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PubMed2004

Pharmacological manipulation of nitric oxide levels in mouse follicle cultures demonstrates key role of extrafollicular control of ovulation.

BACKGROUND: Nitric oxide (NO) is involved in ovulation, but it is uncertain whether the mechanisms responsible are systemic or local. In vivo and in perfused ovaries, inhibition of nitric oxide synthase (NOS) reduces ovulation. This study used a well-characterized system of isolated follicle culture to assess which isoforms of NOS might be involved at the follicular level. METHODS: NOS inhibitors, stimulators and NO donors were used to manipulate the environment of mouse cultured follicles, selectively targeting different isoforms of NOS. Follicle survival and ovulation in vitro were monitored using established markers. RESULTS: Inhibition of endothelial NOS did not affect survival or ovulation of cultured follicles. Inhibition of inducible nitric oxide synthase (iNOS) had mild effects in this system, generally inhibitory of ovulation. NO donors had variable inhibitory effects, including toxic effects. Stimulators of iNOS appeared to show mixed, mostly inhibitory, effects that possibly involved different mechanisms. CONCLUSIONS: The results suggest that relatively minor effects on survival and ovulation in vitro are achieved by modulating the NO pathway, and the marked effects of NOS inhibitors in vivo do not occur in vitro. It is therefore probable that the effects of NOS inhibitors in vivo are mediated via effects outside the follicle.

Animals↗
PubMed1996

Effect of a nitric oxide synthase inhibitor, S-ethylisothiourea, on cultured cells and cardiovascular functions of normal and lipopolysaccharide-treated rabbits.

Nitric oxide (NO) is synthesized from L-arginine by three isoforms of NO synthase (NOS). It is essential to suppress the function of the inducible isoform (macNOS) for amelioration of some inflammatory diseases in which the cytotoxic effect of NO is involved. S-Ethylsiothiourea (S-EIU) was reported to be a potent and specific inhibitor of macNOS. We also confirmed that it rather specifically inhibited the activity of the purified macNOS and the formation of nitrite by RAW264.7 cells compared to NG-monomethyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA), the other isoforms being less effective. S-EIU suppressed the release of nitrite and lactate dehydrogenase from rat vascular smooth muscle cells treated with interleukin-1 beta and forskolin more potently than L-NMA or L-NNA. S-EIU also slightly suppressed internucleosomal DNA cleavage in pancreatic beta-cells induced by NO produced by macNOS. Intravenous administration of either S-EIU at 0.1 mg/kg/min or L-NMA at 1 mg/kg/min increased the blood pressure but decreased the heart rate in normal rabbits, while aminoguanidine at 1 mg/kg/min affected neither cardiovascular function. These inhibitors at these doses caused recovery of the blood pressure in lipopolysaccharide-treated rabbits that exhibited lowered blood pressure similar to that in the case of septic shock. Although S-EIU seemed not to be an adequate inhibitor for therapeutic use in vivo due to its side effects on cardiovascular functions, it is one of the most potent inhibitors of macNOS among reported inhibitors in vitro.

Animals↗
PubMed2004

Inducible nitric oxide synthase mediates delayed cardioprotection induced by morphine in vivo: evidence from pharmacologic inhibition and gene-knockout mice.

BACKGROUND: It is not known whether morphine induces delayed cardioprotection against ischemia and reperfusion. The authors measured the delayed preconditioning induced by morphine and determined the role of inducible nitric oxide synthase (iNOS) in mediating this effect using a pharmacological inhibitor and iNOS gene-knockout mice. METHODS: Adult male wild-type and iNOS gene-knockout (B6, 129) mice were treated with morphine (0.3 or 0.1 mg/kg intraperitoneal) or saline. Twenty-four hours later, mice were subjected to 45 min of coronary artery occlusion followed by 120 min of reperfusion. S-methylthiourea sulfate (3 mg/kg, intraperitoneal) was given 30 min before the occlusion to block iNOS. Infarct size as a percentage of the area at risk was determined by triphenyltetrazolium chloride staining. iNOS and endothelial nitric oxide synthase expression were measured by Western blot. RESULTS: Infarct size was significantly reduced in wild-type mice from 43.1 +/- 5.3% in the saline group to 22.4 +/- 4.4% in the higher-dose morphine group (0.3 mg/kg) (P < 0.05). This cardioprotective effect was abolished by S-methylthiourea sulfate (43.3 +/- 3.9%) and was absent in iNOS gene-knockout mice (42.3 +/- 4.7%). Pretreatment with the lower dose of morphine (0.1 mg/kg) did not reduce infarct size (41.1 +/- 5.4%). A significant increase in myocardial iNOS expression was observed 24 h after morphine administration (0.3 mg/kg but not 0.1 mg/kg; P < 0.05), whereas endothelial nitric oxide synthase remained unchanged. CONCLUSIONS: : Pretreatment with morphine induces delayed cardioprotection in mice. The authors demonstrated an obligatory role for iNOS in mediating morphine-induced delayed cardioprotection.

Analgesics, Opioid↗
PubMed2006

Mechanism of hepatic heme oxygenase-1 induction by isoflurane.

BACKGROUND: The heme oxygenase pathway represents a major cell and organ protective system in the liver. The authors recently showed that isoflurane and sevoflurane up-regulate the inducible isoform heme oxygenase 1 (HO-1). Because the activating cascade remained unclear, it was the aim of this study to identify the underlying mechanism of this effect. METHODS: Rats were anesthetized with pentobarbital intravenously or with isoflurane per inhalation (2.3 vol%). Kupffer cell function was inhibited by dexamethasone or gadolinium chloride. Nitric oxide synthases were inhibited by either N(omega)-nitro-L-arginine methyl ester or S-methyl thiourea. N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1. Protein kinase C and phospholipase A2 were inhibited by chelerythrine or quinacrine, respectively. HO-1 was analyzed in liver tissue by Northern blot, Western blot, immunostaining, and enzymatic activity assay. RESULTS: In contrast to pentobarbital, isoflurane induced HO-1 after 4-6 h in hepatocytes in the pericentral region of the liver. The induction was prevented in the presence of dexamethasone (P < 0.05) and gadolinium chloride (P < 0.05). Inhibition of nitric oxide synthases or reactive oxygen intermediates did not affect isoflurane-mediated HO-1 up-regulation. In contrast, chelerythrine (P < 0.05) and quinacrine (P < 0.05) resulted in a blockade of HO-1 induction. CONCLUSION: The up-regulation of HO-1 by isoflurane in the liver is restricted to parenchymal cells and depends on Kupffer cell function. The induction is independent of nitric oxide or reactive oxygen species but does involve protein kinase C and phospholipase A2.

Acetylcysteine↗
PubMed1999

Selective inhibition of inducible nitric oxide synthase: effects on hemodynamics and regional blood flow in healthy and septic sheep.

OBJECTIVES: To investigate the effects of S-ethylisothiourea (S-EITU) on hemodynamics, oxygen transport, and regional blood flow in healthy and septic sheep. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Eleven healthy, female adult sheep of the Merino breed, divided into a control group (n = 5) and into a group treated with S-EITU (n = 6). INTERVENTIONS: All sheep were chronically instrumented. After a 5-day recovery period, they were randomly assigned to either control or S-EITU groups. While control sheep received only saline, S-EITU was administered in increasing doses of 1, 3, and 9 mg/kg/hr over 1 hr each (nonseptic phase). After 2 days of recovery, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 106 colony-forming units/min) was started in all sheep and maintained for the remainder of the experiment. After 24 hrs of sepsis, the sheep again received their assigned treatment (septic phase). In both the nonseptic and septic phases, the sheep received colored microspheres through a left atrial catheter to allow analysis of regional blood flows. All animals were autopsied at the end of the experiments, and organ probes were removed for blood flow analyses. MEASUREMENTS AND MAIN RESULTS: The administration of S-EITU caused a dose-dependent vasoconstriction in the nonseptic phase. After 24 hrs of Pseudomonas infusion, all sheep developed a hyperdynamic circulatory state, with increased cardiac indices and reduced arterial pressures and systemic vascular resistances. Oxygen extraction decreased significantly, preventing an increase in oxygen consumption, despite an increased oxygen delivery. The hyperdynamic circulation was dose dependently reversed by S-EITU, causing an increase in arterial pressure by peripheral vasoconstriction. Sheep in the control group showed a continuation of the hyperdynamic circulation. The effects of S-EITU on hemodynamics and regional blood flows were comparable under septic and nonseptic conditions. CONCLUSIONS: With the inducible form of nitric oxide synthase expressed under septic, but not under nonseptic conditions, S-EITU was expected to have vasoconstrictive properties only in the septic phase. It produced a comparable vasoconstriction during the nonseptic phase of the experiment. Thus, either S-EITU does not selectively block the inducible nitric oxide synthase in sheep, or other vasodilators besides nitric oxide play an important role in septic vasodilation.

Animals↗
PubMed2000

Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock.

OBJECTIVE: To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival time, hemodynamics, and oxygen transport in a porcine model of live group A streptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-1, histamine, and reactive oxygen species (ROS) in streptococcal shock. DESIGN: Prospective, randomized trial. SETTING: Laboratory at a university hospital. SUBJECTS: Twenty-eight pigs with an average weight of 25 kg. INTERVENTIONS: Sixteen animals received a continuous infusion of live Streptococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received fluids only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs received AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the dose of GAS over 5 hrs. MEASUREMENTS AND MAIN RESULTS: GAS infusion caused a rapid increase in pulmonary, hepatic, and systemic vascular resistance, followed by hypotension with a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, prevented hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arterial blood flow as a fraction of cardiac output increased (all p < .05). Plasma nitrate/nitrite levels decreased in all animals. Inducible NOS and endothelial constitutive NOS activities in liver, gut, and lung were not increased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-1 and methylhistamine increased in all septic animals and were not modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS production caused by GAS. In control animals, AE-ITU caused an increase in mean arterial pressure, liver blood flow, and oxygen delivery. CONCLUSIONS: In this model of porcine GAS-induced septic shock, which was not associated with enhanced NO production, infusion of the NOS inhibitor AE-ITU prolonged survival, prevented hypotension, and improved cardiac contractility, organ perfusion, and tissue oxygenation. These beneficial effects of AE-ITU might be a result of the combined effect of ROS scavenging and modulation of local NO production, thus improving the balance of vasodilator and vasoconstrictor forces and reducing oxidative stress.

Animals↗
PubMed2000

Comparison between selective and nonselective nitric oxide synthase inhibition and phenylephrine in normal and endotoxic swine.

OBJECTIVE: To compare the cardiopulmonary and peripheral circulatory effects of the nonselective nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to the more selective inducible NOS inhibitor S-methylisothiourea (SMT) and to phenylephrine (PE) in endotoxic and normal swine. DESIGN: Prospective, randomized, unblinded study. SETTING: Research laboratory of academic medical center. SUBJECTS: Nonanesthetized, sedated, mechanically ventilated, minimally invasive swine model. INTERVENTIONS: Animals received either lipopolysaccharide (LPS, LPS groups) or equivalent volume of saline (normal groups). LPS animals were further randomized into four groups when mean arterial pressure (MAP) had dropped to <60 mm Hg: the LPS/saline group received saline only; the other groups received either L-NAME, SMT, or PE. These were titrated to elevate MAP by 20-25 mm Hg, and animals were followed for another 3 hrs. Pulmonary artery occlusion pressure was maintained at one to two times baseline with the infusion of saline. Normal groups received the same agents 1 hr after baseline measurements, and drugs were titrated to achieve similar increases in MAP. We measured gastric-arterial PCO2 gradient by tonometry as an index of gastric mucosal perfusion. Left ventricular volumes were determined echocardiographically; right ventricular volumes were determined by a pulmonary arterial catheter equipped with a rapid thermistor. Plasma nitrite/nitrate (NOx) concentrations were measured hourly. MEASUREMENTS AND MAIN RESULTS: In the LPS groups, all agents elevated MAP and systemic vascular resistance similarly. By hr 4, cardiac output had decreased in all groups, but the decrease with L-NAME (35% +/- 16%) occurred earlier (at hr 3) and was larger than the decrease with SMT at hrs 3 and 5 and larger than the decrease with saline at hrs 3 to 5. L-NAME resulted in a larger increase in mean pulmonary arterial pressure (MPAP) when compared with saline (130% +/- 44% vs. 61% +/- 25%; p < .001) and SMT groups (130% vs. 97% +/- 80%; p < .007). Only L-NAME had detrimental effects on right ventricular function as indicated by an increase in right ventricular end-systolic volume (54 +/- 10 to 87 +/-6 mL; p < .05) and right ventricular end-diastolic volume (90 +/-11 to 128 +/- 18 mL; p < .05). SMT decreased both left ventricular end-systolic volume (10.4 +/- 2 to 7.7 +/- 4 mL; p < .05) and left ventricular end-diastolic volume (18.5 +/- 3 to 14.2 +/- 5 mL; p < .05), indicating improved left ventricular function, whereas L-NAME did not affect left ventricular volumes. Both SMT and PE corrected LPS-induced gastric mucosal acidosis, but L-NAME did not. We did not detect changes in plasma NOx concentrations in any of LPS groups. In the normal groups, all agents increased MAP without changes in plasma NOx concentrations. L-NAME caused a larger decrease in cardiac output, but the increase in MPAP was higher with SMT. Both NOS inhibitors led to left ventricular dilation, but PE did not. Only L-NAME caused right ventricular dilation. There were no changes in gastric-arterial PCO2 gradient. CONCLUSIONS: In LPS animals, we failed to detect changes in plasma NOx concentrations. Furthermore, for similar increases in MAP, SMT improved gastric mucosal acidosis, had less adverse effects on right ventricular function and MPAP, and may have improved left ventricular function. However, apart from its bene-ficial effects on left ventricular function, SMT was not superior to PE. The results from normal animals indicate that both NOS inhibitors have adverse effects on cardiac function beyond those attributed to increased MAP.

Animals↗
PubMed2002

Aminoguanidine inhibits mitogen-activated protein kinase and improves cardiac performance and cardiovascular remodeling in failing hearts of salt-sensitive hypertensive rats.

OBJECTIVES: Congestive heart failure (CHF) is associated with inducible nitric oxide synthase (iNOS) expression in the failing human heart, and recently we have also demonstrated that iNOS expression was upregulated in Dahl salt-sensitive hypertensive (DS) rats with cardiac dysfunction and vascular remodeling. Thus, we evaluated whether aminoguanidine (AG), a selective iNOS inhibitor, protects against cardiac dysfunction and vascular remodeling in DS rats receiving a high-salt diet. METHODS: AG (DSHF-AG, 150 mg/kg per day) or vehicle (DSHF-V) were given from left ventricular hypertrophy stage (11 weeks) to CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship (contractility: E(es)) was measured by conductance catheter. RESULTS: Decreased E(es) in DSHF-V was significantly ameliorated by AG treatment. The iNOS mRNA and protein expression and phospho-p42/p44 extracellular signal-regulated kinase (ERK) activities in the left ventricle were significantly upregulated in DSHF-V compared with control rats, and significantly suppressed in DSHF-AG compared with DSHF-V. DSHF-V showed a significant increase of perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by AG treatment. CONCLUSIONS: We demonstrated that the selective iNOS inhibitor, AG, may be at least a potential therapeutic strategy for treating CHF and cardiovascular remodeling.

Animals↗
PubMed2001

Intestinal motility in an in vivo rat model of intestinal ischemia-reperfusion with special reference to the effects of nitric oxide on the motility changes.

BACKGROUND: To clarify the relation between intestinal ischemia-reperfusion (IR) and dysmotility, the authors investigated changes in the motility pattern in the duodenum and jejunum in an in vivo rat model of IR when artery- (and vein-) fed jejunum was clamped transiently. The authors also studied the effect of nitric oxide on the motility changes in this model by means of the administration of L-NAME (N(G)-nitro-L-arginine methyl ester) or S-methylisothiourea sulfate (SMT). MATERIALS AND METHODS: A force transducer was sutured onto the serosal side of the duodenum or jejunum. After a 3-to 4-day recovery period, contractions were recorded during periods of preischemia, ischemia (60 minutes), and reperfusion (90 minutes). An intestinal IR was produced by clamping and releasing the mesenteric artery and vein with artery forceps. RESULTS: In the jejunum, there was a prolongation in the duration of contraction and there were decreases in the number of contractions (NC) during the IR. When treated with L-NAME, no decrease in the NC was observed during the 45 to 90 minutes after reperfusion. S-methylisothiourea sulfate did not affect the IR-induced motility changes significantly. In the duodenum, there was a prolongation in the duration of contraction and a decrease in the NC and AC only during the reperfusion. L-NAME or S-methylisothiourea sulfate inhibited the decreases in the NC during the reperfusion. CONCLUSIONS: Intestinal IR causes motility changes in the ischemic site during the IR and in the nonischemic site during the reperfusion. The IR-induced motility changes partly depend on nitric oxide production.

Animals↗
PubMed2001

Inhibition of inducible nitric oxide synthase reduces bacterial translocation in a rat model of acute pancreatitis.

INTRODUCTION: Translocation of bacteria from the gut into pancreatic necrosis is an important factor in the development of septic complications and mortality in acute pancreatitis. S-methylisothiourea (SMT) is an inducible nitric oxide synthase inhibitor that has been shown to decrease bacteria] translocation in sepsis and thermal injury. AIM: To investigate whether SMT could affect bacterial translocation in acute necrotizing pancreatitis. METHODOLOGY: Forty-five Sprague-Dawley rats were studied. Acute pancreatitis was induced in Group I and Group II by injection of taurocholate and trypsin into the common biliopancreatic duct. Group III underwent laparotomy with the manipulation (but not cannulation) of the pancreas and received saline injection. Group I rats received normal saline as a placebo, and Group II rats received SMT after surgery for 2 days. At 48 hours, blood was drawn for serum amylase determinations. Bacterial translocation to mesenteric lymph nodes and distant sites (pancreas, liver, and peritoneum) were examined. A point scoring system of histologic features was used to evaluate the severity of pancreatitis. RESULTS: Plasma amylase levels and pancreatic histologic score were significantly reduced in Group II rats given SMT compared with those in Group I rats given saline (p < 0.01, p < 0.05, respectively). All Group I rats had bacterial translocation to mesenteric lymph nodes compared with 7 of 12 rats in Group II (p < 0.05). There was no difference in bacterial translocation to distant organs between the two groups, although rates tended to be lower in Group II compared with Group I (p > 0.05). Bacterial counts in the pancreas were significantly reduced in Group II rats compared with those in Group I rats (p < 0.05). CONCLUSION: Treatment with SMT appears to have ameliorated the course of acute pancreatitis; however, mortality was not affected.

Acute Disease↗
PubMed2003

The role of inducible nitric oxide synthase inhibitor, meropenem, and taurine in experimental acute necrotizing pancreatitis.

INTRODUCTION: Translocation of bacteria from the gut is one of the most important factors in the development of septic complications and mortality in acute pancreatitis. AIMS: To investigate whether S-methylisothiourea (SMT), taurine (TAU), and meropenem (MER) could effect bacterial translocation and the course of acute necrotizing pancreatitis. METHODOLOGY: Seventy male Sprague-Dawley rats were studied. Rats were randomly allocated into seven groups. Acute pancreatitis was induced in group II (MER), group III (TAU), group IV (TAU + MER), group V (TAU + SMT), group VI (TAU + MER + SMT), and group VII (positive control) by retrograde injection of taurocholate into the common biliopancreatic duct. Group I rats (sham) received normal saline infusion into the common biliopancreatic duct as negative control. Rats were treated with drug combinations intraperitoneally for 48 hours after induction of pancreatitis. At the 48th hour of induction, all animals were killed, and specimens were collected. RESULTS: Bacterial translocation to peritoneum and pancreas in groups treated with MER were lower than in the other groups. Pancreatic tissue GSHpx and SOD levels were higher in all groups in comparison with levels in group VII. Pancreatic tissue MDA levels were also lower in all treatment groups except group II. The most favorable results were obtained in group VI (TAU + MER + SMT). Also, the lowest pathologic score between the groups in which acute pancreatitis developed was obtained in group VI. CONCLUSIONS: Addition of TAU and SMT to the treatment protocol for acute pancreatitis seems to improve the pathologic score and oxidative stress parameters. Also, antibiotherapy with MER decreases the risk of bacterial translocation.

Animals↗
PubMed1995

S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep.

S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.

Animals↗
PubMed1997

Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock.

Endotoxin and proinflammatory cytokines induce nitric oxide synthase (NOS), and nitric oxide (NO) plays an important role in promoting endotoxin shock. However, the role of NOS in endotoxemic cardiac contractile dysfunction is not defined. To determine whether endotoxemic cardiac contractile dysfunction involves NOS, the present study used a rat model of endotoxemia without shock and examined the effects of glucocorticoids (dexamethasone, a potent inhibitor of inducible NOS, iNOS, expression), isoform nonselective NOS inhibitor (NG-monomethyl-L-arginine, L-NMA) and iNOS selective inhibitor (S-methylisothiourea sulfate, SMT) on cardiac contractile dysfunction. A sublethal dose of endotoxin (from Salmonella typhimurium, .5 mg/kg, i.p.) was given to adult rats, and left ventricular developed pressure (LVDP) examined by Langendorff technique was attenuated in hearts isolated at 4 or 6 h (66.7 +/- 3.4 and 60.3 +/- 5.5 mmHg, respectively, p < .05 vs. 102 +/- 2.4 mmHg in saline control) after endotoxin treatment. Pretreatment of rats with dexamethasone (4.0 mg/kg, i.v., -30 min) partially abolished endotoxin-induced contractile dysfunction at 6 h (LVDP 87.6 +/- 6.8 mmHg, p < .05 vs. endotoxin alone at 6 h). However, pretreatment with L-NMA (30 mg/kg, i.v., -5 min) or SMT (5.0 mg/kg, i.v., -1 min) failed to prevent the contractile dysfunction. Moreover, infusion of L-NMA or SMT in vitro could not restore contractile function in hearts isolated at 6 h after endotoxin treatment. In contrast, inhibition of NOS with L-NMA or SMT in vitro further attenuated coronary flow in endotoxin-treated hearts. Thus, endotoxemic cardiac contractile dysfunction in this non-shock rat model may not involve NOS, and inhibition of NOS may deteriorate coronary perfusion in endotoxemic heart.

Animals↗
PubMed1998

Myocardial dysfunction in the septic rat heart: role of nitric oxide.

Previous studies have demonstrated that sepsis, endotoxin, and cytokine administration cause myocardial dysfunction. Nitric oxide has been implicated in this dysfunction, since in isolated cardiac tissues, dysfunction is prevented when nitric oxide synthase (NOS) inhibitors are present. To determine whether nitric oxide produced by the inducible form of the enzyme (iNOS) contributed to Escherichia coli sepsis-induced myocardial dysfunction, the effects of preventing the induction of the enzyme or inhibiting the activity of the enzyme were determined. Rats, made septic by the injection of E. coil into the dorsal subcutaneous space, demonstrated a decreased intrinsic contractile function when hearts were studied the next day. Perfusion of hearts in vitro with the iNOS inhibitor S-methylisothiourea did not reverse the sepsis-induced contractile dysfunction. However, treatment of animals with S-methylisothiourea or dexamethasone, a glucocorticoid that prevents the synthesis of the iNOS, at the time of induction of sepsis resulted in partial but not complete attenuation of myocardial contractile dysfunction induced by sepsis. Thus, nitric oxide contributed to myocardial dysfunction in an intact animal treated with E. coli but was not the sole factor involved.

Animals↗
PubMed1999

Changes in gut mucosal nitric oxide synthase (NOS) activity after thermal injury and its relation with barrier failure.

This study was designed to investigate changes in mucosal NOS activity after burns and its relation to barrier failure. In Experiment 1, female specific pathogen free (SPF) Sprague-Dawley rats underwent 35% total body surface area (TBSA) burn. One to six days after burn, intestinal permeability was determined from the plasma leakage of fluorescein isothiocyanate (FITC)-dextran 4400, intestinal mucosal cNOS and iNOS activity were assayed using Griess' reagent, and the cellular localization of iNOS was examined using immunostaining. In Experiment 2, S-methylisothiourea (SMT) was given (5 mg/kg, i.p. every 12 h) for 2 days to suppress inducible NOS (iNOS) activity after thermal injury. On postburn Day 2, the effect of SMT on gut mucosal NOS activity, intestinal permeability, and barrier function were evaluated. The activity of iNOS increased 24 h after the injury and up to a maximum of twofold on postburn Day 2, and decreased thereafter. The increase in iNOS activity in gut mucosa correlated well with the increase in intestinal permeability, an index for barrier failure (r = .776, p = .0002). Results from iNOS immunostaining showed that changes in mucosal iNOS activity after the burn occurred mainly in the enterocytes rather than in the macrophages. Administration of SMT decreased mucosal iNOS activity, intestinal permeability, and bacterial translocation incidence to mesenteric lymph node concurrently. In conclusion, thermal injury induces intestinal mucosal iNOS, which is principally in the enterocytes. The increased intestinal iNOS activity was closely related to barrier failure. SMT inhibited intestinal mucosal iNOS activity and prevented barrier failure as demonstrated by a decrease in BT occurrence and intestinal permeability.

Animals↗
PubMed1999

Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice.

Persistent vasodilation refractory to vasopressor agents is characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines within the vasculature is one of the primary mediators of this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure microvascular vasoconstrictive responses to topical suffusion of norepinephrine in mice made septic by cecal ligation and puncture, and contrasted the effects of topical superfusion of the nonselective NOS inhibitor N(G)-methyl-L-arginine (L-NMMA) and the selective inducible NOS (iNOS) inhibitor S-methyl-isothiourea (SMT). Mice with sepsis were less sensitive to the vasoconstrictive effects of norepinephrine than controls (EC50, the concentration that produces half-maximal response 2.0+/-0.6 x 10(-6) M vs. 7.9+/-2.2 x 10(-8) M, P=0.01). Selective inhibition of inducible iNOS with topical SMT (100 microM) markedly increased catecholamine reactivity in mice with sepsis but did not affect reactivity in controls (P=0.0007 for sepsis, P=0.24 for controls). Nonselective NOS inhibition with topical L-NMMA produced a similar increase in catecholamine reactivity in mice with sepsis but not controls (P=0.001 for sepsis, P=0.56 for controls). When excess (1 mM) L-arginine, the substrate for NOS, was added to the superfusion buffer along with both SMT and L-NMMA, arteriolar responsiveness to norepinephrine was decreased to the original values. These experiments demonstrate that iNOS inhibition is as effective as nonselective NOS inhibition in reversing decreased catecholamine reactivity in sepsis. This suggests a crucial role for microvascular activation of iNOS in the pathophysiology of hypotension and decreased vasopressor responsiveness in sepsis.

Animals↗
PubMed2000

Nitric oxide synthase inhibitor ameliorates oral total parenteral nutrition-induced barrier dysfunction.

The expression of inducible nitric oxide synthase (iNOS) is increased in the intestine and results in mucosal damage after endotoxin challenge. Although the oral administration of total parenteral nutrition (TPN) solution promotes bacterial translocation (BT) and increases the intestinal permeability, the role of NO in the nutrition-induced loss of mucosal barrier function remains unclear. The distribution of fluorescein isothiocyanate-dextran (FITC-dextran, 4400) across the lumen of small intestine in rat was examined to investigate the role of NOS activity on the intestinal permeability under oral TPN feeding. Fifty-one rats were randomly divided into 4 groups. Group I (control group) was fed with rat chow, group II received TPN solution orally. Groups III and IV received TPN solution supplemented with NOS inhibitors. On day 9, FITC-dextran was injected into the intestinal lumen. After 30 min, blood samples were taken from portal vein and analyzed for plasma FITC-dextran level by fluorescence spectrophotometry. Samples of small intestine were frozen and sectioned in a cryostat for morphological and NOS histochemical studies. Homogenates of small intestine were used for NOS activity measurement. The plasma level of FITC-dextran showed a significant increase (P < 0.05) in rats fed with oral TPN compared with the control ones. Supplement with NOS inhibitors significantly decreased the intestinal permeability in groups III and IV compared with group II. Similarly, the total NOS activities showed a significant 2-fold increase (P< 0.05) in group II, and NOS inhibitors decreased the elevated NOS activity. These data suggest that oral TPN feeding for 9 days leads to an increase in permeability to dextran and the total NOS activity of small intestine, and both induction of the intestinal permeability and NOS activity were inhibited by treatment with NOS inhibitors. Addition of S-methylisothiourea (SMT), an iNOS selective inhibitor, profoundly inhibited 66% of the induced iNOS activity (P < 0.05) and reduced 74% of the diet-induced increase in intestinal permeability (P < 0.05) in group II. The induced permeability change in rats receiving oral TPN is mainly due to the activity of intestinal mucosal iNOS. The induction of iNOS is an important mediator for intestinal barrier dysfunction. Administration of SMT, which specifically decreases iNOS activity, is useful in the prevention of diet-induced barrier failure.

Administration, Oral↗
PubMed2001

Inhibition of inducible nitric oxide synthase (iNOS) prevents lung neutrophil deposition and damage in burned rats.

This study was designed to investigate the role of NO and effect of iNOS inhibitor on the lung neutrophil deposition and damage after burn. In Experiment 1, specific pathogen-free (SPF) Sprague-Dawley rats underwent 35% total body surface area (TBSA) burn. On the 4th, 8th, 16th, and 24th h after burn, blood was collected for peroxynitrite-mediated dihydrorhodamine 123 (DHR 123) oxidation assay, and lung tissues were harvested for myeloperoxidase (MPO) test and histologic study. Pulmonary microvascular dysfunction was quantitated by measuring the extravasation of Evans blue dye (EBD). In Experiment 2, S-methylisothiourea (SMT) was given (7.5 mg/kg, intraperitoneal immediately post-burn) to suppress iNOS activity. On the 8th h after burn, the effect of SMT on blood DHR 123 oxidation, lung MPO, lung damage, and lung iNOS expression were evaluated. Lung MPO activity increased up to a maximum of 2-fold 8 h after burn. Blood DHR 123 oxidation increased up to a maximum of 2-fold 8 h after burn. Lung permeability increased up to a maximum of 2.5-fold 4 h after burn. SMT significantly decreased lung MPO activity, blood DHR 123 oxidation, and lung permeability by 31%, 41%, and 54%, respectively. SMT markedly decreased the thermal injury-induced perivascular and interstitial inflammatory cell infiltration and iNOS staining in bronchiolar epithelium, endothelial cells, and perivascular and interstitial inflammatory cells. In conclusion, thermal injury induces blood DHR 123 oxidation, lung neutrophil deposition, lung iNOS expression, and lung damage. Peroxynitrite might play an important role in thermal injury-induced lung neutrophil deposition and damage. Specific inhibition of lung iNOS expression and blood DHR 123 oxidation with SMT on thermal injury not only attenuated the lung neutrophil deposition, but also reduced lung damage.

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