MDR1 genotype-dependent regulation of the aldosterone system in humans

Aldosterone plays a major role in the development of both hypertension and heart failure. As aldosterone is a substrate of the ABCB1 (P-glycoprotein) efflux transporter, whose expression and activity has been shown to be linked to the ABCB1 3435C-->T polymorphism, we tested the impact of the ABCB1 3435C-->T polymorphism on aldosterone disposition, blood pressure, cardiac structure, and kidney function.

A homogenous group of 116 young, white male Caucasian individuals with normal or mildlyto moderately elevated, but never treated blood pressure was included. Blood pressure was compared between individuals with ABCB1 3435 CC, CT, and TT genotypes. Moreover, genotype-dependent differences in basal and angiotensin II-stimulated serum aldosterone, cardiac structure, and kidney function were evaluated.

Of the 116 volunteers, 35 had the CC, 51 the CT and 30 the TT genotype. At baseline, no significant genotype-dependent differences in serum aldosterone were observed. After infusion of angiotensin II, the increase in aldosterone serum concentration was significantly higher in the TT group than that in the CT and CC groups (CC +11+/-35, CT +18+/-48, TT +45+/-50 pg/ml, P=0.012). Systolic and diastolic blood pressure, left ventricular structure, and function and baseline renal function were not significantly different. After additional oral sodium load (5 g/day over 1 week) urinary sodium excretion was found to be increased in individuals with the CC or CT genotype only but not in those with the TT genotype (CC +71+/-83, CT +52+/-114, TT -11+/-98 mmol/day, P=0.005).

The present study demonstrates that the ABCB1 3435 genotype affects angiotensin II-stimulated serum aldosterone levels and salt-stimulated urinary sodium excretion. Although blood pressure and cardiac structure were unchanged in this young study population, our findings indicate a new link between MDR1 genotype and the aldosterone system in humans.