Contribution of interaction between nitric oxide and cyclooxygenases to the production of prostaglandins in carrageenan-induced inflammation

BACKGROUND: Nitric oxide (NO) and prostaglandins (PGs) are crucial mediators contributing to generation of inflammatory responses and pain. This study was designed to investigate the effects of peripherally released NO on cyclooxygenase (COX) expression/activation and production of PGs in carrageenan-induced inflammation. METHODS: A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1alpha (metabolite of PGI2) in the dialysate were measured. Carrageenan was injected into the plantar surface of the hind paw during perfusion of the dialysis catheter with modified Ringer's solution or N-monomethyl-L-arginine acetate. In addition, the effects of the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor NS-398 on the production of NO, PGE2, and 6-keto-PGF1alpha were examined. Western blotting was performed to evaluate the expression of COX-1 and COX-2 in the skin at the site of the inflammation. RESULTS: Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by N-monomethyl-L-arginine acetate. SC-560 effectively inhibited the increase in PGE2 and PGI2 concentrations for the first 2 h, and NS-398 inhibited 3-6 h after carrageenan. Western blot analysis showed that the concentrations of both COX-1 and COX-2 in the skin increased after carrageenan. The up-regulation of COX-1 in the skin was observed 3 and 6 h after carrageenan and was not suppressed in the rats treated with N-monomethyl-L-arginine acetate. The up-regulation of COX-2 in the skin was also observed 3 and 6 h after carrageenan and was completely suppressed in the rats treated with N-monomethyl-L-arginine acetate. CONCLUSION: The results of the current study suggest that NO activates COX-1 in the early phase of carrageenan and up-regulates COX-2 expression in the late phase in the skin, resulting in production of PGE2 and PGI2 at the site of inflammation, which would contribute to exacerbation of the inflammatory process.     

Effective inhibition of nitric oxide production by aminoguanidine does not reverse hypotension in endotoxaemic rats

BACKGROUND: Excess production of nitric oxide (NO) by the inducible NO synthase (iNOS) has been implicated in the pathophysiology of septic shock. Using methaemoglobin (metHb) and the stable NO metabolite nitrate as markers of NO formation, we assessed the effect of iNOS blockade by aminoguanidine (AG) on hypotension and NO formation in endotoxaemic rats. METHODS: In 32 male Wistar rats under chloralose anaesthesia, MetHb (at 15 and 330 min, respectively) and plasma nitrate (at 330 min) were determined. Mean arterial pressure, heart rate and haematocrit were monitored. The LPS group (n=8) received bacterial endotoxin (LPS), 3 mg kg(-1) i.v. and was subsequently monitored for 5 h. At 2 h after LPS, the LPS+AG20 group (n=8) received AG, 5 mg kg(-1), and 5 mg kg(-1) h(-1) for the remaining 3 h. The LPS+AG100 group (n=8) instead received 25 mg kg(-1), followed by 25 mg kg(-1) h(-1). The NaCl group (n=8) was given corresponding volumes of isotonic saline. RESULTS: AG decreased the LPS-induced rise in plasma nitrate by about 50% in the LPS+AG20 group. MetHb levels, however, were not appreciably reduced by this dose. Both NO metabolites reached control levels after the higher dose of AG. LPS caused a progressive decrease in haematocrit. AG did not influence the LPS-induced hypotension, tachycardia or haemodilution. CONCLUSION: AG inhibited NO formation in a dose-dependent way. Yet, AG had no haemodynamic effects, suggesting a minor cardiovascular influence of iNOS in this endotoxin model, in parallel to what has been found in microbial sepsis.     

Regulatory effects of inducible nitric oxide synthase on cyclooxygenase-2 and heme oxygenase-1 expression in experimental glomerulonephritis.

BACKGROUND: We explored whether inducible nitric oxide synthase (iNOS) driven nitric oxide (NO) production regulates expression of iNOS, endothelial NOS (eNOS), Cyclooxygenase-2 (COX-2), and Hemeoxygenase-1 (HO-1) proteins in a rat model of glomerulonephritis induced by antibody raised in rabbits against rat glomerular basement membrane (anti-GBM). METHODS: Rats were injected either with non-immune serum (control), or anti-GBM serum. In a group of rats N6-(1-iminoethyl)-L-lysine (L-NIL) was administered prior to injection of anti-GBM serum to inhibit iNOS activity. Urinary nitrite plus nitrate (NOx) excretion was assessed to determine the extent of iNOS inhibition by L-NIL. Urinary albumin excretion was assessed to determine extent of proteinuria. Urinary PGE2 was assessed as a marker of COX activity. Glomeruli were harvested 24 h after injection of anti-GBM serum and ED1, COX-2, iNOS, eNOS and HO-1 expression was analysed by Western blot analysis. RESULTS: iNOS activity in glomeruli was effectively reduced in L-NIL-treated nephritic animals. In these animals, there was exacerbation of proteinuria and reduction in urinary PGE2 levels without changes in the extent of macrophage infiltration in glomeruli. In nephritic animals, there was an increase in glomerular protein levels of COX-2, HO-1 and iNOS, but not of eNOS. While L-NIL treatment reduced glomerular HO-1, levels of COX-2 and iNOS increased; but not that of eNOS. CONCLUSIONS: The observations indicate that in glomerulonephritis iNOS-driven NO production acts as a negative feedback regulator of iNOS itself, suppresses COX-2 levels, and maintains HO-1 levels.     

一氧化氮、诱导性一氧化氮合酶在实验性大鼠腹主动脉瘤中的作用

目的:探讨一氧化氮(NO)和诱导性一氧化氮合酶(iNOS)在实验性大鼠腹主动脉瘤形成中的作用和机制.方法:建立大鼠腹主动脉瘤灌注模型,对照组予以生理盐水腹主动脉灌注,余下予以猪胰弹性蛋白酶灌注制作腹主动脉瘤模型,并分为实验组(术后腹腔注射生理盐水)、药物组(术后腹腔注射氨基胍),观察各组大鼠血清NO、腹主动脉瘤壁组织学和基质金属蛋白酶-9(MMP-9)、iNOS的变化.结果:生理盐水灌注组大鼠术前术后血清NO无明显变化,iNOS、MMP-9表达弱阳性或阴性,动脉壁炎性细胞浸润轻、弹性蛋白降解少;实验组血清NO显著升高,iNOS及MMP-9表达强阳性,炎性细胞浸润重、弹性蛋白几乎完全降解;应用氨基胍后iNOS变化不明显,而NO显著降低,MMP-9表达显著减弱,炎性细胞浸润和弹性蛋白降解明显减轻.结论:iNOS、MMP-9的表达和血清NO水平在实验组均显著升高.iNOS及其合成的NO能促进腹主动脉壁炎性细胞的浸润、中膜基质的降解和MMPs的表达,从而导致了腹主动脉瘤的生成.     

Contribution of Interaction between Nitric Oxide and Cyclooxygenases to the Production of Prostaglandins in Carrageenan-induced Inflammation

Background: Nitric oxide (NO) and prostaglandins (PGs) are crucial mediators contributing to generation of inflammatory responses and pain. This study was designed to investigate the effects of peripherally released NO on cyclooxygenase (COX) expression/activation and production of PGs in carrageenan-induced inflammation.

Methods: A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1[alpha] (metabolite of PGI2) in the dialysate were measured. Carrageenan was injected into the plantar surface of the hind paw during perfusion of the dialysis catheter with modified Ringer's solution or NG-monomethyl-l-arginine acetate. In addition, the effects of the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor NS-398 on the production of NO, PGE2, and 6-keto-PGF1[alpha] were examined. Western blotting was performed to evaluate the expression of COX-1 and COX-2 in the skin at the site of the inflammation.

Results: Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by NG-monomethyl-l-arginine acetate. SC-560 effectively inhibited the increase in PGE2 and PGI2 concentrations for the first 2 h, and NS-398 inhibited 3-6 h after carrageenan. Western blot analysis showed that the concentrations of both COX-1 and COX-2 in the skin increased after carrageenan. The up-regulation of COX-1 in the skin was observed 3 and 6 h after carrageenan and was not suppressed in the rats treated with NG-monomethyl-l-arginine acetate. The up-regulation of COX-2 in the skin was also observed 3 and 6 h after carrageenan and was completely suppressed in the rats treated with NG-monomethyl-l-arginine acetate.     

环氧合酶2对脓毒症大鼠免疫功能的影响

目的 研究环氧合酶2(cyclooxygenase-2,COX-2)在脓毒症大鼠肝组织炎症反应中的表达及其对免疫功能的影响.方法 选择质量相近的Wistar大鼠54只,分为假手术组(6只)、脓毒症组(24只)、NS-398干预组(24只).通过建立盲肠结扎穿孔脓毒症动物模型,用RT-PCR方法检测肝组织COX-2mRNA的表达,ELISA法检测血清IL-6、IL-10、TNF-α水平,流式细胞仪检测T淋巴细胞亚群CD4+、CD8+细胞的变化,同时观察肝脏病理变化.结果 (1)脓毒症组病理损伤重,NS-398干预组损伤减轻.(2)COX-2mRNA:假手术组呈低表达,脓毒症组、NS-398干预组升高,但NS-398干预组较脓毒症组明显偏低.(3)IL-6:脓毒症组较假手术组和NS-398干预组明显增高(F=125.582,134.712,54.760,121.441,P＜0.05).(4)IL-10:NS-398干预组高于假手术组和脓毒症组(F=39.064,34.382,51.115,8.174,P＜0.05).(5)TNF-α:脓毒症组、NS-398干预组增高,但两组比较差异无统计学意义(x2=5.600,6.162,7.136,7.200,P＞0.05).(6)CD4+/CD8+比值:NS-398干预组高于脓毒症组(F=17.448,15.055,30.068,64.210,P＜0.05).结论 COX-2在脓毒症中发挥重要作用,其作用途径可能是通过改变促炎、抗炎细胞因子之间以及CD4+、CD8+细胞之间的平衡,使机体免疫状态紊乱而实现的.     

Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2

BACKGROUND: Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury. METHODS: Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS. RESULTS: LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels. CONCLUSIONS: These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.     

Inhibition of inducible nitric oxide synthase limits nitric oxide production and experimental aneurysm expansion

PURPOSE: 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. CONCLUSION: 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.     

COX-2及其选择性抑制剂NS-398对激光术后创面修复的实验研究

目的：探讨COX-2及其选择性抑制剂NS-398对激光术后大鼠创面修复的影响。方法：点阵CO2激光照射形成大鼠创伤模型,分为正常、术后第1、3、5、7、10、14天共7个时相点,基质对照组、NS-398药物组术后分别外用75%酒精、NS-398,肉眼观察创面结痂及愈合时间,HE染色计数中性粒细胞、成纤维样细胞,免疫组化方法检测COX-2、PGE2及TGF-β1的表达情况。结果：NS-398药物组结痂时间明显短于对照组,各组间愈合时间无统计学差异;术后第1、3天,NS-398药物组中性粒细胞的数量及PGE2、TGF-β1表达量均明显低于对照组;术后第5天,NS-398药物组成纤维样细胞的数量明显高于对照组;激光术后（尤炎症期）大鼠创面明显表达COX-2。结论：COX-2对大鼠创面修复的炎症期及细胞增殖期具有重要作用;NS-398能降低激光术后创面炎症反应及瘢痕形成率,同时不会延缓创面愈合。     

COX-2与VEGF-C在直肠癌中的表达及其在淋巴转移中的意义

目的探讨直肠癌中VEGF-C及COX-2表达的关系及意义.方法用COX-2特异性抑制剂NS-398及其催化产物PGE2作用于大肠癌LOVO细胞,应用Western blot方法检测VEGF-C蛋白表达.应用免疫组化方法检测45例直肠腺癌组织VEGF-C及COX-2表达情况.结果NS-398明显抑制LOVO细胞VEGF-C蛋白的表达.经PGE2作用后,VEGF-C蛋白表达上调.直肠癌组织中VEGF-C及COX-2的表达具有明显相关性.结论COX-2上调VEGF-C表达,促进肿瘤淋巴转移.     

Role of nitric oxide in hemorrhagic shock-induced bacterial translocation

BACKGROUND: Hemorrhagic shock-induced bacterial translocation is an etiologic factor in the pathogenesis of multiple system organ damage. Excessive production of nitric oxide (NO) during hemorrhagic shock may lead to cellular injury and gut barrier failure that promotes bacterial translocation. We investigated the effect of aminoguanidine (AG) and N(G)-nitro-l-arginine methyl ester (l-NAME), both inhibitors of NO synthase, on hemorrhagic shock- induced bacterial translocation in the rat. MATERIALS AND METHODS: Anesthetized male Sprague-Dawley rats were subjected to a hemorrhagic shock protocol for 30 min followed by intravenous injection (1 mL/kg body wt) with normal saline, AG (100 mg/kg), or l-NAME (10 mg/kg). Tissues/organs were examined histologically for damage and bacterial translocation. Plasma nitrate/nitrite was measured using a procedure based on the Griess reaction, and nitric oxide synthase (NOS) expression was determined immunohistochemically. RESULTS: The shocked animals treated with saline died within 90 min, and deaths were associated with 100% bacterial translocation, increased tissue/organ damage, and elevated nitrate/nitrite production. In contrast, both AG and l-NAME increased the survival time of shocked rats to >72 h, abrogated bacterial translocation, reduced tissue/organ damage, and prevented excessive nitrate/nitrite production and upregulation of expression of endothelial NOS and inducible NOS. CONCLUSIONS: Prevention of bacterial translocation by pharmacologic agents such as aminoguanidine and l-NAME could be an important therapeutic approach to lessen mortality rates following hemorrhagic shock.     

Iodinated contrast induced renal vasoconstriction is due in part to the downregulation of renal cortical and medullary nitric oxide synthesis

OBJECTIVES: The loss of renal function continues to be a frequent complication of the iodinated contrast agents used to perform diagnostic angiography and endovascular procedures. This study examined the hypothesis that contrast-induced renal injury is partly due to a decrease in cortical and medullary microvascular blood flow after the downregulation of endogenous renal cortical and medullary nitric oxide (NO) synthesis. METHODS: Anesthetized male Sprague-Dawley rats (300 g) had microdialysis probes or laser Doppler fibers inserted into the renal cortex to a depth of 2 mm and into the renal medulla to a depth of 4 mm. Laser Doppler blood flow was continuously monitored, and the microdialysis probes were connected to a syringe pump and perfused in vivo at 3 muL/min with lactated Ringer's solution. Dialysate fluid was collected at time zero (basal) and 60 minutes after infusion of either saline or Conray 400 (6 mL/kg). Both groups were treated with saline carrier, N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 30 mg/kg), L-arginine (400 mg/kg), or superoxide dismutase (10,000 U/kg), an oxygen-derived free radical scavenger. Dialysate was analyzed for total NO and eicosanoid synthesis. The renal cortex and medulla were analyzed for inducible NO synthase (iNOS), cyclooxygenase-2 (COX2), prostacyclin synthase, and prostaglandin E(2) (PGE(2)) synthase content by Western blot analysis. RESULTS: Conray caused a marked decrease in cortical and medullary blood flow with a concomitant decrease in endogenous cortical NO, PGE(2), and medullary NO synthesis. The addition of L-NAME to the Conray further decreased cortical and medullary blood flow and NO synthesis, which were restored toward control by L-arginine. Neither L-NAME nor L-arginine (added to the Conray) altered cortical or medullary eicosanoids release. Medullary PGE(2) synthesis decreased when superoxide dismutase was added to the Conray treatment, suggesting that oxygen-derived free radicals had a protective role in maintaining endogenous medullary PGE(2) synthesis after Conray treatment. Conray did not significantly alter iNOS, COX-2, prostacyclin synthase, or PGE(2) synthase content. CONCLUSIONS: These findings suggest that the downregulation of renal cortical and medullary NO synthesis contributes to the contrast-induced loss of renal cortical and medullary microvascular blood flow. Preservation of normal levels of renal cortical and medullary NO synthesis may help prevent or lessen contrast-induced renal vasoconstriction and lessen contrast-induced renal injury found after diagnostic and therapeutic endovascular procedures.     

Differential salutary effects of nonselective and selective COX-2 inhibitors in postoperative ileus in rats

BACKGROUND: Postoperative ileus (PI) is a common surgical complication, the treatment of which consists of supportive measures. AIM: The effects of several cyclooxygenase (COX) inhibitors and their interaction with L-arginine/nitric oxide synthase (NOS) pathway were tested in a rat PI model. METHODS: Intestinal transit was measured as Evans blue migration after skin incision, laparotomy, or laparotomy followed by evisceration and gut handling. RESULTS: In contrast to a selective inducible NOS (iNOS) blocker, L-N(6)-(1-iminoethyl)lysine hydrochloride (L-NIL), N(omega)-nitro-L-arginine methyl ester (L-NAME) reversed the additional inhibitory effects of gut manipulation after laparotomy on the gastrointestinal transit (GI) in a dose-dependent, L-arginine-sensitive manner. Laparotomy and manipulations of small intestine increased blood plasma nitrites and nitrates level (NOx), an effect preventable by L-NAME. Indomethacin, resveratrol (selective COX-1 blocker), and COX-2 antagonists, nimesulide, NS-398, DuP-697, and L-752860, attenuated the additional inhibitory effects of gut manipulation following laparotomy in a dose-dependent manner. In contrast, only nimesulide, NS-398, DuP-697, and L-752860 partly, but significantly, reversed the effects of laparotomy on the intestinal transit. Administration of L-NAME subsequent to COX inhibitors abolished the salutary effects of the latter, implying that at least the synthesis of either NO or prostanoids must remain unaffected to enable a return of GI transit during the postoperative period. CONCLUSION: In addition to NO synthesized by constitutive NOS (cNOS), prostaglandins produced by both COX-1 and COX-2 participate in the pathogenesis of PI, albeit in different pathological mechanisms. Thus laparotomy stimulated COX-2 activity, whereas gut manipulation led to an excessive cNOS activity and prostaglandin synthesis by COX-1.     

NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line.

The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E2 (PGE2) synthesis. This study examines the expression and regulation of the prostaglandin synthesizing enzymes cyclooxygenase-1 (COX-1) and -2 in the CCD. By indirect immunofluorescence using isoform-specific antibodies, COX-1 and -2 immunoreactivity was localized to all cell types of the murine M-1 CCD cell line. By immunohistochemistry, both COX-1 and COX-2 were localized to intercalated cells of the CCD on paraffin-embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE2 synthesis. These results demonstrate that COX-2 is the major contributor to the pool of PGE2 synthesized by the CCD. By Western blot analysis, COX-2 expression was significantly upregulated by incubation with either indomethacin or NS-398. These drugs did not affect COX-1 protein expression. Evaluation of COX-2 mRNA expression by Northern blot analysis after NS-398 treatment demonstrated that the COX-2 protein upregulation occurred independently of any change in COX-2 mRNA expression. These studies have for the first time localized COX-2 to the CCD and provided evidence that the intercalated cells of the CCD express both COX-1 and COX-2. The results also demonstrate that constitutively expressed COX-2 is the major COX isoform contributing to PGE2 synthesis by the M-1 CCD cell line. Inhibition of COX-2 activity in the M-1 cell line results in an upregulation of COX-2 protein expression.     

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 elastase-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.