The effect of oral contraceptives on the nitric oxide system and renal function.
We have demonstrated that oral contraceptive (OC) users exhibit elevated angiotensin II levels and angiotensin II type 1 receptor expression, indicative of renin-angiotensin system (RAS) activation, yet the renal and systemic consequences are minimal, suggesting that there is increased vasodilatory activity, counteracting the effect of RAS activation. We hypothesized that the nitric oxide (NO) system would be upregulated in OC users and that this would be reflected by a blunted hemodynamic response to l-arginine infusion. All subjects were studied after a 7-day controlled sodium and protein diet. Inulin and para-aminohippurate clearance techniques were used to assess renal function. l-Arginine was infused at 100, 250, and 500 mg/kg, each over 30 min. Skin endothelial NO synthase mRNA expression was assessed by real-time PCR. While OC nonusers exhibited significant increases in effective renal plasma flow (670.8 +/- 35.6 to 816.2 +/- 59.7 ml.min(-1).1.73 m(-2)) and glomerular filtration rate (133.4 +/- 4.3 to 151.0 +/- 5.7 ml.min(-1).1.73 m(-2), P = 0.04) and declines in renal vascular resistance (81.1 +/- 6.1 to 63.5 +/- 6.2 mmHg.ml(-1).min, P = 0.001) at the lower l-arginine infusion rates, the responses in OC users were blunted. While l-arginine reduced mean arterial pressure at the 250 and 500 mg/kg doses in OC nonusers, OC users only exhibited a decrease in mean arterial pressure at the highest infusion rate. In contrast, tissue endothelial NO synthase mRNA levels were higher in the OC users (P = 0.04). In summary, these findings suggest that the NO system is upregulated by OC use in young, healthy women. Increased activity of the NO pathway may modulate the hemodynamic effects of RAS activation in OC users.
Cherney
D Z I
DZ
Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto.
Scholey
J W
JW
Cattran
D C
DC
Kang
A K
AK
Zimpelmann
J
J
Kennedy
C
C
Lai
V
V
Burns
K D
KD
Miller
J A
JA
D000328:Adult; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003276:Contraceptives, Oral / Q000494:pharmacology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007444:Inulin / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D003276:Contraceptives, Oral; D012333:RNA, Messenger; D009569:Nitric Oxide; D007444:Inulin; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D010130:p-Aminohippuric Acid