The lipoxygenase–cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit Serenella Rotondo a , Giuseppe Dell'Elba a , Stefano Manarini a , Chiara Cerletti b , Virgilio Evangelista a, ⁎ a Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030, Santa Maria Imbaro (CH), Italy b Centre for High Technology Research and Education in Biomedical Sciences, Catholic University, 86100, Campobasso, Italy Received 17 March 2006; received in revised form 19 June 2006; accepted 22 June 2006 Available online 28 June 2006 Abstract Licofelone is an analogue of arachidonic acid that inhibits 5-lipoxygenase (LOX), cyclooxygenase (COX)-1 and COX-2. We investigated the effects of licofelone on cardiovascular derangements and production of thromboxane (Tx)A 2 induced by the inflammatory agonist n-formyl-methionyl-leucyl-phenylalanine (fMLP) in the rabbit, in comparison with those of aspirin or rofecoxib, inhibitors of COX-1 and COX-2, respectively. In control rabbits, injection of fMLP (30 nmol/kg) in the jugular vein evokes ischemic electrocardiographic (ECG) changes in the first 1– 5 min, i.e. a profound depression of the ST segment and inversion of the T wave. Simultaneously, fMLP induces bradycardia and hypotension and increases TxB 2 blood levels. All changes are transient. Licofelone (60 mg/kg/5 days, p.os) prevented fMLP-induced ECG ischemic changes in all treated animals, reverted bradycardia and hypotension, and significantly reduced TxB 2 . Aspirin (10 mg/kg/5 days, p.os) prevented ischemic ECG alterations in 2 out of 5 treated animals and did not modify either bradycardia or hypotension. One rabbit died two min after fMLP. In 2 rabbits, aspirin reduced TxB 2 levels by more than 80% respect to mean control values; the remaining two rabbits produced an amount of TxB 2 similar to controls. These two rabbits also showed ischemic ECG changes. Rofecoxib (10 mg/kg/5 days, p.os) did not prevent fMLP-induced ischemic ECG alteration, bradycardia and hypotension, and did not significantly modify the increase of TxB 2 . These results indicate that the capacity of licofelone to efficiently suppress TxA 2 production, is responsible for the protection from the cardiovascular derangement triggered by an inflammatory stimulus. © 2006 Elsevier B.V. All rights reserved. Keywords: Cardiovascular ischemia; COX-1/COX-2-dependent TxA 2 ; Licofelone; Leukocyte activation 1. Introduction Licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2, 3,dihydro-1H-pyrrolizine-5-yl]-acetic acid, previously named ML3000) is a substrate analogue of arachidonic acid and therefore inhibits 5-LOX, COX-1 and COX-2, decreasing eicosanoid production (Tries et al., 2002). It has been spe- cifically developed to overcome the gastrointestinal (GI) side-effects associated to non-steroidal anti-inflammatory drugs (NSAIDs) therapy (Laufer, 2001). In experimental models, licofelone has been shown to have good GI and general tolerability profile, along with analgesic and anti-inflammatory properties (Laufer et al., 1994a,b, 1995). The GI safety advantage of licofelone over conventional NS AIDs has been recently confirmed in healthy individuals (Bias et al., 2004). Licofelone has been also demonstrated to modulate poly- morphonuclear leukocyte/platelet interaction (Rotondo et al., 2002) and to inhibit platelet activation in vitro (Rotondo et al., 2004). Antithrombotic therapy with aspirin, which at low doses acts as a selective inhibitor of platelet COX-1 activity, is well established (Patrono et al., 2001). However, the beneficial anti- European Journal of Pharmacology 546 (2006) 95 – 101 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +39 0872 570 291; fax: +39 0872 570 299. E-mail address: evangelista@negrisud.it (V. Evangelista). 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2006.06.052