Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system

Abstract

In the brain, angiotensinergic pathways play a major role in chronic regulation of cardiovascular and electrolyte homeostasis. Increases in plasma angiotensin II (Ang II), aldosterone, [Na+] and cytokines can directly activate these pathways. Chronically, these stimuli also activate a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels and endogenous ouabain (EO). This pathway increases AT1R and NADPH oxidase subunits and maintains/further increases the activity of angiotensinergic pathways. These brain pathways not only increase the setpoint of sympathetic activity per se, but also enhance its effectiveness by increasing plasma EO and EO-dependent reprogramming of arterial and cardiac function. Blockade of any step in this slow pathway or of AT1R prevents Ang II-, aldosterone- or salt and renal injury-induced forms of hypertension. MR/AT1R activation in the CNS also contributes to the activation of sympathetic activity, the circulatory and cardiac RAAS and increase in circulating cytokines in HF post MI. Chronic central infusion of an aldosterone synthase inhibitor, MR blocker or AT1R blocker prevents a major part of the structural remodeling of the heart and the decrease in LV function post MI, indicating that MR activation in the CNS post MI depends on aldosterone, locally produced in the CNS. Thus, Ang II, aldosterone and EO are not simply circulating hormones that act on the CNS but rather they are also paracrine neurohormones, locally produced in the CNS, that exert powerful effects in key CNS pathways involved in the long-term control of sympathetic and neuro-endocrine function and cardiovascular homeostasis.

Bidirectional link between diabetes mellitus and coronavirus disease 2019 leading to cardiovascular disease: A narrative review

“…RAAS plays an important role in maintaining cardiovascular health and electrolyte balance[ 146 ] and has been well-described before. In COVID-19 patients, the SARS-CoV-2 gains entry into the cells by attaching to the ACE2 receptor of the cell.…”

“…The reduced levels of ACE2 receptors and increased levels of Ang II after a SARS-CoV-2 infection can lead to atherosclerotic CVD in two possible ways. First, an increased Ang II level causes stimulation of the adrenal gland, triggering the production of the mineralocorticoid hormone aldosterone[ 146 ], which causes Na (sodium) and water retention in the collecting duct of the kidney[ 152 ]. This increases blood volume and blood pressure[ 153 ], causing endothelial dysfunction that progresses to atherosclerotic CVD.…”

Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment

“…11 The potential explanation may be related to their differential blockade of the 2 angiotensin receptors (AT 1 and AT 2 ) in the brain. 12,13 Activation of AT 1 promotes neurotoxic mechanisms, such as oxidative stress, neuroinflammation, endothelial dysfunction, cerebral hypoperfusion and cholinergic depletion. [14][15][16] Stimulation of AT 2 counteracts these mechanisms.…”

Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

“…Cardiac steroids (CSs), such as the cardenolides ouabain (OUA) and digoxin, and bufadienolides, such as marinobufagenin (MBG), were originally discovered in plants and amphibian skin and are known for their positive inotropic effect [3]. Endogenous cardiac steroids (ECSs), compounds identical or similar to CSs, are present in human tissues and circulation [4,5]. Although the biosynthetic pathway was not fully elucidated, ECSs seem to be synthetized in the adrenal gland and brain [6,7] and are considered hormones involved in numerous physiological and pathological processes, among them cell growth, salt homeostasis, regulation of blood pressure, and behavior [6][7][8][9].…”