Effect of COX-1/COX-2 inhibition versus selective COX-2 inhibition on coronary vasodilator responses to arachidonic acid and acetylcholine.
The effect of a nonselective COX-1/COX-2 inhibitor, naproxen, was compared with a COX-2-selective inhibitor (SC-58236) on coronary vasodilatory responses in the anesthetized dog. Coronary vasodilation was induced by direct intracoronary injection of acetylcholine (ACH) and arachidonic acid (AA) in control animals and in those treated with either naproxen (1, 3, or 10 mg/kg p.o. 24 h prior to the experiment) or SC-58236 (1, 5, or 15 mg/kg p.o. 24 h prior to the experiment). Naproxen, at 10 mg/kg, significantly attenuated the AA-induced vasodilation (prostacyclin dependent) with no effect on ACH-induced vasodilation (nitric oxide dependent). SC-58236 failed to attenuate either AA- or ACH-induced vasodilation. Ex vivo assays were utilized to establish inhibition of COX-2 (lipopolysaccharide-stimulated prostaglandin E2 formation) and COX-1 (serum thromboxane B2) in blood taken from dogs administered 1, 3, or 10 mg/kg naproxen or 15 mg/kg SC-58236. Naproxen (3 and 10 mg/kg) and SC-58236 (15 mg/kg) markedly reduced the lipopolysaccharide-induced prostaglandin E2 formation, whereas SC- 58236 (15 mg/kg) had no effect on serum thromboxane B2. Naproxen significantly reduced thromboxane B2 at all three doses studied. Furthermore, naproxen (10 mg/kg p.o.) significantly inhibited the AA-induced platelet aggregation (thromboxane B2 dependent), whereas SC-58236 had no effect. Collectively, these results demonstrate that SC-58236 is selective for COX-2, while naproxen is a nonselective inhibitor. These data also suggest that vasodilatory responses to AA in the dog are primarily COX-1 dependent. Selective COX-2 inhibition does not affect either prostacyclin or nitric oxide mediated vasodilation in the canine coronary circulation.
Gross
Garrett J
GJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisc. 53226-3548, USA. ggross@mcw.edu
Moore
Jeannine
J
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009288:Naproxen / Q000008:administration & dosage / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000109:Acetylcholine; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009288:Naproxen; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; D013929:Thromboxane B2; D014665:Vasodilator Agents; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides