S-Substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage

Jang, Daniel; Szabó, Csaba; Murrell, George A. C.

doi:10.1016/0014-2999(96)00369-x

Cited by 25 publications

(12 citation statements)

References 18 publications

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“…In organ culture systems, NOS inhibitors were able to reduce significantly the stimulatory effect of IL‐1β on nitrite production only at the high concentration (1000 μM), with some exception for aminogua‐nidine in femoral head caps and L ‐NAME on both samples. These results confirm the weak inhibitory potency of L ‐NAME on inducible NOS isoform (Stefanovic‐Racic et al , 1995; Jang et al , 1996) and the need for a high concentration of aminoguanidine to obtain some correcting effect against IL‐1 (Jarvinen et al , 1995; Blanco et al , 1995; Murrell et al , 1996). L ‐NMMA inhibited nitrite production in both cartilage samples, as recently reported for cytokine‐stimulated chondrocytes (Stefanovic‐Racic et al , 1995; Jang et al , 1996).…”

Section: Discussionsupporting

confidence: 63%

“…The five NOS inhibitors were used in the concentration range of 1 to 1000 μM. These products have shown different inhibitory profile towards NOS in various biological systems: N ω ‐monomethyl‐ L ‐arginine ( L ‐NMMA) and N ω ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME), known to be active on constitutive and inducible NOS (Rees et al , 1990); aminoguanidine (AG), known to be more active on inducible NOS than on constitutive form; S‐methylisothiourea (SMT), known to be selective of inducible NOS in cultured macrophages (Southan et al , 1995) and S‐aminoethyl‐isothiourea (AETU) recently shown to be more selective of inducible NOS of cartilage (Jang et al , 1996). Dexamethasone (0.1 to 100 μM) was tested in similar experimental conditions in order to assess the effect of corticosteroids in both systems.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of IL‐1‐induced cartilage injury by NO synthase inhibitors: a comparative study with rat chondrocytes and cartilage entities

Cipolletta

Jouzeau

Gégout-Pottie

et al. 1998

British J Pharmacology

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1 Nitric oxide (NO) is produced in diseased joints and may be a key mediator of IL-1 eects on cartilage. Therefore, we compared the potency of new [aminoguanidine (AG), S-methylisothiourea (SMT), S-aminoethylisothiourea (AETU)] and classical [N o -monomethyl-L-arginine (L-NMMA), N onitro-L-arginine methyl ester (L-NAME)] NO synthase (NOS) inhibitors on the inhibitory eect of recombinant human interleukin-1b (rhIL-1b) on rat cartilage anabolism. Three dierent culture systems were used: (1) isolated chondrocytes encapsulated in alginate beads; (2) patellae and (3) femoral head caps. 2 Chondrocyte beads and cartilage entities were incubated in vitro for 48 h in the presence of rhIL-1b with a daily change of incubation medium to obtain optimal responses on proteoglycan synthesis and NO production. Proteoglycan synthesis was assessed by incorporation of radiolabelled sodium sulphate [Na 2 35 SO 4 ] and NO production by cumulated nitrite release during the period of study. 3 Chondrocytes and patellae, as well as femoral head caps, responded concentration-dependently to IL1b challenge (0 to 250 U ml 71 and 0 to 15 U ml 71 respectively) by a large increase in nitrite level and a marked suppression of proteoglycan synthesis. Above these concentrations of IL-1b (2500 U ml 71 and 30 U ml 71 respectively), proteoglycan synthesis plateaued whereas nitrite release still increased thus suggesting dierent concentration-response curves. 4 When studying the eect of NOS inhibitors (1 to 1000 mM) on NO production by cartilage cells stimulated with IL-1b (25 U ml 71 or 5 U ml 71 ), we observed that: (i) their ability to reduce nitrite level decreased from chondrocytes to cartilage samples, except for L-NMMA and AETU; (ii) they could be roughly classi®ed in the following rank order of potency: AETU4L-NMMA5SMT4AG5L-NAME and (iii) AETU was cytotoxic when used in the millimolar range. 5 When studying the eect of NOS inhibitors on proteoglycan synthesis by cartilage cells treated with IL-1b, we observed that: (i) they had more marked eects on proteoglycan synthesis in chondrocytes than in cartilage samples; (ii) they could be roughly classi®ed in the following rank order of potency: L-NAME5L-NMMA44AG4SMT44AETU and (iii) potentiation of the IL-1 eect by AETU was consistent with cytotoxicity in the millimolar range. 6 D-isomers of L-arginine analog inhibitors (1000 mM) were unable to correct nitrite levels or proteoglycan synthesis in IL-1b treated cells. L-arginine (5000 mM) tended to reverse the correcting eect of L-NMMA (1000 mM) on proteoglycan synthesis, thus suggesting a NO-related chondroprotective eect. However, data with L-NAME and SMT argued against a general inverse relationship between nitrite level and proteoglycan synthesis. 7 Dexamethasone (0.1 to 100 mM) (i) failed to inhibit NO production in femoral head caps and chondrocytes beads whilst reducing it in patellae (50%) and (ii) did not aect or worsened the inhibitory eect of IL-1b on proteoglycan synthesis. Such results suggested a corticosteroid-resistance of rat chondrocy...

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Section: Discussionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Modulation of IL‐1‐induced cartilage injury by NO synthase inhibitors: a comparative study with rat chondrocytes and cartilage entities

Cipolletta

Jouzeau

Gégout-Pottie

et al. 1998

British J Pharmacology

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“…This suggests that, in contrast to in vitro culture conditions, the resident time of SMT in joints is probably too short to allow its diffusion into the extracellular matrix. The notion of this limited diffusion of SMT in cartilage is further supported by in vitro studies showing that SMT is better able to reduce nitrite levels in chondrocytes than in cartilage specimens (12,41). The enhanced inhibition of NO synthesis observed when L-NMA was delivered by mini osmotic pumps provided additional evidence that the diffusion capacity of NOS inhibitors into articular tissues was crucial for their in vivo efficacy.…”

Section: Discussionmentioning

confidence: 94%

Cartilage protection by nitric oxide synthase inhibitors after intraarticular injection of interleukin-1? in rats

Presle

Cipolletta

Jouzeau

et al. 1999

Arthritis & Rheumatism

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Our findings show that in rats: 1) NO may be an early mediator of the effect of IL-1beta on cartilage, 2) NO inhibition may have therapeutic relevance, although it is not sufficient to fully reverse the deleterious effects of IL-1beta, 3) among NOS inhibitors tested, only amino acid derivatives are effective, 4) protection can be achieved by local administration of NOS inhibitors, and 5) systemic and sustained delivery of the NOS inhibitor with the highest efficacy after intraarticular injection provides the most benefit.

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“…Variability in results is likely attributable in part to different standards of measurement, different models of I/R, and most importantly, to the different selectivity of inhibitors for each NOS isoform. 23,24 As highly selective inhibitors for individual isoenzymes have been developed, the potential for understanding the roles of NO has increased, raising with it the possibility of clinical application. 6 This study observed the effects of (3(aminomethyl)benzyl)acetamidine (1400W), a highly selective iNOS inhibitor, on the contractile function and NOS protein expression of reperfused skeletal muscle.…”

mentioning

confidence: 99%

Inhibition of iNOS with 1400W improves contractile function and alters nos gene and protein expression in reperfused skeletal muscle

Patel

Allen

et al. 2004

Microsurgery

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This study examined the effects of 1400W, an inhibitor of inducible nitric oxide (iNOS), on contractile function and iNOS expression in reperfused skeletal muscle. The right extensor digitorum longus (EDL) muscle of 104 rats underwent a sham operation or 3-h ischemia followed by 3-h or 24-h reperfusion (I/R). Rats received 3 mg/kg 1400W, 10 mg/kg 1400W, or water subcutaneously. Results showed that EDL contractile function in both 1400W-treated groups significantly outperformed the controls at 24-h but not at 3-h reperfusion. Although iNOS expression increased in all three I/R groups during reperfusion, a significantly smaller increase was found in 1400W-treated muscles after 3-h reperfusion, and more dramatically so after 24-h reperfusion. Our results indicate that inhibition of iNOS preserved the contractile function in reperfused skeletal muscle, perhaps via downregulating iNOS expression. Protection by 1400W at 24-h reperfusion suggests that the role of iNOS in exaggerating reperfusion injury is more prominent in the later stages of injury.

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S-Substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage

Cited by 25 publications

References 18 publications

Modulation of IL‐1‐induced cartilage injury by NO synthase inhibitors: a comparative study with rat chondrocytes and cartilage entities

Modulation of IL‐1‐induced cartilage injury by NO synthase inhibitors: a comparative study with rat chondrocytes and cartilage entities

Cartilage protection by nitric oxide synthase inhibitors after intraarticular injection of interleukin-1? in rats

Inhibition of iNOS with 1400W improves contractile function and alters nos gene and protein expression in reperfused skeletal muscle

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