Contribution of COX-1 products to contractions of the mouse aorta and bronchus.

Cyclooxygenase (COX) mediates the production of prostaglandin (PG)H2, the precursor to down-stream prostanoids, from arachidonic acid. COX exists in two isoforms; constitutively expressed COX-1, and inducible COX-2. In the mouse bronchus, COX-1 derived dilator prostanoids predominate whereas in mouse aorta, COX-1 derived constrictor prostanoids predominate (C023, this meeting). Here we have investigated the effect of NSAIDs and COX-2 selective drugs on contraction of vessels (aorta) and airway (bronchi) of the mouse.
Male COX-1-/- mice or C57Bl6 wild type mice (25-30g) were killed by cervical dislocation, and rings of aorta and bronchus were mounted in isometric wire myographs. Tissues were incubated with: COX-2 selective drugs, 10-5M lumiracoxib, 10-5M parecoxib, and NSAIDs, 10-4M naproxen, 10-5M ibuprofen, or 5l DMSO (vehicle control). Contractions of aortae induced by U46619 (10-9 to 3x10-7M), phenylephrine (PE; 10-9 to 10-5M) were recorded and expressed as kPa by taking account of the vessel diameters. Contractions of bronchi to U46619 (10-8 to 3x10-6M) and acetylcholine (Ach; 10-8 to 3x10-4M) were recorded, and expressed as % of the maximum response to KCl (0.124M).
Figure 1. Concentration response curve to U46619 in (A.) wild type and (B.) COX-1-/- aortae. Tissues were incubated in the presence of 10-5M lumiracoxib for 30 minutes. Data shown is mean ± SEM, n=4-6; * p<0.05 by two way ANOVA.
Lumiracoxib (Fig.1A), parecoxib, naproxen and ibuprofen inhibited contraction induced by the thromboxane mimetic U46619 in wild type mouse aorta, but not in COX-1-/- aorta (Fig.1B). Incubation with all COX inhibitor drugs increased U46619 contraction in wild type bronchi, and not COX-1-/- mice. These observations indicate that COX-2 selective drugs lumiracoxib and parecoxib have inhibitory effects on COX-1 activity. This is consistent with the evidence that COX-2 selective drugs have cardiovascular side effects.
This work was funded by the Wellcome Trust.
COX-1-/- mice were provided by Prof A. Ahluwalia and Dr. R. Scotland