Abstract
Central nervous system (CNS) administration of angiotensin II (Ang II) raises blood pressure (BP). The rise in BP reflects increased sympathetic outflow and a slower neuromodulatory pressor mechanism mediated by CNS mineralocorticoid receptors (MR). We investigated the hypothesis that the sustained phase of hypertension is associated also with elevated circulating levels of endogenous ouabain (EO), and chronic stimulation of arterial calcium transport proteins including the sodium-calcium exchanger (NCX1), the type 6 canonical transient receptor potential protein (TRPC6), and the sarcoplasmic reticulum calcium ATPase (SERCA2). Wistar rats received a chronic intra-cerebroventricular infusion of vehicle (C) or Ang II (A, 2.5 ng/min, for 14 days) alone or combined with the MR blocker, eplerenone (A+E, 5 µg/day), or the aldosterone synthase inhibitor, FAD286 (A+F, 25 µg/day). Conscious mean BP increased (P<0.05) in A (123±4 mm Hg) vs all other groups. Blood, pituitary and adrenal samples were taken for EO radioimmunoassay (RIA), and aortas for NCX1, TRPC6 and SERCA2 immunoblotting. Central infusion of Ang II raised plasma EO (0.58±0.08 vs C 0.34±0.07 nM (P<0.05), but not in A + E and A + F groups as confirmed by off-line liquid chromatography (LC)-RIA and LC-multistage mass spectrometry. Two novel isomers of EO were elevated by Ang II; the second less polar isomer increased >50-fold in the A+F group. Central Ang II increased arterial expression of NCX1, TRPC6 and SERCA2 (2.6, 1.75 and 3.7-fold, respectively; P<0.01)) but not when co-infused with E or F. Adrenal and pituitary EO were unchanged. We conclude that brain Ang II activates a CNS-humoral axis involving plasma EO. The elevated EO reprograms peripheral ion transport pathways known to control arterial Na+ and Ca2+ homeostasis; this increases contractility and augments sympathetic effects. The new axis likely contributes to the chronic pressor effect of brain Ang II.
Highlights
The central nervous system (CNS) plays a significant role in human essential hypertension and in many experimental models of hypertension [1,2]
Sustained central infusion of angiotensin II (Ang II) elevates circulating endogenous ouabain (EO) (Fig. 1A), a vasopressor steroid, and augments the expression of three key proteins involved in Ca2+ and Na+ transport, and in Ca2+ homeostasis and signaling, in arterial myocytes (Fig. 2)
All the humoral, vascular and hemodynamic effects of icv Ang II we observed were prevented by the central administration of eplerenone, a potent and highly selective mineralocorticoid receptors (MR) blocker [32], and, to a lesser extent, by inhibition of aldosterone synthase by FAD286 [22]
Summary
The central nervous system (CNS) plays a significant role in human essential hypertension and in many experimental models of hypertension [1,2]. The CNS influences BP via peripheral sympathetic nerve activity (SNA) and via long-range endocrine mechanisms including adrenocorticotropic hormone (ACTH), growth hormone, angiotensin II (Ang II) and vasopressin [2,3,4,5]. Circulating Ang II can enter the CNS via fenestrated epithelia in the hypothalamus and is generated within the brain [6,7,8]. Increases in central Ang II raise sympathetic nerve activity, elevate the plasma levels of vasopressin and ACTH and increase BP [9]. The observation that the prolonged peripheral administration of low, sub-pressor doses of Ang II elevates BP gradually [10,11,12] led to the idea of an auto-potentiating CNS based neurogenic pressor mechanism that becomes increasingly important in sustaining hypertension [13,14]. The chronic pressor effect of peripheral and central Ang II is amplified by raising salt intake [15,16], and requires activation of brain mineralocorticoid receptors (MR) by local aldosterone and/or corticosterone [14]
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