Submitted on November 30, 2007
Accepted on April 1, 2008
The Renal Hemodynamic Effect of Cyclooxygenase 2 Inhibition in Young Men and Women with Uncomplicated Type 1 Diabetes Mellitus
David Z.I. Cherney1, James William Scholey2, Rania Nasrallah3, Maria G. Dekker4, Cameron Slorach5, Timothy J. Bradley5, Richard L. Hebert6, Etienne B. Sochett4, and Judith A. Miller7*
1 Medicine, University Health Network, Toronto, Canada
2 Medicine, University Health Network, Toronto, Canada; Toronto General Division, Toronto, Canada
3 CMM, Kidney Research Centre, University of Ottawa, Ottawa, Canada
4 Pediatric Endocrinology, Hospital for Sick Children, Toronto, Canada
5 Pediatric Cardiology, Hospital for Sick Children, Toronto, Canada
6 Department of Cellular and Molecular Medicine, Kidney Research Centre, University of Ottawa, Ontario, Canada
7 Medicine, Toronto General Hospital, Toronto, Canada
* To whom correspondence should be addressed. E-mail: judith.miller{at}utoronto.ca.
In experimental studies, cyclooxygenase 2 (COX2)-derived vasodilatory prostaglandins play a more prominent role in arterial vasoregulation in females. The gender-dependent effect of COX2 modulation in humans with type 1 DM is unknown. Accordingly, we examined the renal hemodynamic role of prostaglandins by assessing the response to COX2 inhibition in young men and women with type 1 DM. We also used a graded angiotensin II infusion to determine whether gender-based differences were mediated by effects of COX2 inhibition on the renin angiotensin system (RAS). We hypothesized that COX2 inhibition would be associated with preferential vasoconstriction in women, and would augment their response to angiotensin II.
Baseline renal function and the response to an angiotensin II infusion were assessed during clamped euglycemia, and again after COX2 inhibition (celecoxib 200 mg daily for 14 days) in 12 men and 9 women, after 1 week on a controlled protein and sodium diet. COX2 inhibition was associated with increases in filtration fraction (p=0.045) and renal vascular resistance and a decline in renal blood flow (p=0.04) in women compared to men. Before COX2 inhibition, women exhibited a decline in GFR in response to angiotensin II. COX2 inhibition abolished this effect, while the response was not altered in men.
In summary, COX2 inhibition was associated with hemodynamic effects that differed based on gender. The angiotensin II response suggests that in uncomplicated type 1 DM, prostaglandins may contribute to RAS-mediated gender differences that we have observed previously. Our results are consistent with data suggesting augmented female prostanoid dependence.
