Upregulation of the Renin-Angiotensin-Aldosterone-Ouabain System in the Brain Is the Core Mechanism in the Genesis of All Types of Hypertension

Abstract

Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease blood pressure in resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered. These findings promoted the concept that the central nervous system may actually be involved in the pathogenesis of essential hypertension, which is closely associated with excess sodium intake. We have demonstrated that endogenous digitalis plays a key role in hypertension associated with excess sodium intake via sympathetic activation in rats. Increased sodium concentration inside the brain activates epithelial sodium channels and the renin-angiotensin-aldosterone system in the brain. Aldosterone releases ouabain from neurons in the paraventricular nucleus in the hypothalamus. Angiotensin II and aldosterone of peripheral origin reach the brain to augment sympathetic outflow. Collectively essential hypertension associated with excess sodium intake and obesity, renovascular hypertension, and primary aldosteronism and pseudoaldosteronism all seem to have a common cause originating from the central nervous system.

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

“…5 Intranasally administered ANGII, as well as brain ANGII, may act in a paracrine manner to influence neuronal activity of centers involved in blood pressure regulation. 6,36 Hence, the function of ANGII and its degradation products seems to depend on the compartment of its action. Recent findings in rats underline this point of view: a chronic infusion of ANG 1-7 in the lateral ventricle of the brain attenuated the development of deoxycorticosterone acetate salt-induced hypertension.…”

“…6,36 Hence, the function of ANGII and its degradation products seems to depend on the compartment of its action. Recent findings in rats underline this point of view: a chronic infusion of ANG 1-7 in the lateral ventricle of the brain attenuated the development of deoxycorticosterone acetate salt-induced hypertension.…”

“…Besides its systemic effects on the blood vessels and different organ systems, local ANGII is crucially involved in the central nervous regulation of blood pressure. [1][2][3][4][5][6] ANGII receptors, mainly type 1 receptors (AT1) and also type 2 receptors (AT2), are expressed in several cerebral nuclei where they mediate effects of locally produced ANGII. [7][8][9][10] Inhibition of central nervous ANGII synthesis reversed hypertension in spontaneously hypertensive rats.…”

Endogenous Ouabain

“…27, 33 The amplifier incorporates neuromodulatory components including local aldosterone synthesis, MRs, ENaCs, and increased synthesis and/or levels of EO in the brain. 39–42 Prolonged stimulation of this CNS amplifier, especially by Na + or low dose Ang II, increases sympathetic nerve activity (SNA), often to discrete vascular beds. 43 In addition, however, activation of the CNS amplifier raises the circulating levels of peptide hormones including ACTH, a stimulator of adrenal EO secretion, 44 vasopressin and growth hormone.…”

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease

“…The hypothalamic component of the neurohumoral pathway involves local aldosterone production, mineralocorticoid receptors, ENaCs, local EO release and α2 Na + pumps (Huang & Leenen, ; Van Huysse & Hou, ; Leenen, ; Gabor & Leenen, ; Van Huysse et al . ; Takahashi, ). This ‘brain EO’ enhances hypothalamic Ang type 1 receptor (AT 1 R) signalling (Huang et al .…”