Speaker: Megan Wenner Dissertation Defense
Date: Wed Jan 7th
Time: 2:00 pm
Place: Townsend 132.
Title: The Role of COX-2 Inhibition in Salt Sensitivity of Blood Pressure.
Committee:Dr. William Farquhar (Chair), Dr. David Edwards, Dr. William Rose, Dr. Darcy
Reisman, Dr. Michael Stillabower, and Dr. Timothy Gardner.
Abstract:Salt-sensitivity can occur in both normotensive and hypertensive individuals, and may
be clinically relevant in determining future cardiovascular events. The literature suggests nonselective cyclooxygenase inhibitors may be associated with sodium and water retention along
with an increase in blood pressure; thus the effects of non-selective cyclooxygenase inhibitors
on blood pressure and renal sodium handling have been well established. However, data
regarding the blood pressure response during selective cyclooxygenase-2 (COX-2) inhibition
are conflicting. Recent data in experimental animals suggests that COX-2 inhibition causes
salt sensitivity of blood pressure, yet data are lacking in humans. Therefore, the purpose of this
study was to determine if COX-2 inhibition increases salt sensitivity of blood pressure in
humans. We hypothesized that increases in blood pressure would be greater during selective
COX-2 inhibition compared to placebo after dietary sodium manipulation, indicating a link
between COX-2 inhibition and salt sensitivity. A secondary aim of this study was to determine
the renal and vascular effects of COX-2 inhibition under well-controlled dietary sodium intake.
We hypothesized that COX-2 inhibition would decrease sodium excretion during salt loading
conditions. Twelve human subjects completed two separate 17-day dietary trials (once under
placebo conditions, once under celecoxib conditions; 100mg twice per day). The 17-day
dietary trial consisted of 3-days of a normal salt diet, one week of a high salt diet and one week
of a low salt diet. Data were collected on the last day of each sodium condition. By design,
sodium intake was greater on the high salt diet compared to the low salt diet (HS: 7987 ± 12
mg, LS: 480 ± 12 mg; p < 0.001). Urinary sodium excretion (24-hour) was greater on the high
salt diet (p < 0.001) with no differences between placebo and celecoxib (p=0.26). There were
no differences in 24-hour mean arterial pressure (MAP) between salt (p=0.89) or drug (p=0.85)
conditions. The change in MAP from low to high sodium conditions was used to assess salt
sensitivity of blood pressure. The change in MAP was not different during placebo (0.25 ±1.4
mmHg) compared to celecoxib (-0.58 ± 0.4 mmHg). Therefore, there were no differences in
salt sensitivity between celecoxib and placebo (p=0.3). Urine flow rate and free water
clearance were not different between celecoxib and placebo (p>0.5 for both). Several indices
of vascular stiffness were not different between placebo and celecoxib (augmentation index
p=0.35; pulse wave velocity p=0.49; flow mediated dilation p=0.82; total peripheral resistance
p=0.41), nor was there a main effect of salt (augmentation index p=0.23; pulse wave velocity
p=0.22; flow mediated dilation p=0.49; total peripheral resistance p=0.86). In conclusion,
celecoxib did not induce salt sensitivity of blood pressure in this group of healthy subjects.
There was no effect of celecoxib on renal or vascular function. Additional studies are needed
to determine if chronic use of COX-2 inhibitors (ie, more than 17 days, or at higher doses)
contribute to salt sensitivity, and whether these findings translate to hypertensives.