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(Circulation. 2005;112:1024-1029.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Contribution of Cyclooxygenase-2 to Elevated Biosynthesis of Thromboxane A₂ and Prostacyclin in Cigarette Smokers

Brendan F. McAdam, MD, MRCPI; Daniel Byrne, MSc; Jason D. Morrow, MD; John A. Oates, MD

From the Department of Medicine, Divisions of Cardiovascular Medicine (B.F.M.) and Clinical Pharmacology (J.D.M., J.A.O.), General Research Center (D.B.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Brendan F. McAdam, MD, MRCPI, Department of Medicine, Vanderbilt University Medical Center, Nashville TN 37232-8802. E-mail brendan.mcadam{at}vanderbilt.edu

Received February 14, 2005; revision received May 9, 2005; accepted May 31, 2005.

Background— Cigarette smoking is highly pathogenic to the vasculature. In smokers, the biosynthesis of both thromboxane (Tx) A₂ and prostacyclin is increased. We hypothesized that the excess in prostacyclin biosynthesis in smokers was derived from the inducible cyclooxygenase-2 (COX-2). We further hypothesized that if the overproduction of prostacyclin in smokers were restraining platelet activation, then inhibition of COX-2 would lead to an increase in the activation of platelets, with a corresponding increase in the biosynthesis of TxA₂.

Methods and Results— Smokers and nonsmokers received rofecoxib 25 mg twice daily or placebo for 1 week each in random sequence. The systemic biosynthesis of TxA₂ and prostacyclin was assessed by analysis of their respective urinary metabolites, 11-dehydrothromboxane B₂ (Tx-M) and 2'3-donor–6-keto-PGF₁ (PGI-M). Serum TxB₂ was measured as an indicator of platelet COX-1 activity. Results are expressed as mean±SE with median and range. The elevated PGI-M in smokers (189±25, median 174, range 85 to 390 pg/mg creatinine) was reduced by rofecoxib to 78±27, median 71.5, range 50 to 135 pg/mg creatinine (P=0.002), and in nonsmokers, PGI-M at baseline (115±10, median 107, range 67 to 198 pg/mg creatinine) fell to 56±15, median 50, range 34 to 125 pg/mg creatinine (P=0.001) with rofecoxib. The increased excretion of Tx-M in smokers (284±26, median 252, range 200 to 569 pg/mg creatinine) was reduced by 21% to 223±16, median 206, range 154 to 383 pg/mg creatinine by rofecoxib (P=0.04) but was not changed in nonsmokers. Levels of serum TxB₂ were not different in smokers and nonsmokers and were unaffected by rofecoxib.

Conclusions— The increased prostacyclin biosynthesis in smokers is derived largely from the inducible COX-2. COX-2 also contributes to the increased biosynthesis of TxA₂ in smokers, most likely from inflammatory cells.

Key Words: thromboxane • inflammation • smoking • drugs • platelets

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