Influence of the M235T Polymorphism of Human Angiotensinogen (AGT) on Plasma AGT and Renin Concentrations after Ethinylestradiol Administration¹

Abstract

The T235 allele of the angiotensinogen (AGT) gene is associated with plasma AGT concentration and pregnancy-induced hypertension. The aim of this study was to compare changes in the circulating renin-angiotensin system after short-term (2 days) and repeated (7 days) administration of 50 g ethinylestradiol (EE) in homozygous normotensive men (TT and MM). After repeated EE administration, renin stimulation was induced by a single oral dose of 40 mg furosemide, followed by 50 mg captopril, 12 h later. The short-term administration of EE did not induce a significant differential genotype-dependent increase in AGT concentration. In the 7-day study, TT subjects had higher peak plasma AGT concentrations than MM subjects. The more pronounced AGT increase in TT subjects resulted in similar plasma renin activity at a lower plasma active renin concentration, with a higher plasma renin activity/active renin ratio. The difference between genotypes in renin secretion resulted in readjustment of angiotensins production. In conclusion, the T235 allele of the AGT gene is associated with greater stimulation of AGT secretion in plasma after EE administration. In the short-term, complete readjustment of the circulating renin-angiotensin system occurs, through a decrease in renin release, which blunts the effects of the increase in AGT concentration. (J Clin Endocrinol Metab 85: [4331][4332][4333][4334][4335][4336][4337] 2000) M ECHANISMS RESPONSIBLE for estrogen-induced hypertension have been discussed for many years (1, 2). One of the major biological effects of the synthetic estrogens contained in oral contraceptive pills is a marked and dose-dependent increase in renin substrate concentration in plasma (3) caused by an increase in its hepatic synthesis (4). Plasma angiotensinogen (AGT) concentration is at about the Km of its reaction with renin; therefore, changes in AGT concentration may affect the in vitro and in vivo generation of angiotensin (Ang) I (5, 6). Estrogen-induced increases in plasma AGT concentration are thought to be a susceptibility factor for the increase in blood pressure observed in patients using oral estrogen-containing contraceptives (7). However, physiologically, changes in plasma AGT concentration are usually accompanied by inversely proportional changes in renin secretion, because the increase in plasma Ang II concentration after an increase in plasma AGT concentration, regulates renin release via a short-term negative feed-back loop (2,8). This readjustment of renin release and secretion limits the direct effects of plasma AGT concentration changes on blood pressure, provided that the negative feedback mechanism controlling renin secretion operates normally. It has been suggested that, in women who become hypertensive while using oral contraceptives, the increase in circulating Ang II concentration resulting from higher AGT concentrations does not exert the expected inhibitory effect on renin release and secretion (9).The discovery that the human AGT gene is involved in essential hypertensio...