Unraveling the Mechanism of Renin-Angiotensin- Aldosterone System Activation and Target Organ Damage in Hypertensive Blacks

Abstract

See related article, pp 62-69T he International Society on Hypertension in Blacks consensus statement in 2010 noted that, in the setting of high dietary sodium intake, hypertensive blacks have particularly impressive responses to renin-angiotensin-aldosterone system (RAAS) blockade. 1 The statement went on to point out that the excessive target-organ damage (TOD) in hypertensive blacks can be attributed to RAAS activation. Although a normal-to-"high-renin" hypertensive state is most prevalent, the classic hypertension literature has categorized blacks as typically having a "low-renin" state. 2 There is somewhat of a paradox in the observation that blacks, despite having a low-renin state, have high serum aldosterone concentrations. 3 Blacks experience disproportionately higher rates of hypertension-related TOD compared with whites. 4 The mediators of the higher rates of TOD noted in blacks are most likely directly attributed to high levels of downstream mediators of the RAAS, such as aldosterone and angiotensin II. The mechanism by which a low-renin state can be associated with such an apparently active RAAS is not clearly defined.The article by Michel et al, 5 in this issue of Hypertension, addresses the mechanism by which RAAS activation affects blood pressure (BP) regulation in a population of African ancestry. Specifically, the authors evaluated plasma renin, plasma angiotensinogen (AGT), and serum aldosterone concentrations in 579 South African blacks. They demonstrated an inverse relationship between plasma renin concentrations and BP (PϽ0.001) on one hand, as well as plasma renin concentrations and dietary sodium intake (24-hour urinary Na ϩ /K ϩ , PϽ0.0001) on the other hand. Despite this inverse relationship, there was a direct and independent association between AGT concentrations and systolic BP (PϽ0.005) in a subset of participants with urinary Na ϩ /K ϩ at or more than the sample median (proxy for high sodium intake). Furthermore, in this same subset, there was an independent and direct relationship between AGT and serum aldosterone concentrations (PϽ0.0001). This observation was strengthened by the incremental increase in the multivariate-adjusted relationship between AGT and both serum aldosterone concentrations and systolic BP across tertiles of urinary Na ϩ /K ϩ . These impressive relationships were not observed in the subset of participants with urinary Na ϩ /K ϩ less than the sample median.The primary function of circulating AGT is to act as a substrate for renin, resulting in the biologically active peptides angiotensin I and angiotensin II. It is important to appreciate that the Michaelis-Menten constant for the renin-AGT reaction approximates the concentration of circulating AGT. 6 Therefore, AGT concentrations, as opposed to renin concentrations, may be the rate-limiting factor in the generation of angiotensin I. Angiotensin II subsequently stimulates aldosterone secretion downstream in the RAAS cascade. Although the relationship between AGT and BP has been established for several decades,...

Animal models for the study of primary and secondary hypertension in humans

“…Renin is suppressed and fluid reabsorption is increased, thereby producing a low renin-volume overload model of hypertension (43). Using this model, key sodium-independent mechanisms for mediating hypertension, including upregulation of Ang-II receptors in the central nervous system (44), elevated vasopressin (45), increased oxidative stress (46) and endothelin (47), have been identified.…”

A favorable cardiometabolic profile is associated with the G allele of the genetic variant rs5068 in African Americans: The Multi-Ethnic Study of Atherosclerosis (MESA)

“…One possible explanation could be related to the relative deficiency of the nitric oxide system and exaggerated activation of the renin-angiotensin-aldosterone system that characterize African Americans. [ 33 – 35 ] Among this ethnicity, slightly higher values of NP like the ones observed in the carriers of the rs5068 minor allele may impact metabolism and confer a favorable metabolic risk profile but they might not be sufficient to counteract deficient nitric oxide or inappropriately augmented aldosterone actions for which a stronger activation of the NP system might be required. Conversely, another possible explanation for the lack of association could be related to the selection criteria of MESA which excluded any subject with clinically apparent cardiovascular disease at baseline.…”