Involvement of the Renin-Angiotensin System in Stress: State of the Art and Research Perspectives

Abstract

Background: Along with other canonical systems, the renin-angiotensin system (RAS) has shown important roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that nonclassical components, including Ang III, Ang IV, AT₂ and AT₄, can also be involved in stress.

Objective and methods: This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder.

Results and conclusion: In general, activation of the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available since they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.

Keywords: Renin-angiotensin system; angiotensin receptor blockers; angiotensin-converting enzyme inhibitors; neurobiology; stress.

Fig. (1)

The renin-angiotensin system cascade: updated simplified view. Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1-7), angiotensin-(1-7); Ang-(1-9), angiotensin-(1-9), Ang A, angiotensin A; AT₁, angiotensin type-1 receptor; AT₂, angiotensin type 2 receptor; Mas, Ang-(1-7) receptor Mas; MrgD, Mas-related G-protein coupled receptor; IRAP, insulin-regulated amino peptidase; APA, aminopeptidase A; APN, aminopeptidase N; DCase; DC, decarboxylase; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; PCP, prolyl carboxypeptidase; Thimetoligopeptidase (TOP); SNS, sympathetic nervous system.

Fig. (2)

Schematic diagram of the RAS axis in stress-related disorders. Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1-7), angiotensin (1-7); AT₁, angiotensin type-1 receptor; Mas, Ang-(1-7) receptor Mas; ACEi, angiotensin-converting enzyme inhibitor; ARBs, angiotensin-receptor blockers; DIZE, diminazene aceturate; XNT, 1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl)sulfonyloxy]-9H-xanthene-9-one; AVE0991, Mas-receptor agonist; CGEN-856S, Mas-receptor agonist; SNS, sympathetic nervous system; PSNS, parasympathetic nervous system.

Fig. (3)

Main effects of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in stress-related disorders.