Effects of Oral Contraceptive Use on the Renal and Systemic Vascular Response to Angiotensin II Infusion

Abstract

Abstract.We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT 1 ) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 Ϯ 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT 1 and/or AT 2 receptormediated activation of the nitric oxide pathway, and AT 1 receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT 1 receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT 1 receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT 1 receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.Gender and estrogen status are important determinants of renin angiotensin system (RAS) function and the renal and systemic response to angiotensin II (Ang II) (1-3). This laboratory has previously shown that ethinyl estradiol use in the form of the oral contraceptive (OC) pill results in dramatic increases of circulating RAS components, including Ang II; yet, in normal women, the hemodynamic consequences are modest, consisting of a small increase in BP and filtration fraction (1). Ang II, the primary effector of the RAS, is a multifunctional peptide hormone, the actions of which are primarily mediated by two receptors, Ang II type 1 (AT 1 ) and type 2 (AT 2 ). The majority of the physiological and pathophysiological effects of Ang II occur via the AT 1 receptor. The function of the AT 2 receptor is controversial, but it may act in opposition to AT 1 receptors (4). It has been reported in some (5-8) but not all (1-3) studies that high estrogen decreases circulating renin and Ang II levels, downregulates AT 1 receptor expression in vascular smooth muscle cells, adrenal cortex, and hypothalamus (9 -11), and upregulates renal AT 2 receptor expression (4). It has also been demonstrated that the hemodynamic response to Ang II infusion is blunted in high-estrogen states, such as the luteal phase of the normal menstrual cycle (3), and in normal pregnancy (12)(13)(14). Therefore, we hypothesized that wome...

Gender Differences in the Renal Response to Renin-Angiotensin System Blockade

“…Therefore, estrogen alone may have affected AT 1 receptor expression; however, this is unlikely because at the time of both skin biopsies, women were in the luteal phase, and estrogen levels did not differ. In this set of experiments, the AT 1 receptor expression results correlate well with the physiologic responses, as in a previous study from this laboratory (6). Taken together, these two observations suggest that AT 1 receptor mRNA levels are associated with responsiveness to AngII and AngII blockade.…”

“…Experiments were performed in duplicate or triplicate and repeated at least once. Data are presented as the ratio of human AT 1 receptor mRNA/GAPDH mRNA, in arbitrary units (6).…”

“…In women, the baseline AngII infusion was administered during the luteal (high estrogen) phase of the menstrual cycle. Skin biopsies were obtained from 10 participants in each group on the first study day and on the last study day, under sterile conditions, after subcutaneous installation of local anesthetic with Xylocaine, as described previously (6).…”

Oral Contraceptives, Angiotensin-Dependent Renal Vasoconstriction, and Risk of Diabetic Nephropathy

“…This laboratory reported reduced renal blood flow and a blunted renal hemodynamic response to Ang II in healthy women using highestrogen dose OCs (10). Ingestion of lowestrogen dose OCs also results in RAS activation with respect to the kidney (11,12).…”

IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin–angiotensin system activity

“…[26][27][28][29][30] Shoback et al originally hypothesized that a blunted vascular response to AngII was a reflection of high local tissue AngII concentrations and tissue renin-angiotensinaldosterone system activity. 28 Our findings of a decreased sensitivity to AngII in subjects with IgAN compared with gender and blood pressure-matched controls thus, considering this hypothesis, likely reflects differences in tissue-specific RAS activity.…”