Non-modulation as an intermediate phenotype in essential hypertension

Gordon H. Williams, Robert G. Dluhy, Richard P. Lifton, Thomas J. Moore, Ray Gleason, Roger Williams, Steven Hunt, Paul N. Hopkins, Norman K. Hollenberg

Research output: Contribution to journalArticle

89 Citations (Scopus)


Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng·kg-1·min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p<0.000023) and Ang II infusion (p<0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing. Thus, this analysis supports the hypothesis that non-modulators are a discrete subset of the essential hypertensive population, suggesting that this trait may be useful as an intermediate phenotype in human hypertension.

Original languageEnglish
Pages (from-to)788-796
Number of pages9
Issue number6
Publication statusPublished - Dec 1992
Externally publishedYes



  • Aldosterone
  • Angiotensin II
  • Genetics
  • Hypertension, non-modulating
  • Renal circulation

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Williams, G. H., Dluhy, R. G., Lifton, R. P., Moore, T. J., Gleason, R., Williams, R., Hunt, S., Hopkins, P. N., & Hollenberg, N. K. (1992). Non-modulation as an intermediate phenotype in essential hypertension. Hypertension, 20(6), 788-796.