Inhibition of inducible nitric oxide synthase limits nitric oxide production and experimental aneurysm expansion.
OBJECTIVE
Nitric oxide (NO), frequently cited for its protective role, can also generate toxic metabolites known to degrade elastin. Both abdominal aortic aneurysms (AAAs) and inducible nitric oxide synthase (iNOS) are associated with inflammatory states, yet the relationship between NO production by iNOS and AAA development is unknown. The current study examines iNOS expression, NO production, and the effects of selective inhibition of iNOS by aminoguanidine in experimental AAA.


METHODS
An intra-aortic elastase infusion model was used. Control rats received intra-aortic saline infusion and postoperative intraperitoneal saline injections (Group 1). In the remaining groups, intra-aortic elastase infusion was used to induce aneurysm formation. These rats were treated with intraperitoneal injections of saline postoperatively (Group 2), aminoguanidine postoperatively (Group 3), or aminoguanidine preoperatively and postoperatively (Group 4). Aortic diameter and plasma nitrite/nitrate levels were measured on the day of surgery and postoperative day 7. Aortas were harvested for biochemical and histologic analysis on postoperative day 7.


RESULTS
Infusion of elastase produced AAAs (P <.001) with significant production of iNOS (P <.05) and nitrite/nitrate (P <.003) compared with controls. Selective inhibition of iNOS with aminoguanidine in elastase-infused aortas significantly reduced aneurysm size (P <.01) compared with elastase infusion alone. Aminoguanidine-treated rats displayed suppression of iNOS expression and plasma nitrite/nitrate production not significantly different from the control group. Histologic evaluation revealed equivalent inflammatory infiltrates in elastase-infused groups.


CONCLUSIONS
Expression of iNOS is induced and plasma nitrite/nitrate levels are increased in experimental AAA. Inhibition of iNOS limits NO production and iNOS expression, resulting in smaller aneurysm size. NO production by iNOS plays an important role with detrimental effects during experimental aneurysm development.
Section of Vascular Surgery and the Sigfried and Janet Weis Center for Research, Geisinger Medical Center, Danville, PA 17822-2150, USA.
J M
JM
Johanning
D P
DP
Franklin
D C
DC
Han
D J
DJ
Carey
J R
JR
Elmore
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D009573:Nitrites / Q000378:metabolism; D010196:Pancreatic Elastase; D051381:Rats; D017208:Rats, Wistar
D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010196:Pancreatic Elastase; C004479:pimagedine