Nonselective nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized that COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into 3 groups: no drug (control, n = 7), a nonselective COX inhibitor (naproxen 400 mg daily, NAP, n = 7), or a selective COX-2 inhibitor (celecoxib 200 mg daily, CBX, n = 7). After 7 weeks, physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate-pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased vascular endothelial growth factor and phosphorylated endothelial nitric oxide synthase expression in the NAP and CBX groups. Myocardial tumor necrosis factor-α was increased in both treated groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Nonselective and selective COX inhibition does not alter myocardial perfusion but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk.
From the *Department of Surgery, Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI; †Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and ‡Department of Surgery, Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, RI.
Received for publication August 26, 2010; accepted october 8, 2010.
Funding for this project was provided to F. W. Sellke by National Heart, Lung, and Blood Institute (RO1HL46716, RO1HL69024, and RO1HL85647), National Institutes of Health 5T32-HL0074 (M.P.R.), and the Irving Bard Memorial Fellowship (M.P.R. and L.M.C.).
Dr. F. W. Sellke has research support from Ikaria (Clinton, NJ) and Orthologic (Tempe, AZ) and is a consultant for Novo Nordisk (Princeton, NJ), CSL Behring, and Cubist Pharmaceutical (Lexington, MA). Dr. F. W. Sellke was a consultant for the law firms representing Pfizer (Princeton, NJ) in the Bextra and Celebrex litigation, but no funding was received for this study, and there was no consultation or notification regarding this study.
The author report no conflicts of interest.
Reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, 593 Eddy St, APC 424 Providence, RI 02903 (e-mail: firstname.lastname@example.org).