterior Hypothalamic Nucleus

Abstract

Abstract-In the rat, activation of ␣ 2 -adrenergic receptors in the anterior hypothalamic nucleus inhibits sympathetic nervous system activity. Furthermore, local release of atrial natriuretic peptide inhibits norepinephrine release in this nucleus, blocking local activation of ␣ 2 -adrenergic receptors, and thereby contributes to NaCl-sensitive hypertension in spontaneously hypertensive rats. To further test the specificity of this mechanism, either ␣ 2 -adrenergic receptor agonists or atrial natriuretic peptide was microinjected into anterior hypothalamic nucleus of conscious C57BL/6 mice in which the ␣ 2 -adrenergic receptor was functionally deleted by a single point mutation (nϭ10 per group). In control mice, microinjection of either clonidine or guanabenz (10 Ϫ3 to 10 Ϫ7 mol/L) caused a rapid fall in mean arterial pressure that lasted for several minutes. In the knockout mice there was no response to the injection of either dose of either agonist. Microinjection of atrial natriuretic peptide (10 Ϫ6 to 10 Ϫ7 mol/L) caused a rapid increase in mean arterial pressure (8.2Ϯ1.3 and 6.55Ϯ1.2 mm Hg, respectively) in the control mice that was similar to the responses previously observed in Wistar-Kyoto rats. In contrast, the microinjections did not significantly alter mean arterial pressure in the knockout mice. These experiments demonstrate that in the anterior hypothalamic nucleus of the mouse (and probably in the rat) ␣ 2A -adrenergic receptors mediate both sympathoinhibitory responses to ␣ 2 -adrenergic receptor agonists and the action of atrial natriuretic peptide. Key Words: hypertension, experimental Ⅲ hypothalamus Ⅲ receptors, adrenergic Ⅲ norepinephrine Ⅲ rats I n spontaneously hypertensive rats (SHR), high NaCl diets stimulate the sympathetic nervous system (SNS) and thereby exacerbate hypertension. Specifically, a high NaCl diet decreases norepinephrine release in the anterior hypothalamic nucleus (AHN), which in turn decreases activation of local ␣ 2 -adrenergic receptors. 1,2 This interaction is mediated, at least in part, by the neurotransmitter/neuromodulator atrial natriuretic peptide (ANP), which inhibits norepinephrine release. 3 Together, these findings suggest that in the AHN, both ANP and ␣ 2 -adrenergic receptors play a role in cardiovascular regulation in SHR.In normotensive rats, local ␣ 2 -adrenergic receptors also contribute to the sympathoinhibitory role of the AHN, and stimulation of these receptors decreases arterial pressure. 1 Thus, whereas ␣ 2 -adrenergic receptors in the AHN are important to the pathogenesis of NaCl-sensitive hypertension, they also play a role in arterial pressure regulation in normotensive rats. 1 Furthermore, in normotensive rats, norepinephrine release in AHN is regulated in part by ANP, a potent natriuretic hormone that is synthesized in the cardiac atria, released into the circulation, and regulates salt and water balance and blood pressure, primarily through actions on the kidney. 4,5 ANP is also locally synthesized in the brain, and as a neurotransmitter/neur...

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