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INFLAMMATION AND IMMUNOPHARMACOLOGY
Departments of Pharmacology (M.D.L., D.M., M.E., F.S., J.B.), Biochemistry (R.B., A.S., C.H.), and Chemistry (W.-R.U.), ALTANA Pharma AG, Konstanz, Germany; and Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany (R.T.S.)
Received for publication
November 15, 2005
Accepted
December 15, 2005.
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Abstract |
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). In contrast, the inducible NOS (iNOS) isoform is transcriptionally regulated and, once induced by pro-inflammatory stimuli, generates micromolar range quantities of nitric oxide (Stuehr et al., 1991). Although iNOS induction plays a beneficial role in host defense against invading pathogens, uncontrolled release of excessive amounts of nitric oxide from iNOS is postulated to contribute to pathophysiology in a number of acute and chronic inflammatory and autoimmune diseases (Cuzzocrea et al., 2002; Razavi et al., 2004).
Hyperdynamic septic shock is characterized by pathological vasodilatation and reduction of vascular resistance, eventually leading to an uncompensated fall in blood pressure and inadequate organ perfusion. Infusion of catecholamine vasoconstrictors is usually employed to stabilize blood pressure in hyperdynamic septic shock states refractory to volume administration (Beale et al., 2004). Hyporesponsiveness of the large resistance vessels to vasopressor administration is observed in a number of septic patients with hypotension despite sufficient volume substitution (Groeneveld et al., 1986). Consequently, with the aim to maintain adequate systemic blood pressure, either high-dose infusion of vasoconstrictors at the cost of excessive peripheral vasoconstriction and increased oxygen debt or experimental rescue drugs such as vasopressin or methylene blue have to be administered (Tsuneyoshi et al., 2001; Stanchina and Levy, 2004).
It has been postulated that excessive release of nitric oxide from iNOS is causally implicated in detrimental vasodilatation and the loss of vascular responsiveness to vasopressor therapy in septic shock (Tsuneyoshi et al., 1996). Animal models of systemic inflammation mimic certain aspects of human septic shock such as volume-resistant hypotension and vascular hyporesponsiveness to vasopressor agents.
Several authors demonstrated the efficacy of different NOS inhibitors to restore normal blood pressure in animal models of lipopolysaccharide-induced hypotension (Ruetten et al., 1996; Rosselet et al., 1998; Ichinose et al., 2003). In addition, inhibition of nitric oxide release proved effective to counteract vascular hyporesponsiveness and vasopressor resistance associated with systemic inflammation in vivo (Gray et al., 1991; Cai et al., 1996) or in isolated vessels in vitro (Hollenberg et al., 1993; Tsuneyoshi et al., 1996), supporting the concept that inhibition of iNOS could represent an interesting therapeutic target in septic shock. However, the overall effect of iNOS inhibition on morbidity and mortality of septic animals remains controversial, depending on the animal model and the selectivity profile of the employed inhibitor. Although inhibitors with a preferential inhibition of the inducible NOS isoform yielded beneficial effects on organ dysfunction or survival (Wu et al., 1995; Liaudet et al., 1998; Rosselet et al., 1998; Schwartz et al., 2001), administration of nonselective NOS inhibitors was associated with unfavorable outcome in several studies of endotoxic shock (Liaudet et al., 1998; Cohen et al., 2000; Schwartz et al., 2001). The hypothesis that nonselective NOS inhibition bears the risk of enhancing inflammation-induced organ dysfunction was confirmed by the unfavorable outcome of a clinical phase III trial on the efficacy of NG-monomethyl-L-arginine (L-NMMA) in septic shock. Although the actual mechanism underlying the overall adverse effect of L-NMMA remains unknown (Lopez et al., 2004), excessive vasoconstriction of pulmonary or microcirculatory vessels secondary to coinhibition of physiological nitric oxide release from eNOS could have exerted deleterious effects on organ oxygen supply and cardiovascular function in L-NMMA-treated patients (Dellinger and Parrillo, 2004). Therefore, high iNOS selectivity and lack of interference with physiological nitric oxide release from e/nNOS is considered highly desirable for any future drug targeting nitric oxide production in septic patients (Cobb, 2001; Dellinger and Parrillo, 2004).
We recently identified imidazopyridine derivatives as a novel class of iNOS inhibitors with potent enzymatic and cellular activity. BYK191023, a member of this novel iNOS inhibitor class, displays L-arginine-competitive inhibition of NOS activity with pIC50 values of 7.07 (iNOS), 4.79 (nNOS), and 3.81 (eNOS), respectively, thus reflecting excellent inducible isoform selectivity (Strub et al., 2005). In the present study, we assessed the in vivo inhibitory potency of BYK191023 on iNOS activity in lipopolysaccharide-challenged rats. In addition, we tested the therapeutic effect of selective iNOS inhibition by BYK191023 on lipopolysaccharide-induced vascular hyporesponsiveness and systemic hypotension, two aspects of septic shock frequently ascribed to excessive nitric oxide release from iNOS. Our results underpin the value of BYK191023 as a selective pharmacological tool and as a potential novel therapeutic agent in septic shock.
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Materials and Methods |
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Inhibition of iNOS Activity in Lipopolysaccharide-Challenged Rats as Assessed by Determination of Plasma NOx Levels. For all experiments, BYK191023 was dissolved in 0.9% NaCl with 2.5% of polyethylene glycol 400 under acidification to pH 2 to 3 with 1 N HCl. Lower concentrations were prepared from the stock solution (50 mM) by dilution in 0.9% NaCl.
Rats received an i.v. injection of 0.5 mg/kg lipopolysaccharide in 1 ml/kg dissolved in 0.9% NaCl + 0.1% hydroxylamine via the tail vein. After 30 min, the animals were anesthetized by i.p. injection of thiopental (Trapanal; ALTANA Pharma AG; 56 mg/kg) followed by i.m. injection of 60 mg/kg ketamine (Ketavet; Pharmacia and Upjohn, Erlangen, Germany). Anesthetized animals were tracheostomized to facilitate spontaneous breathing, and PE catheters were inserted into the left arteria carotis and the right internal vena jugularis. Body temperature was maintained constant at 37°C. NaCl (0.9%; 5 ml/kg/h) was infused via the venous catheter until 180 min after lipopolysaccharide injection. At 180 min, an arterial blood sample of 0.5 ml was drawn for the determination of nitrite/nitrate (NOx) levels, which were determined using the Griess assay. Immediately thereafter, BYK191023 or vehicle was injected i.v. The loading dose of 3/10/30 µmol/kg BYK191023 was administered as a bolus followed by continuous infusion of 3/10/30 µmol/kg/h in a volume of 1.0 and 5.0 ml/kg/h, respectively. At 270 and 360 min after lipopolysaccharide challenge (i.e., 90 and 180 min after start of treatment), additional blood samples were drawn for NOx determination. The inhibition of NOx increase from 180 to 360 min by BYK191023 was calculated individually for each animal [1 – (
NOx (treated animal)/mean NOx (lipopolysaccharide/vehicle))] and expressed as percentage mean inhibition for each treatment group.
Prevention of Lipopolysaccharide-Induced Late Hypotension in Rats. Rats were anesthetized and instrumented as described before. In addition, a laparotomy was performed, and the bladder was catheterized for collection of urine. Animals were mechanically ventilated with ambient air (VSM Ventilation Sequencer Module Type 698; Hugo Sachs Elektronik, March-Hugstetten, Germany) at a frequency of 70 min–1 and an inspiration cycle of 20%. Tidal volume was adjusted individually to yield a PCO2 of approximately 40 mm Hg (ABL 700; Radiometer, Willich, Germany). Blood pressure and heart rate were recorded continuously with a pressure transducer coupled to the arterial catheter. Automatic calculation of heart rate and mean arterial pressure (MAP) was done with the program NOTOCORD-Hem (NOTOCORD, Croissy sur Seine, France). After a 20-min equilibration phase, lipopolysaccharide was infused via the venous catheter at a dose of 16 mg/kg/h for 1 h (2 ml/kg/h) followed by infusion of 0.9% NaCl (5 ml/kg/h) for 2 h. Nonendotoxemic control animals received physiological saline instead of lipopolysaccharide. At 180 min after start of lipopolysaccharide infusion, an arterial blood sample of 0.5 ml was drawn for determination of NOx plasma levels, and animals were randomized to treatment. BYK191023 or vehicle was injected as an i.v. loading dose (50 µmol/kg in 1 ml/kg) followed by continuous i.v. infusion (50 µmol/kg/h in 5 ml/kg/h) for 3 h until 360 min.
Determination of Vascular Responsiveness in Lipopolysaccharide-Challenged Rats. Conscious rats were injected i.v. with lipopolysaccharide (2 mg/kg in 1 ml/kg) via the tail vein. After anesthesia (thiopental and ketamine, as described before), a tracheotomy was performed, catheters were inserted into the arteria carotis, the vena jugularis, and the vena femoralis, and 0.9% NaCl was administered as a continuous infusion simultaneously via both venous catheters (2.5 ml/kg/h per catheter, i.e., 5 ml/kg/h total infusion volume) until t = 180 min. At t = 180 min, animals received a bolus injection of either test compound or vehicle (1 ml/kg), followed by continuous infusion of test compound or vehicle (2.5 ml/kg/h) via the vena jugularis (BYK191023 or vehicle) and via the vena femoralis (L-arginine or vehicle). From 330 to 380 min, pressor responses to subsequent i.v. bolus injections of increasing doses of norepinephrine (0.3, 1, and 3 nmol/kg in 1 ml/kg) and sodium nitroprusside (3, 10, and 30 nmol/kg in 1 ml/kg) were recorded. MAP was averaged for 1-min intervals, and maximum change versus baseline within 10 min was calculated. Details on the treatment groups are depicted in Table 1.
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Determination of Plasma Nitrite/Nitrate Levels. Nitrite/nitrate levels in plasma were determined with the Griess assay. In brief, immediately after arterial blood sampling, the samples were centrifuged (6000g, 4°C) for 10 min, and the resulting supernatant was diluted 1:5 in deionized water and transferred to microfilter cups (Ultrafree-MC Centrifugal Filter Units, 10 kDa; Millipore GmbH, Schwalbach, Germany). After further centrifugation of the microfilter cups for 60 min to get rid of hemoglobin, the NOx concentration of the resulting filtrate solution was determined with a commercially available Griess assay test kit (Total Nitric Oxide Assay Kit; Assay Designs, Ann Arbor, MI) according to the manufacturer's instructions.
Statistics. Data are presented as means ± S.E.M. Statistical differences were determined by Tukey's Multiple Comparison test or by Bonferroni Multiple Comparison test of selected groups after one-way or two-way ANOVA, as indicated. In case of unequal variances (Bartlett's test, p < 0.05), data were log transformed before analysis. If log transformation failed to equalize variances, the Kruskal-Wallis test, followed by Dunn's test was used. A value of p < 0.05 was considered significant. All tests were performed with Prism, version 4.03 for Windows (GraphPad Software, Inc., San Diego, CA).
Materials. BYK191023 was synthesized at ALTANA Pharma. Lipopolysaccharide (Salmonella typhosa), (–)-norepinephrine bitartrate salt hydrate, L-arginine hydrochloride, sodium nitroprusside dehydrate, and hydroxylamine hydrochloride were purchased from Sigma (Deisenhofen, Germany), polyethylene glycol 400 was from Serva (Heidelberg, Germany), Ketavet was obtained from Pharmacia and Upjohn, 0.9% NaCl was supplied by B. Braun (Melsungen, Germany), and Trapanal was from ALTANA Pharma.
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Results |
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0.5 h).
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Determination of plasma NOx values from samples drawn at 180 and 360 min demonstrated an 83% inhibition of NOx increase in BYK191023-treated animals compared with the lipopolysaccharide/vehicle group (p < 0.01). In line with our previous data, no increase in basal NOx levels (28 ± 14 µMat 180 min versus 25 ± 10 µM at 360 min) was found in saline-treated control animals.
Effect of BYK191023 on Blood Pressure of Nonendotoxemic Anesthetized Rats. To exclude the possibility that despite the high in vitro selectivity of BYK191023 for iNOS versus eNOS/nNOS (Strub et al., 2005), the observed stabilization of MAP in endotoxemic rats was due to inhibition of constitutively expressed NOS, we investigated the effect of BYK191023 on MAP in saline-treated animals. As depicted in Fig. 3, blood pressure in nonseptic, saline-challenged animals treated with BYK191023 did not differ from that in vehicle-treated controls, arguing against any iNOS-independent vasopressor activity of BYK191023.
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To assess whether vascular hyporesponsiveness in lipopolysaccharide-challenged animals was limited to suppression of vasopressor responses to 
-adrenergic receptor stimulation or rather represented a general stimulus-independent phenomenon, we subjected the animals to additional injections of the endothelium-independent vasodilator sodium nitroprusside. In line with impaired norepinephrine pressor responses, endotoxemic rats displayed a significantly diminished depressor response compared with control rats after repeated stimulation with increasing doses of sodium nitroprusside (Fig. 4B). Treatment with BYK191023 partially reversed vascular sodium nitroprusside hyporesponsiveness by 33 ± 32% (3 nmol/kg sodium nitroprusside dose), 49 ± 22% (10 nmol/kg), and 41 ± 20% (30 nmol/kg), respectively.
To substantiate the view that the beneficial effects of BYK191023 were mediated via inhibition of nitric oxide release from iNOS, we included a treatment group that in addition to BYK191023 (50 µmol/kg + 50 µmol/kg/h) received a 10-fold excess of the NOS substrate L-arginine (500 µmol/kg + 500 µmol/kg/h). Since BYK191023 has been shown to be an L-arginine-competitive inhibitor of iNOS (Strub et al., 2005), coinfusion of excess L-arginine should counteract the inhibitory effect of BYK191023 on NO production and thus reverse its beneficial effects on vascular hyporesponsiveness. Reversal of BYK191023-mediated iNOS inhibition by excess L-arginine was verified by measuring the increase in plasma NOx levels after treatment (Fig. 5). Although coinfusion of BYK191023 with vehicle yielded a 91 ± 7% inhibition of the lipopolysaccharide-induced NOx increase, the extent of NOx inhibition was significantly reduced (56 ± 14%; p < 0.05) in animals receiving an additional infusion of L-arginine, indicating a significant albeit only partial reversal of BYK191023 mediated iNOS inhibition. Concerning vascular responsiveness, coinfusion of L-arginine completely abrogated the beneficial effects of BYK191023 on vasopressor responses to norepinephrine, whereas the restoration of sodium nitroprusside responsiveness conferred by iNOS inhibition was only partially reversed (Fig. 4, A and B).
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Discussion |
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; Cuzzocrea et al., 2001, 2002; Ichinose et al., 2003; Matejovic et al., 2004). During severe sepsis, uncontrolled excess synthesis and release of nitric oxide by iNOS are considered a potential contributor to pathological vasodilatation, eventually leading to severe hypotension with insufficient organ perfusion and consequently multiorgan failure (Titheradge, 1999; Cobb, 2001). Although clinical trials with the nonspecific NOS inhibitor L-NMMA in patients with septic shock yielded unfavorable results (Bakker et al., 2004; Lopez et al., 2004), inhibition of iNOS-derived nitric oxide by selective drugs is still considered an interesting target for novel therapeutic agents in septic shock (Ichinose et al., 2003).
In the present study, we characterized the in vivo effects of BYK191023, a novel and potent iNOS inhibitor with an excellent isoform selectivity profile versus eNOS (>1000-fold) and nNOS (200-fold) (Strub et al., 2005), on delayed hypotension and vascular hyporesponsiveness conferred by systemic lipopolysaccharide administration to rats. Injection of lipopolysaccharide is commonly employed to induce iNOS in animal models, resulting in massive synthesis and release of NO, which can indirectly be measured by determination of plasma NOx levels (Tracey et al., 1995). The substantial increase in plasma NOx upon lipopolysaccharide challenge is considered to be due to induction of iNOS since no changes in plasma NOx levels were observed in lipopolysaccharide-challenged iNOS gene-deficient mice (Laubach et al., 1995; MacMicking et al., 1995). In the curative treatment setting employed in our studies, i.e., start of treatment at 3 h after lipopolysaccharide, infusion of BYK191023 dose-dependently attenuated the increase in plasma NOx levels associated with lipopolysaccharide challenge with an ED50 of 14.9 µmol/kg/h (Fig. 1), demonstrating that in contrast to inhibitors of iNOS induction or iNOS dimerization (Ichinose et al., 2003), BYK191023 acts via inhibition of already induced and active iNOS. This conclusion is supported by our experiments on reversal of NOx inhibition by additional L-arginine substitution (Fig. 5) as well as by data from in vitro studies demonstrating arginine-competitive inhibition of iNOS activity rather than interference with iNOS expression or iNOS dimerization (Strub et al., 2005). The in vivo potency of BYK191023 was comparable with that of L-NMMA (ED50 = 11.1 µmol/kg/h) but lower than that of 1400W (ED50 = 2.3 µmol/kg/h) under our model-specific conditions, reflecting the relatively high clearance of BYK191023 in the rat. We then studied whether reduction of plasma NOx levels by BYK191023 treatment translated into a more clinically relevant parameter, i.e., prevention of lipopolysaccharide-induced hypotension. High-dose lipopolysaccharide infusion resulted in an early biphasic fall in MAP within the 1st h, followed by gradual normalization of MAP values by 2 to 3 h after start of lipopolysaccharide infusion and a steady decrease in MAP from 3 to 6 h. Continuous administration of BYK191023 starting at 3 h after lipopolysaccharide challenge completely prevented the development of systemic hypotension observed in the vehicle-treated endotoxemic animals and maintained MAP at levels indistinguishable from those of saline-challenged controls. These data are in line with a number of studies demonstrating prevention of hypotension or restoration of normal blood pressure in lipopolysaccharide-challenged animals by pharmacological interference with nitric oxide production. However, many studies employed either non- or poorly iNOS-selective NOS inhibitors such as NG-nitro-L-arginine methyl ester (Filep et al., 1997; Strunk et al., 2001), L-NMMA (Gray et al., 1991; Zhang et al., 1997), N6-(1-iminoethyl)-L-lysine (L-NIL) (Schwartz et al., 2001; Strunk et al., 2001), or aminoguanidine (Wu et al., 1995; Ruetten et al., 1996), the latter exhibiting additional activities apart from NOS inhibition (Picard et al., 1992). Consequently, it has been difficult to depict whether the reported antihypotensive effects stemmed from reversal of pathological iNOS-mediated vasodilatation or were merely secondary to vasoconstriction via interference with physiological eNOS activity. To verify that the observed counteraction of lipopolysaccharide-induced hypotension was indeed due to iNOS inhibition and not mediated via coinhibition of constitutive NOS activity, the effect of BYK191023 on systemic blood pressure in saline-challenged rats was studied. In contrast to similar experiments with the nonselective compound L-NMMA (data not shown), administration of BYK191023 at a dose that prevented hypotension in lipopolysaccharide-challenged rats did not exert any MAP increase in nonendotoxemic control animals, arguing against a major involvement of constitutive NOS inhibition in the observed beneficial effects in endotoxemic animals (Fig. 3). These results confirm data from infusion studies with the selective iNOS inhibitors 1400W (Wray et al., 1998; Cheng et al., 2003) and GW273629 (Alderton et al., 2005) and corroborate the view that excessive NO production by iNOS is a major mechanism underlying the development of hypotension in the course of systemic inflammation. According to our data, selective inhibition of iNOS by BYK191023 without interfering with constitutively expressed e/nNOS activity should be sufficient for the desired therapeutic effect on macrocirculation.
In studies with volunteers as well as in animal models of systemic inflammation, challenge with lipopolysaccharide or immune stimuli from Gram-positive bacteria rapidly confers vascular hyporesponsiveness to exogenous catecholamine therapy (Ruetten et al., 1996; Pleiner et al., 2003). Clinically, desensitization of the large resistance vessels to vasoconstrictor administration is a critical event associated with an increased risk of morbidity in septic shock patients depending on exogenous catecholamine therapy for maintaining an adequate blood pressure level.
We were interested whether selective iNOS inhibition by BYK191023 at a dose that effectively abolished lipopolysaccharide-induced delayed hypotension also reversed vascular hyporesponsiveness, as reported for several less selective iNOS inhibitors (Gray et al., 1991; Wu et al., 1995; Cai et al., 1996). In our studies, pressor responses to norepinephrine were severely compromised in endotoxemic animals compared with saline-treated controls when tested at 5 to 6 h after challenge. In addition, lipopolysaccharide-challenged animals displayed a significantly impaired blood pressure response to injection of the endothelium independent vasodilator sodium nitroprusside, indicating lipopolysaccharide-induced stimulus-independent vasoplegia rather than a selective desensitization to adrenergic agonists. Administration of BYK191023 at 3 h after lipopolysaccharide challenge improved the compromised pressor and depressor responses of lipopolysaccharide-challenged animals to stimulation with norepinephrine and sodium nitroprusside, respectively. This partial restoration of normal responsiveness was due to competitive inhibition of the L-arginine/nitric oxide pathway and not related to other unidentified effects of BYK191023 since coadministration of a 10-fold excess of the substrate L-arginine largely reversed the beneficial effects of BYK191023 treatment. The improvement of depressor responses to sodium nitroprusside was less efficiently reversed by L-arginine coadministration than the positive effect of BYK191023 therapy on pressor responses to norepinephrine (Fig. 4, B and A), providing evidence for a higher susceptibility to iNOS-mediated desensitization of -adrenergic vasoconstriction compared with soluble guanylate cyclase-dependent vasodilation. Treatment with BYK191023 only partially restored normal vascular responsiveness to norepinephrine and sodium nitroprusside despite nearly complete suppression of plasma NOx levels, suggesting additional pathways of vascular desensitization inaccessible to iNOS inhibitor therapy. However, we employed a curative administration schedule, where iNOS inhibition therapy was initiated at a time when plasma NOx levels were already significantly increased. Since it has been demonstrated that the induction, but not necessarily the maintenance of lipopolysaccharide-induced long-term vasoplegia, depended on NOS activity (Silva-Santos et al., 2002), it seems feasible that in our model, the therapeutic treatment phase of 2 to 3 h prior to determination of the vascular responsiveness was too short to allow recovery of already-desensitized vessels, and the beneficial effect of BYK191023 merely reflected prevention of further vascular damage. Thus, a prolongation of BYK191023 therapy could result in a more pronounced restoration of vascular responsiveness compared with the acute reversal of hyporesponsiveness observed in our current experimental setting.
The actual mechanism responsible for the prevention or reversal of inflammation-induced hypotension by selective iNOS inhibition has not been definitely identified yet. Based on our data, it seems reasonable to propose that inhibition of excess NO release from iNOS by BYK191023 normalized vascular tone and blood pressure in endotoxic shock either directly via counteraction of the NO-mediated pathological vasodilatation or indirectly by restoring vascular responsiveness to endogenous vasoconstrictors.
Although future studies in large animal models of sepsis as well as in septic shock patients are warranted to demonstrate whether normalization of vascular resistance by selective iNOS inhibition beneficially affects morbidity and mortality, reversal of pathologic hypotension by BYK191023 in the present rodent endotoxin model holds promise for a potential clinical benefit of this novel class of short-acting and highly selective iNOS inhibitors.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: NOS, nitric-oxide synthase; eNOS, endothelial NOS; nNOS, neuronal NOS; iNOS, inducible NOS; L-NMMA, NG-monomethyl-L-arginine; NOx, nitrate/nitrite; BYK191023, 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine; MAP, mean arterial pressure; ANOVA, analysis of variance; 1400W, N-(3-(amino methyl)benzyl)acetamidine; GW273629, 3-[[2-[(1-iminoethyl)amino]ethyl]sulfonyl]-L-alanine.
Address correspondence to: Dr. Martin D. Lehner, ALTANA Pharma AG, Byk-Gulden-Strasse 2, 78467 Konstanz, Germany. E-mail: martin.lehner{at}altanapharma.com.
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Alderton WK, Angell AD, Craig C, Dawson J, Garvey E, Moncada S, Monkhouse J, Rees D, Russell LJ, Russell RJ, et al. (2005) GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo. Br J Pharmacol 145: 301–312.[CrossRef][Medline]
Alderton WK, Cooper CE, and Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357: 593–615.[CrossRef][Medline]
Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, Watson D, Grossman S, Donaldson J, and Takala J (2004) Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med 32: 1–12.[CrossRef][Medline]
Beale RJ, Hollenberg SM, Vincent JL, and Parrillo JE (2004) Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 32: S455–S465.[CrossRef][Medline]
Cai M, Sakamoto A, and Ogawa R (1996) Inhibition of nitric oxide formation with L-canavanine attenuates endotoxin-induced vascular hyporeactivity in the rat. Eur J Pharmacol 295: 215–220.[CrossRef][Medline]
Cheng X, Leung SW, Lo LS, and Pang CC (2003) Selective versus non-selective suppression of nitric oxide synthase on regional hemodynamics in rats with or without lipopolysaccharide-induced endotoxemia. Naunyn-Schmiedeberg's Arch Pharmacol 367: 372–379.[CrossRef][Medline]
Cobb JP (2001) Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise. Surg Infect (Larchmt) 2: 93–100.[Medline]
Cohen RI, Shapir Y, Davis A, Loona R, and Scharf SM (2000) Comparison between selective and nonselective nitric oxide synthase inhibition and phenylephrine in normal and endotoxic swine. Crit Care Med 28: 3257–3267.[CrossRef][Medline]
Cuzzocrea S, Chatterjee PK, Mazzon E, McDonald MC, Dugo L, Di P, Serraino I, Britti D, Caputi AP, and Thiemermann C (2002) Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis. Eur J Pharmacol 453: 119–129.[CrossRef][Medline]
Cuzzocrea S, Mazzon E, Dugo L, Barbera A, Centorrino T, Ciccolo A, Fonti MT, and Caputi AP (2001) Inducible nitric oxide synthase knockout mice exhibit resistance to the multiple organ failure induced by zymosan. Shock 16: 51–58.[Medline]
Dellinger RP and Parrillo JE (2004) Mediator modulation therapy of severe sepsis and septic shock: does it work? Crit Care Med 32: 282–286.[CrossRef][Medline]
Filep JG, Delalandre A, and Beauchamp M (1997) Dual role for nitric oxide in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats. Circ Res 81: 840–847.
Gray GA, Schott C, Julou-Schaeffer G, Fleming I, Parratt JR, and Stoclet JC (1991) The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. Br J Pharmacol 103: 1218–1224.[Medline]
Groeneveld AB, Bronsveld W, and Thijs LG (1986) Hemodynamic determinants of mortality in human septic shock. Surgery 99: 140–153.[Medline]
Hollenberg SM, Cunnion RE, and Zimmerberg J (1993) Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. Am J Physiol 264: H660–H663.[Medline]
Ichinose F, Hataishi R, Wu JC, Kawai N, Rodrigues AC, Mallari C, Post JM, Parkinson JF, Picard MH, Bloch KD, et al. (2003) A selective inducible NOS dimerization inhibitor prevents systemic, cardiac and pulmonary hemodynamic dysfunction in endotoxemic mice. Am J Physiol 285: H2524–H2530.
Laubach VE, Shesely EG, Smithies O, and Sherman PA (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 92: 10688–10692.
Liaudet L, Rosselet A, Schaller MD, Markert M, Perret C, and Feihl F (1998) Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock. J Infect Dis 177: 127–132.[Medline]
Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, et al. (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32: 21–30.[CrossRef][Medline]
MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, and Hutchinson N (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641–650.[CrossRef][Medline]
Matejovic M, Krouzecky A, Martinkova V, Rokyta R Jr, Kralova H, Treska V, Radermacher P, and Novak I (2004) Selective inducible nitric oxide synthase inhibition during long-term hyperdynamic porcine bacteremia. Shock 21: 458–465.[CrossRef][Medline]
Picard S, Parthasarathy S, Fruebis J, and Witztum JL (1992) Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors. Proc Natl Acad Sci USA 89: 6876–6880.
Pleiner J, Mittermayer F, Schaller G, Marsik C, Macallister RJ, and Wolzt M (2003) Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress. J Am Coll Cardiol 42: 1656–1662.
Razavi HM, Wang lF, Weicker S, Rohan M, Law C, McCormack DG, and Mehta S (2004) Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase. Am J Respir Crit Care Med 170: 227–233.
Rosselet A, Feihl F, Markert M, Gnaegi A, Perret C, and Liaudet L (1998) Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care Med 157: 162–170.[Medline]
Ruetten H, Southan GJ, Abate A, and Thiemermann C (1996) Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br J Pharmacol 118: 261–270.[Medline]
Schwartz D, Brasowski E, Raskin Y, Schwartz IF, Wolman Y, Blum M, Blantz RC, and Iaina A (2001) The outcome of non-selective vs selective nitric oxide synthase inhibition in lipopolysaccharide treated rats. J Nephrol 14: 110–114.[Medline]
Silva-Santos JE, Terluk MR, and Assreuy J (2002) Differential involvement of guanylate cyclase and potassium channels in nitric oxide-induced hyporesponsiveness to phenylephrine in endotoxemic rats. Shock 17: 70–76.[CrossRef][Medline]
Stanchina ML and Levy MM (2004) Vasoactive drug use in septic shock. Semin Respir Crit Care Med 25: 673–681.[CrossRef][Medline]
Strub A, Ulrich WR, Hesslinger C, Eltze M, Fuchss T, Strassner J, Strand S, Lehner M, and Boer R (2006) The novel imidazopyridine BYK191023 is a highly selective inhibitor of the inducible nitric-oxide synthase. Mol Pharmacol 69: 328–337
Strunk V, Hahnenkamp K, Schneuing M, Fischer LG, and Rich GF (2001) Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 92: 681–687.
Stuehr DJ, Cho HJ, Kwon NS, Weise MF, and Nathan CF (1991) Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci USA 88: 7773–7777.
Titheradge MA (1999) Nitric oxide in septic shock. Biochim Biophys Acta 1411: 437–455.[Medline]
Tracey WR, Tse J, and Carter G (1995) Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric-oxide synthase inhibitors. J Pharmacol Exp Ther 272: 1011–1015.
Tsuneyoshi I, Kanmura Y, and Yoshimura N (1996) Nitric oxide as a mediator of reduced arterial responsiveness in septic patients. Crit Care Med 24: 1083–1086.[CrossRef][Medline]
Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, and Boyle WA 3rd (2001) Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 29: 487–493.[CrossRef][Medline]
Wray GM, Millar CG, Hinds CJ, and Thiemermann C (1998) Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin. Shock 9: 329–335.[Medline]
Wu CC, Chen SJ, Szabo C, Thiemermann C, and Vane JR (1995) Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 114: 1666–1672.[Medline]
Zhang H, Rogiers P, Smail N, Cabral A, Preiser JC, Peny MO, and Vincent JL (1997) Effects of nitric oxide on blood flow distribution and O2 extraction capabilities during endotoxic shock. J Appl Physiol 83: 1164–1173.
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