CYP2C9 genotype modifies activity of the renin–angiotensin–aldosterone system in hypertensive men

Abstract

The CYP2C9*3 allele was associated with lower activity of the renin-angiotensin-aldosterone system in hypertensive men, which may reflect a more efficient sodium reabsorption capacity. CYP2C9*2 and CYP2C9*3 alleles do not influence the antihypertensive effect of losartan in men with essential hypertension and normal kidney function.

Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin–angiotensin–aldosterone system in normotensive men

“…We, therefore, wanted to further test the role of CYP2C9 genotypes on PRA, plasma aldosterone concentrations, and BP responses to a standardized high and low-salt intake in young normotensive individuals. In agreement with the recently reported findings in hypertensive individuals [14], we also observed a reduced PRA in CYP2C9 Ã 3 carriers. This observation was made under both high and low-standardized salt intake.…”

“…In the recently reported study in hypertensive patients, CYP2C9 Ã 2 or CYP2C9 Ã 3 exhibited also no significant effect on baseline BP [14]. In contrast, a lower frequency of CYP2C9 Ã 3 was found in Chinese hypertensive patients compared with healthy controls suggesting a protective effect of this variant [23].…”

“…Very recently, an association of the CYP2C9 Ã 3 allele with lower activity of the RAAS in moderately hypertensive men and in patients with treatment-resistant hypertension was shown [14]. We, therefore, wanted to further test the role of CYP2C9 genotypes on PRA, plasma aldosterone concentrations, and BP responses to a standardized high and low-salt intake in young normotensive individuals.…”

“…For aldosterone levels, the effect of the CYP2C9 Ã 3 allele was only present under low-salt intake. As a functional basis for the observed downregulation of the RAAS, an enhanced sodium reabsorption by activation of ENaC in the kidney owing to CYP2C9 Ã 3-associated reduction in EET synthesis was suggested [14]. CYP2C9 metabolizes arachidonic acid to EETs and has been shown to be a major epoxygenase participating in EET biosynthesis in the human kidney [11].…”

“…CYP2C9 Ã 2 (Arg144Cys) and CYP2C9 Ã 3 (Ile359-Leu) both lead to decreased enzyme function [12,13]. Very recently, CYP2C9 genotype-related differences in plasma renin activity (PRA) and plasma aldosterone levels were observed in hypertensive patients [14]. It was proposed that the reduced activity of the reninangiotensin-aldosterone system (RAAS) in carriers of CYP2C9 Ã 3 might reflect a reduction in EET synthesis leading to increased activity of the renal epithelial sodium channel (ENaC) and sodium reabsorption, and thus salt-sensitive hypertension in these individuals [14].…”