Nitric oxide in experimental aneurysm formation: early events and consequences of nitric oxide inhibition.
Mounting evidence suggests that nitric oxide (NO) plays an important role in aneurysm pathogenesis. Nitric oxide synthase (NOS) expression, hemodynamic consequences of NO inhibition, and the effect of NO on matrix metalloproteinase (MMP) expression during aneurysm formation are unknown. In this study, a standard intraaortic elastase infusion rat model was used. Control animals received intraaortic elastase infusion and intraperitoneal saline injections. Experimental groups received intraaortic elastase infusion and intraperitoneal injections of aminoguanidine (500 mg/kg) or L-NAME (2 mg/kg or 10 mg/kg). Aortic diameter, blood pressure, and NO metabolites were measured at surgery and postoperative (POD) 7. A second series of rats were randomly infused with intraaortic elastase or saline and aortas were analyzed on POD 1, 3, and 7 with Western blotting for iNOS, eNOS, and MMP-9 expression. Infusion of elastase produced aneurysms (p > 0.0001) in all rats. Inhibition of NO with aminoguanidine or L-NAME limited aneurysm expansion in all groups (p > 0.05). Nitric oxide metabolites were increased (p < 0.003) in control rats on POD 7. Arterial hypertension was present in all treated animals (p < 0.05). Early up-regulation on POD 1 of iNOS (p < 0.003) was noted in elastas-infused animals, but there was no iNOS expression with saline infusion. MMP-9 expression was present in both groups, with a significant increase in expression for elastase-infused animals noted on POD 7. iNOS expression is up-regulated early in experimental aneurysm formation, followed by increases in MMP-9 expression. Inhibition of NO limits aneurysmal expansion despite production of arterial hypertension.
Johanning
Jason M
JM
Sigfried and Janet Weis Center for Research, Section of Vascular Surgery, Geisinger Medical Center, Danville, PA 17822-2150, USA.
Armstrong
Peter J
PJ
Franklin
David P
DP
Han
David C
DC
Carey
David J
DJ
Elmore
James R
JR
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000502:physiology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D023421:Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D010196:Pancreatic Elastase / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester