Abstract
Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.
Highlights
Brain orexin system hyperactivity contributes to neurogenic hypertension
B1 receptor (B1R) knockdown mitigates upregulation of the paraventricular nucleus (PVN) pro‐hypertensive orexin receptors. mRNA levels of both orexin receptors were upregulated (P < 0.05) in the PVN of deoxycorticosterone acetate (DOCA)-salt treated hypertensive WT mice when compared with sham-treated controls
We further examined orexin receptor protein expression in both WT and B1R knockout (B1RKO) mice using hypothalamic PVN punches
Summary
Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of saltsensitive hypertension. In African American patients, the elderly and patients with congestive heart failure or chronic renal failure all exhibit AVP-dependent hemodynamic changes, and these populations exhibit low levels of circulating r enin[13,14] These parallels suggest that the high level of uncontrolled neurogenic hypertension in these patient groups may be better controlled with a pharmacotherapeutic targeting the central orexin and AVP hyperactivities. We hypothesize that knockdown of B1R in a mouse model will mitigate neurogenic hypertension, at least partly, by reducing the pro-hypertensive hypothalamic orexin system
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