Future Directions in Cardiovascular Pharmacology: Examples from the Renin-Angiotensin System

Schematic of the enzymes and processing of substrates for the renin-angiotensin system. Ang II is formed through the actions of angiotensin converting enzyme (ACE). Ang-(1-7) can be formed through several enzymatic reactions: 1) proteolytic cleavage of Ang I or Ang-(1-12)––a proteolytic cleavage product of angiotensinogen––by neprilysin, or 2) proteolytic cleavage of Ang II by ACE2. Note that neprilysin and ACE2 inactivate Ang II, whereas ACE inactivates Ang-(1-7). Thus, there is reciprocal down-regulation of the opposing peptide by the enzymes responsible for producing each peptide. Each peptide acts on its own distinct receptors (see white text boxes), with the Ang II type 1 receptor (AT₁R) mediating the majority of the pro-hypertensive actions of Ang II and the Ang-(1-7) receptor activating pathways that serve as physiologic antagonists to the actions of Ang II. The actions of the AT₂R are not yet clear, although several effects of PD123319 mimic the actions of Ang-(1-7). ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; NEP, neprilysin; AT₁R, AT₁ receptor; AT₂R, AT₂ receptor; AT_(1-7) R, Ang-(1-7) receptor, also known as Mas; Sartans, AT₁R antagonists, losartan class; PD123319, AT₂R antagonist; D-Ala, D-Ala⁷-Ang-(1-7), the Ang-(1-7) receptor antagonist; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase.