The lipoxygenase-cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit.
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.
Rotondo
Serenella
S
Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030, Santa Maria Imbaro, CH, Italy.
Dell'Elba
Giuseppe
G
Manarini
Stefano
S
Cerletti
Chiara
C
Evangelista
Virgilio
V
D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007783:Lactones / Q000494:pharmacology; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D013450:Sulfones / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism*; D013997:Time Factors
D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D013450:Sulfones; C116926:rofecoxib; D007975:Leukotriene B4; D013928:Thromboxane A2; D009240:N-Formylmethionine Leucyl-Phenylalanine; C088092:licofelone; D001241:Aspirin