Novel Antihypertensive Medications to Target the Renin-Angiotensin System: Mechanisms and Research

Figures

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  Fig. 1.. The renin-angiotensin system (RAS) pathways. Renin cleaves angiotensinogen to form angiotensin (Ang) I, which is further proteolyzed by angiotensin-converting enzyme (ACE) to produce Ang II. In the harmful branch of the RAS, Ang II can directly stimulate Ang II type I receptor (AT1R), leading to increased blood pressure (BP) through mechanisms such as blood vessel constriction, increased release of aldosterone and arginine-vasopressin, reduced baroreflex responsiveness, lower nitric oxide (NO) production, and decreased sodium excretion. Additionally, AT1R activation can occur through Ang III, which is generated when aminopeptidase A (APA) acts on Ang II. Conversely, the protective branch of the RAS involves the stimulation of Mas receptor (MasR), Mas-related G protein-coupled D (MrgD), Ang II type II receptor (AT2R), and Ang II type IV receptor (AT4R), primarily via NO, thereby inducing vasodilation and natriuresis to lower BP. MasR is mainly activated by Ang (1-7), formed through Ang II cleavage by ACE2, or ACE action on Ang (1-9). Ang (1-9) is formed predominantly through the cleavage of Ang I by ACE2. Moreover, Ang (1-7) can be cleaved by aspartate decarboxylase (AD) to…

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  Fig. 2.. The mechanism of zilebesiran in hepatic cells. After binding to asialoglycoprotein receptors on the cell surface, zilebesiran enters the cells through endocytosis. It then attaches to RNA-induced silencing complex (RISC), and the small interfering RNA (siRNA) separates into passenger and guide strands. The passenger strand is broken down, while the guide strand enables activated RISC to bind the angiotensinogen (AGT) messenger RNA (mRNA). Upon binding, the AGT mRNA is degraded, thus reducing the production of AGT. “↓” in the Fig. 2 means the reduction of AGT production. Created with Adobe Illustrator 2023.

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  Fig. 3.. Hypotensive mechanisms involving PRO20 targeting of the renin/(pro)renin receptor (PRR) axis. On one hand, PRO20 can prevent activation of the PRR enzyme in the brain by blocking calcium influx in neurons and decreasing the levels of Ang II in the brain stem, cortex, and hypothalamus, thereby exerting an anti-hypertensive effect. On the other hand, PRO20 can decrease the expression of α-epithelial sodium channel (α-ENaC) in the collecting duct to reduce sodium reabsorption and enhance sodium-water excretion. It does this by inhibiting the activation of renal PRR and the intrarenal RAS. “Brain PRR enzymatic activation↓” means the decrease of brain PRR enzymatic activation; “brain Ang II↓” means the reduction of the brain Ang II production; “collecting duct α-ENaC expression↓” means the decrease of collecting duct α-ENaC expression; “sodium reabsorption↓” means the reduction of sodium reabsorption; “sodium-water excretion↑” means the increase of sodium-water excretion; “blood pressure↓” means the decrease of blood pressure. Created with Adobe Illustrator 2023.

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  Fig. 4.. Mechanisms underlying the hypotensive effects of GSK2586881, Ang (1-7), and AVE0991. “Natriuresis↑” means the promotion of natriuresis; “vasodilatation↑” means the promotion of vasodilatation; “baroreflex↑” means the promotion of baroreflex; “blood pressure↓” means the decrease of blood pressure. Created with Adobe Illustrator 2023.

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  Fig. 5.. The hypotensive mechanisms involving alamandine targeting of the alamandine/MrgD receptor (MrgDR) axis. “Vasodilatation↑” means the promotion of vasodilatation; “oxidative stress↓” means the inhibition of oxidative stress; “blood pressure↓” means the decrease of blood pressure. Created with Adobe Illustrator 2023.

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  Fig. 6.. Hypotensive mechanisms of C21 and β-Pro7Ang III by targeting the renin/ACE/Ang II/AT2R axis. NO, nitric oxide; BK, bradykinin. “NO and BK↑” means the increase of NO and BK production; “natriuresis↑” means the promotion of natriuresis; “blood pressure↓” means the decrease of blood pressure. Created with Adobe Illustrator 2023.

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  Fig. 7.. Hypotensive mechanisms of NI956, EC33, and firibastat in targeting the brain RAS. “Natriuresis↑” means the promotion of natriuresis; “sympathetic neuron activity↓” means the decrease of sympathetic neuron activity; “plasma arginine-vasopressin↓” means the reduction of plasma arginine-vasopressin concentration; “Ang (1-7)↑” means the increase of Ang (1-7) production; “blood pressure↓” means the decrease of blood pressure. Created with Adobe Illustrator 2023.