Role of cyclooxygenase (COX) in modulating vascular smooth muscle cell (VSMC) proliferation

16A

ORALS: COX Inhibitors and Cardiorenal Function: Implications for the Management of Hypertension

OR-34 ROLE OF CYCLOOXYGENASE (COX) IN MODULATING VASCULAR SMOOTH MUSCLE CELL (VSMC) PROLIFERATION Asifa Haider, Nicholas R. Ferreri. Pharmacology, New York Medical College, Valhalla, NY, United States. The aim of this study was to investigate the role of COX in modulating vsmc proliferation. Serum and tumor necrosis factor-␣ (TNF) are known to increase COX expression and activity in vsmc. TNF [1nM]-mediated, COX-2-dependent, PGI2 and TXA2 production increased approximately 4.5-fold and 2-fold, respectively. Addition of serum (0-5%) increased vsmc proliferation in a dose-dependent manner; addition of 5% serum for 48hr increased cell number by 3-fold. TNF potentiated the response to 5% serum by ⬃34%, an effect that also was confirmed by evaluating the changes in S and G2/M phases of the cell cycle using laser scanning cytometry. Exposure of vsmc to 5% serum for 20hr increased the percentage of cells in S and G2/M phases by 55%; TNF increased this response by an additional 50%. Treatment with NS-398 [1␮M], a selective COX-2 inhibitor, prevented progression of the cell cycle induced by 5% serum and TNF⫹5% serum. The role of COX-2 was further investigated by increasing its expression and activity using NO-donors. Papanonoate (PN; 500␮M), an NO donor, unlike TNF, preferentially increased PGI2 but not TXA2 synthesis (control: 86⫾ 17, PN: 428⫾ 54 pg 6-ketoPGF1␣/␮g protein; p⬍0.01, n⫽3). Sodium nitroprusside (SNP; 50␮M), another NO-donor, increased PGI2 synthesis, which was blocked by NS-398 (1␮M)(control: 16.69⫾1.08; SNP 50 ␮M: 53.81⫾8.90, SNP⫾NS-398: 18.75⫾4.17 pg/␮g protein; p⬍0.01, n⫽3). SNP as well as Detanonoate (DN; 1mM) increased COX-2 protein expression, without affecting COX-1 protein expression. However, treatment with these NO-donors decreased cell number, an effect prevented by NS-398. The data indicate that NO donors preferentially stimulate PGI2 production by vsmc. TNF, on the other hand, stimulates both PGI2 and TXA2 synthesis. Thus, increased COX-2 activity can lead to an increased proliferative response of vsmc in the presence of co-mitogens; whereas in the absence of a mitogen, NO inhibits vsmc proliferation in a COX-2-dependent manner. Key Words: Cyclooxygenase, Nitric Oxide, Vascular Smooth Muscle Cell Proliferation

OR-35 CHRONOPHARMACOLOGY OF ASPIRIN: ADMINISTRATION-TIME DEPENDENT EFFECTS ON BLOOD PRESSURE IN WOMEN AT HIGH RISK FOR PREECLAMPSIA Ramon C. Hermida, Diana E. Ayala, Manuel Iglesias. Bioengineering & Chronobiology Labs., University of Vigo, Vigo, Spain; Obstetrics & Gynecology Dept., Hospital Clinico Universitario, Santiago, Spain. This study extends previous results on the effects of low-dose aspirin (ASA) on blood pressure (BP) in pregnant women who were at a higher risk of developing preeclampsia than the general obstetric population and who received ASA at different times of the day according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 341 pregnant women (181 primipara) randomly assigned to 1 of 6 possible groups according to treatment (either placebo or ASA, 100 mg/day, starting at 12-16 weeks of gestation) and the time of treatment: on awakening (Time-1), 8 hours after awakening (Time-2), or before bedtime (Time-3). BP for each woman was automatically monitored for 48 consecutive hours every 4 weeks from the day of recruitment until delivery, as well as at puerperium. The women under investigation provided a total of 2511 BP profiles. Effects of medication and time of ingestion upon BP were evaluated by ANOVA. There was no effect of ASA on BP at Time-1 (compared with placebo). A BP reduction was,

0895-7061/02/$22.00

AJH–April 2002–VOL. 15, NO. 4, PART 2

however, highly statistically significant when ASA was given at Time-2 and, to a greater extent, at Time-3 (mean reductions of 12.6/8.5 mm Hg in 24-hour mean for systolic/diastolic BP at the time of delivery as compared to placebo given at bedtime). Differences in BP among women receiving ASA at different circadian times disappeared at puerperium (P⬎0.096). There was no effect of ASA or placebo on heart rate at any time of administration. Results indicate a highly significant effect of ASA on BP that is markedly dependent on the time of ASA administration with respect to the rest-activity cycle. Timed use of ASA at low dose effectively contributes to BP control in women at high risk for preeclampsia and could thus eventually reduce the incidence of hypertensive complications in pregnancy, as previously documented [Hermida et al. Hypertension. 1999;34:1016-1023]. SUPPORT: DGES, PM98-0106; PGICT00-PXI-32205PN; Univ. Vigo. Key Words: Aspirin, Ambulatory Blood Pressure Monitoring, Preeclampsia

OR-36 RENOVASCULAR SAFETY PROFILE OF ETORICOXIB Sean P. Curtis, Ned Braunstein, Rhoda Sperling, Jennifer Ng, Sumiko Shingo, Gina Bergman. Clinical Research, Merck Research Laboratories, Rahway, NJ, United States. Background: Rofecoxib and celecoxib, the first selective COX-2 inhibitors introduced into the marketplace, have recognized mechanism-based renovascular effects similar to those associated with the non-selective NSAIDs which are dual COX-1 and COX-2 inhibitors. Specifically, edema, blood pressure elevation, attenuation of the effects of anti-hypertensive agents, and acute renal failure were manifest in a small percentage of patients. Objective: To assess the renovascular safety of etoricoxib, a new highly selective COX-2 inhibitor. Methods: The etoricoxib development program contains information on 3348 patients participating in 8 phase III studies in osteoarthritis, rheumatoid arthritis, chronic low back pain, and surveillance endoscopy. Grouped together, the patients in these studies represent 1491 placebo, 658 etoricoxib 60 mg/day, 889 etoricoxib 90 mg/day, 472 etoricoxib 120 mg/day, 1034 naproxen 1000mg/day, 226 ibuprofen 2400 mg/day treated patients. As part of the program-wide safety survey, lower extremity edema adverse experiences (AEs) and hypertension AEs, as well as discontinuations due to these AEs were analyzed. Results: The overall incidence of lower extremity edema occurred in 28 (1.9%), 21 (3.2%), 13 (1.5%), 6 (1.3%), 24 (2.3%), and 4 (1.8%) of patients in the placebo, 60, 90, 120-mg etoricoxib, naproxen, and ibuprofen groups, respectively. Discontinuations due to lower extremity edema were infrequent in all active treatment groups; in 3 (0.3%), 2 (0.3%), 1 (0.1%), 0 (0.0%), 0 (0.0%), and 1 (0.4%) of patients in the placebo, 60, 90, 120-mg etoricoxib, naproxen, and ibuprofen groups, respectively. Hypertension occurred in 30 (2.0%), 26 (4.0%), 30 (3.4%), 22 (4.7%), 30 (2.9%), and 15 (6.6%) of patients in the placebo, 60, 90, 120-mg etoricoxib, naproxen, and ibuprofen groups, respectively. Few patients discontinued due to hypertension: 0(0.0%), 1(0.2%), 2(0.2%), 2(0.4%), 1(0.1%), and 0 (0.0%) of patients in the placebo, 60, 90, 120-mg etoricoxib, naproxen, and ibuprofen groups, respectively. There were no incidences of acute renal failure in any treatment group. Conclusions: Based on this combined data review, the risk of lower extremity edema and hypertension AEs with etoricoxib was low and generally similar to comparator NSAIDs. There was no compelling evidence of dose-related trends for these AEs with the various etoricoxib doses studied. Key Words: Cyclooxygenase-2 Inhibitors, Etoricoxib, Renovascular Safety

© 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.