Suppression of experimental aortic aneurysms: comparison of inducible nitric oxide synthase and cyclooxygenase inhibitors.
The rat model of abdominal aortic aneurysm (AAA) is associated with inflammation, destruction of extracellular matrix, and production of both inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9). Indomethacin, a nonselective cyclooxygenase inhibitor, may prevent AAA formation by inhibiting cyclooxygenase-2 (COX-2) activity. We hypothesized that indomethacin, rofecoxib (selective COX-2 inhibitor), and 1400 W (selective iNOS activity inhibitor) would decrease aneurysm formation in the rat model. Forty-six male Wistar rats underwent intraaortic elastase infusion in two parallel studies based on medication delivery route. Sixteen rats were randomized to rofecoxib or water by gastric lavage. Thirty rats were randomized to subcutaneous saline, indomethacin, or 1400 W. Heart rate, blood pressure and aortic diameters were measured. Western Blot and mRNA analysis for MMP-9 and iNOS was performed on postoperative day 7 aortic segments. Elastin degradation and inflammation were evaluated by immunohistochemistry. Elastase infusion produced AAA in all rats. 1400 W significantly limited aneurysm expansion (p = 0.01) whereas treatment with indomethacin and rofecoxib did not. Only 1400 W significantly increased blood pressure (p < 0.001). Indomethacin alone statistically decreased MMP-9 (p < 0.011). 1400 W resulted in greater conservation of aortic elastin than indomethacin (p = 0.025). All groups demonstrated statistically similar expression of iNOS. In conclusion, selective iNOS activity inhibitor, 1400 W, significantly decreased aneurysm size and preserved aortic elastin without altering MMP-9 levels. Indomethacin significantly decreased MMP-9 expression without decreasing aneurysm size. Rofecoxib did not significantly decrease MMP-9 expression or aneurysm size. Inhibition of iNOS limits aneurysmal expansion by mechanisms other than MMP-9 inhibition. MMP-9 inhibition by indomethacin is not sufficient to limit aneurysm expansion in our model.
Armstrong
Peter J
PJ
Section of Vascular Surgery, Sigfried and Janet Weis Center for Research, Geisinger Medical Center, Danville, PA 17822-2150, USA.
Franklin
David P
DP
Carey
David J
DJ
Elmore
James R
JR
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000517:prevention & control*; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000494:pharmacology*
D000578:Amidines; D001596:Benzylamines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007783:Lactones; D061965:Matrix Metalloproteinase Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D013450:Sulfones; C116926:rofecoxib; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D020780:Matrix Metalloproteinase 9; D007213:Indomethacin