A Not-So-Modest Proposal That a “Modest” Increase in Aldosterone Causes Hypertension and More
Whether primary aldosteronism is as widespread as some believe, a topic debated recently in this journal by Calhoun1 and Kaplan,2 may not be as relevant as whether the commonly observed prevailing level of aldosterone is too high for the amount of sodium that we consume. I would like to make the case here (with help from a Nobel Laureate) that the usual level of aldosterone contributes to the development of hypertension in many people, indeed, possibly many more than even the most generous estimate for the prevalence of primary aldosteronism.
Not long after the angiotensinogen gene/hypertension association was described in 1992,3 Oliver Smithies’ laboratory showed in a transgenic mouse that levels of angiotensinogen and blood pressure were proportional to the number of copies of the angiotensinogen gene.4 It provided proof of principal that blood pressure was under the influence of the endogenous load of angiotensinogen. In the present issue of Hypertension,5 this same laboratory now provides similar complimentary proof to the earlier report by Vasan et al6 that higher but normal levels of aldosterone are predictive of a future elevation in blood pressure. They did this by manipulating the gene for aldosterone synthase (AS; CYP11B2), an essential enzyme for synthesis of aldosterone, by making the 3′ untranslated region of its mRNA more stable, thereby increasing its expression; the generated mice are referred to as AShi/hi mice.
The causes of common forms of hypertension or essential hypertension are mostly unknown. Although the Guytonian principle that an increase in the kidney’s retention of sodium underlies a sustained increase in blood pressure is well accepted, the specific sodium transport systems involved have been difficult to delineate. The article from Smithies’ laboratory,5 however, would seem to place some of the burden on the distal nephron.
Aldosterone defends against sodium loss. A fully responsive renin-angiotensin-aldosterone system was essential for survival when the environment was nearly devoid of salt. In today’s world, the question becomes whether the renin-angiotensin-aldosterone system decreases sufficiently under conditions where comparatively speaking extraordinary amounts of sodium are consumed. In the AShi/hi, aldosterone levels were similar to those in the wild-type mouse under conditions of normal-salt intake and similarly suppressed with high-salt intake. However, when confronted with the high-salt intake, aldosterone secretion in the AShi/hi did not seem to suppress quite enough, and blood pressure increased. The differences between the AShi/hi and the wild-type mice were small, but under the right conditions, the high-salt challenge, the slightly more than appropriate level of aldosterone in the AShi/hi led to increased sodium reabsorption in the distal nephron. This, then, could be considered a specific renal mechanism for the development of hypertension.
The greater aldosterone secretion in the AShi/hi was obviously not secondary to any increment in angiotensin II. In human hypertension, secretion rates of aldosterone may not always parallel the renin-angiotensin system. When African Americans with hypertension were compared with a white French-Canadian population with hypertension, the African Americans had lower levels of plasma renin activity, but the aldosterone/renin ratio was higher;7 the renin-angiotensin system appeared to have responded to a volume-expanded state, whereas the aldosterone component demonstrated elements of autonomy. One might ask whether the present study supports the evidence that variations in AS contribute to differences in blood pressure. Possibly, but significant genetic association studies with AS have been difficult to confirm.
Not everyone who consumes the modern-day diet becomes hypertensive, at least not right away. The challenge to maintaining a normal blood pressure posed by the high-salt diet can be further aggravated by, and probably as a regular rule frequently does when there is hypertension, increased uptake at one or more nephron sites for the reclamation of sodium. For this to manifest in hypertension, the distal nephron would need to fail to adjust because of an aldosterone level that was too high, thus becoming a “second (or requisite) hit.” Possibly the Smithies’ laboratory could be convinced to add another component to the model, one where there is also an increase in sodium reabsorption more proximally in the nephron.
And it should also be noted, almost as an aside, that when the AShi/hi and the wild-type mice were infused with angiotensin II, the AShi/hi mice produced more aldosterone, which was accompanied by cardiac hypertrophy and fibrosis. Thus, both animal models were exposed to the same dose of angiotensin II, but those with the higher aldosterone levels experienced the greater damage. This, then, further confirms aldosterone’s role to adversely affect sites outside of the distal nephron.8
The authors of the article described the increase in aldosterone as “modest,” and, thus, it would seem reasonable to consider the not-so-modest proposal (in contrast to Jonathan Swift’s 1729 essay, no satire is intended here) that a modest increase in the aldosterone level often participates in the development of hypertension and its complications. This is no doubt an oversimplification, but it is in keeping with evidence that blocking aldosterone’s actions or inhibiting the distal nephron directly substantially improves blood pressure control in many patients with hypertension.9,10 We are grateful once again to Oliver Smithies and coworkers for their enlightenment. And to Dr Smithies, a winner of the 2007 Nobel Prize in Medicine or Physiology, congratulations!
Sources of Funding
Supported in part by NIH grant HL35795 and by the VA Medical Center, Indianapolis, Ind.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Calhoun DA. Is there an unrecognized epidemic of primary aldosteronism? Pro. Hypertension. 2007; 50: 447–453.
Kaplan NM. Is there an unrecognized epidemic of primary aldosteronism? Con. Hypertension. 2007; 50: 454–458.
Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci. 1995; 92: 2735–2739.
Makhanova N, Hagaman J, Kim H-S, Smithies O. Salt-sensitive blood pressure in mice with increased expression of aldosterone synthase. Hypertension. 2008; 51: 134–140.
El Gharbawy AH, Nadig VS, Kotchen JM, Grim CE, Sagar KB, Kaldunski M, Hamet P, Pausova Z, Gaudet D, Gossard F, Kotchen TA. Arterial pressure, left ventricular mass, and aldosterone in essential hypertension. Hypertension. 2001; 37: 845–850.
Saha C, Eckert GJ, Ambrosius WT, Chun TY, Wagner MA, Zhao Q, Pratt JH. Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. Hypertension. 2005; 46: 481–487.