Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension.
BACKGROUND
Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K(+), a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K(+)) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans.


METHODS
Nineteen healthy normotensive young men (n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA.


RESULTS
African Americans had diminished urinary excretion of not only kallikrein (P =.007), but also K(+) (P <.001) and aldosterone (P =.015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K(+); P =.019) or directly (by the exogenous mineralocorticoid fludrocortisone; P =.027), despite achievement of substantial increments in K(+) excretion after KCl (P =.002), and multiple other mineralocorticoid effects after fludrocortisone (P =.005). The kallikrein increment after KCl was best predicted by renin activity (P =.001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group (P >.4).


CONCLUSIONS
Restoration of K(+) and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.
Wong
Caroline M
CM
Department of Medicine and Center for Molecular Genetics, University of California, San Diego 92161, USA.
O'Connor
Daniel T
DT
Martinez
Joseph A
JA
Kailasam
Mala T
MT
Parmer
Robert J
RJ
D000328:Adult; D001741:Black or African American; D000704:Analysis of Variance; D005438:Fludrocortisone / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007610:Kallikreins / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism* / Q000494:pharmacology; D015999:Multivariate Analysis; D010641:Phenotype; D011189:Potassium Chloride / Q000494:pharmacology
D008901:Mineralocorticoids; D011189:Potassium Chloride; D007610:Kallikreins; D005438:Fludrocortisone