Alamandine but not angiotensin-(1–7) produces cardiovascular effects at the rostral insular cortex

Abstract

Experiments aimed to evaluate the tissue distribution of Mas-related G-protein coupled receptor D (MrgD) revealed the presence of immunoreactivity for the MrgD protein in the rostral insular cortex (rIC), an important area for autonomic and cardiovascular control. In order to investigate the relevance of this finding, we evaluated the cardiovascular effects produced by the endogenous ligand of MrgD, alamandine, in this brain region. Mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded in urethane anesthetized rats. Unilateral microinjection of equimolar doses of alamandine (40pmol/100nl), angiotensin-(1-7), angiotensin II, angiotensin A and Mas/MrgD antagonist D-Pro7-Ang-1-7 (50pmol/100nl), Mas antagonist A779 (100pmol/100nl) or vehicle (0.9% NaCl) were made in different rats (N=4-6 per group) into rIC. To verify the specificity of the region, a microinjection of alamandine was also performed into intermediate insular cortex (iIC). Microinjection of alamandine in rIC produced an increase in MAP (Δ=15±2mmHg), HR (Δ=36±4bpm) and RSNA (Δ=31±4%), but was without effects at iIC. Strikingly, an equimolar dose of angiotensin-(1-7) at rIC did not produce any change in MAP, HR and RSNA. Angiotensin II and angiotensin A produced only minor effects. Alamandine effects were not altered by A-779, a Mas antagonist, but were completely blocked by the Mas/MrgD antagonist D-Pro7-Ang-(1-7). Therefore, we have identified a brain region in which alamandine/MrgD receptor but not angiotensin-(1-7)/Mas could be involved in the modulation of cardiovascular-related neuronal activity. This observation also suggests that alamandine might possess unique effects unrelated to angiotensin-(1-7) in the brain.

Site-Specific Regulation of Stress Responses Along the Rostrocaudal Axis of the Insular Cortex in Rats

“…It was identified that the sites in the posterior IC causing pressor and tachycardiac responses were located more rostrally than those evoking arterial pressure and HR decreases ( Verberne and Owens, 1998 ). Recent results have confirmed a site-specific control of cardiovascular function under basal conditions in the posterior region of the IC ( Marins et al, 2016 , 2021 ).…”

“…A site-specific control of the cardiovascular function under basal conditions (i.e., non-stressed) along the rostrocaudal axis of the IC has been described in rodents ( Verberne and Owens, 1998 ; Marins et al, 2016 , 2021 ). Indeed, stimulation of the IC (electrical or chemical with excitatory amino acids) evidenced that activation of anterior regions evoked mainly decreases in arterial pressure ( Hardy and Holmes, 1988 ; Hardy and Mack, 1990 ; Sun, 1992 ).…”

Alamandine alleviated heart failure and fibrosis in myocardial infarction mice

“…Likewise, each of the components in the non-canonical branch of RAS, including Ang-(1-7), Ang-(1-9), ACE2, AT2R, and Ala, has also been shown to counteract the effects of AngII/AT1R axis [ 95 ]. Among them, Ala possessed its biological actions by binding to its endogenous receptor Mas-related G protein-coupled receptor member D (MrgD), which was blocked by the AT2R antagonist PD123319 or Mas/MrgD antagonist D-Pro(7)-angiotensin-(1-7) [ 12 , 96 ]. To our minds, since Ala was formed from the hydrolysis of Ang A via ACE2 [ 97 ], it could be a viable alternative to well-established ACE2 activators in order to achieve higher Ala levels.…”

Diverse biological functions of the renin‐angiotensin system

“…60 However, like the classical axis, it also promotes excitatory effects associated with the sympathetic nervous system. 61 The functions of local RAS in the heart may suggest that drugs like ACEi and ARBs should greatly affect cardiac RAS. But Ang II tissue levels-and therefore its effects remains largely unchanged according to the clinical data.…”

“…Currently, it is known that MrgD and alamandine are present in cardiomyocytes and have some cardioprotective effects mainly through ACE2/Ang 1–7/MasR axis 60 . However, like the classical axis, it also promotes excitatory effects associated with the sympathetic nervous system 61 …”