INVOLVEMENT OF CYCLOOXYGENASE 2 (COX-2) IN INTRINSIC TONE OF ISOLATEDGUINEA-PIG TRACHEA

Indomethacin and related nonsteroidal anti-inflammatory drugs relax pr ostanoid-dependent intrinsic tone of isolated guinea pig trachea by in hibiting cyclooxygenase (COX). Recently, a second isoform of COX (COX- 2) was discovered, which differed from COX-1 with respect to protein s tructure, transcriptional regulation, and susceptibility to inhibition by pharmacological agents. It is now known that indomethacin nonselec tively inhibits COX-1 and COX-2, whereas NS-398 is a selective inhibit or of COX-2. In the present study we compared the activity of a select ive (NS-398) and nonselective (indomethacin) COX-2 inhibitor on intrin sic tone of isolated guinea pig trachea. NS-398 greater than or equal to indomethacin produced a reversal of intrinsic tone with a similar c oncentration-dependent (10 nM to 1 mu M) time course (T-max approximat ely 20-45 min), potency (EC(50) 1.7 and 5.6 nM, respectively), and max imal response. Contractions to cholinergic nerve stimulation (45 V, 0. 5 ms, 0.1-32 Hz) and histamine were similarly modulated in tissues rel axed with the selective or nonselective COX-2 inhibitors. Immunoblot a nalyses showed that COX-2 protein synthesis was induced in both the ca rtilage and smooth muscle portions of the trachea during changes in in trinsic tone. These findings are consistent with pharmacological resul ts and provide the first demonstration that prostanoid tone in isolate d guinea pig trachea is dependent on COX-2 activity. The results also suggest that the activity of indomethacin in this preparation is likel y related to COX-2 inhibition.