The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. The classical RAS consists of a circulating endocrine system in which the principal effector hormone is angiotensin (ANG) II. ANG is produced by the action of renin on angiotensinogen to form ANG I and its subsequent conversion to the biologically active octapeptide by ANG-converting enzyme. ANG II actions are mediated via the ANG type 1 receptor. Here, we discuss recent advances in our understanding of the components and actions of the RAS, including local tissue RASs, a renin receptor, ANG-converting enzyme-2, ANG (1-7), the function of the ANG type 2 receptor, and ANG receptor heterodimerization. The role of the RAS in the regulation of cardiovascular and renal function is reviewed and discussed in light of these newly recognized components.

—The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Virtually all of the biological actions of the principle effector peptide angiotensin II (ANG II) have been attributed to an action at the type 1 (AT₁) ANG receptor. Until recently, the functional role of the type 2 (AT₂) receptor, if any, has been unknown, possibly because the AT₂receptor has a low degree of expression compared with that of the AT₁receptor. Evidence has now accumulated that the AT₂receptor opposes functions mediated by the AT₁receptor. Whereas the AT₁receptor stimulates cell proliferation, the AT₂receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT₁receptor stimulates protein phosphorylation and the AT₂receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT₂receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT₁receptor. Work from our laboratory and others indicates that the AT₂receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT₂receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT₂receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT₁receptor.

The vast majority of the known biological effects of the renin–angiotensin system are mediated by the type-1 (AT ₁ ) receptor, and the functions of the type-2 (AT ₂ ) receptor are largely unknown. We investigated the role of the AT ₂ receptor in the vascular and renal responses to physiological increases in angiotensin II (ANG II) in mice with targeted deletion of the AT ₂ receptor gene. Mice lacking the AT ₂ receptor (AT ₂ -null mice) had slightly elevated systolic blood pressure (SBP) compared with that of wild-type (WT) control mice ( P < 0.0001). In AT ₂ -null mice, infusion of ANG II (4 pmol/kg/min) for 7 days produced a marked and sustained increase in SBP [from 116 ± 0.5 to 208 ± 1 mmHg ( P < 0.0001) (1 mmHg = 133 Pa)] and reduction in urinary sodium excretion (U _Na V) [from 0.6 ± 0.01 to 0.05 ± 0.002 mM/day ( P < 0.0001)] whereas neither SBP nor U _Na V changed in WT mice. AT ₂ -null mice had low basal levels of renal interstitial fluid bradykinin (BK), and cyclic guanosine 3′,5′-monophosphate, an index of nitric oxide production, compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion increased renal interstitial fluid BK, and cyclic guanosine 3′,5′-monophosphate by ≈4-fold ( P < 0.0001) whereas no changes were observed in AT ₂ -null mice. These results demonstrate that the AT ₂ receptor is necessary for normal physiological responses of BK and nitric oxide to ANG II. Absence of the AT ₂ receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension. These results strongly suggest that the AT ₂ receptor plays a counterregulatory protective role mediated via BK and nitric oxide against the antinatriuretic and pressor actions of ANG II.

Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.