Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The hypotensive effects of glyceryl trinitrate (GTN, 0.5 mg kg-1) but not of 3-morpholino-sydnonimine (SIN-1, 0.125 mg kg-1) in anaesthetized rats were attenuated following a seven day (using a q.i.d. dosing schedule) oral treatment with isosorbide-5-mononitrate (IS-5-MN; 5 mg kg-1) indicative of the induction of tolerance to GTN but not to SIN-1. The hypotensive effects of GTN did not decline when the sulphydryl (SH) containing angiotensin converting enzyme inhibitor (ACE-1), captopril (CPT, 5 mg kg-1) or the structurally unrelated SH-containing, N-acetylcysteine (NAC, 10 mg kg-1) but not the non-SH-containing ACE-I, enalaprilat (ENA, 5 mg kg-1) were given together with IS-5-MN for the seven days treatment. 2. The attenuated hypotensive effects of GTN (0.5 mg kg-1) in rats treated with IS-5-MN were also restored when CPT (1 mg kg-1) or NAC (2.5 mg kg-1) but not ENA (1 mg kg-1) was administered intraperitoneally (i.p.) 30 min before GTN. Furthermore, in control rats, CPT or NAC but not ENA given i.p. 30 min before GTN, potentiated its haemodynamic effects. These effects were blocked by methylene blue (10 mg kg-1). At the same doses, CPT or NAC did not affect the hypotensive effects of SIN-1. 3. The reduced ability of cultured tolerant smooth muscle cells (SMC, 24 x 103 cells) or endothelial cells(EC, 40 x 103 cells) to potentiate the anti-platelet effects of GTN (44 microM) was restored by CPT or NAC but not by ENA or glutathione (all at 0.5 mM). Potentiation of the anti-platelet effects of tolerant SMC or EC by CPT or NAC was abolished by co-incubation with oxyhaemoglobin (Oxy-Hb, 10 microM)indicative of nitric oxide (NO) formation.4. When GTN (150-2400 microM) was incubated with CPT, NAC or glutathione but not ENA (all at 0.1 mM) for 30 min in Krebs buffer at 37 degrees C a concentration-dependent increase in nitrite (NO2-)formation was observed. 5. The antiplatelet effects of GTN (5.5-352 microM) were potentiated by co-incubation with CPT or NAC but not with ENA or glutathione (all at 0.5 mM). The concentration of GTN required to inhibit platelet aggregation by 50% (IC50) was 110 +/- 2 microM for GTN alone, 14 +/- 2 microM for GTN in the presence of NAC and 30 +/- 2 microM for GTN in the presence of CPT. The potentiation of the effects of GTN by CPT or NAC was inhibited by co-incubation with Oxy-Hb (10 microM). By themselves, CPT or NAC did not inhibit platelet aggregation.6. The ability of CPT to restore (a) the haemodynamic effects of GTN in tolerant rats and (b) the reduced capacity of tolerant SMC or EC to potentiate the anti-platelet effects of GTN is not related to its ACE inhibitory activity.7. CPT also potentiated the hypotensive effects of GTN in non-tolerant rats, and in vitro CPT released NO from GTN in the absence of a GTN to NO converting cell, so that it is unlikely that reversal of tolerance by CPT is due to the replenishment of intracellular thiols. Rather it can be explained by the ability of CPT to release NO from GTN in the extracellular space. This extracellular formation of NO from GTN by CPT would then compensate for the impaired enzymic biotransformation of GTN to NO that develops during tolerance as was originally proposed for NAC.
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PMID:Release of nitric oxide from glyceryl trinitrate by captopril but not enalaprilat: in vitro and in vivo studies. 835 44

1. In the present study we examined whether interleukin-1 beta (IL-1 beta) increases the activity of adenylyl cyclase in vascular smooth muscle cells and determined its role in the cytokine-induced expression of the inducible nitric oxide synthase (iNOS) and activation of nuclear transcription factor-kappa B (NF-kappa B). In addition the interaction between cyclic AMP- and cyclic GMP-elevating agonists on the IL-1 beta-stimulated expression of iNOS was examined. 2. Exposure of vascular smooth muscle cells to IL-1 beta stimulated the formation of cyclic AMP but not of cyclic GMP. The intracellular level of cyclic AMP reached a maximum within 1 h and then gradually declined over the next 5 h. This IL-1 beta (60 u ml-1)-stimulated formation of cyclic AMP was modest (about 3 fold at 60 u ml-1 for 1 h) compared to that evoked by isoprenaline (about 9 fold at 3 x 10(-6) M for 2 min). 3. The IL-1 beta (60 u ml-1 for 24 h)-stimulated accumulation of nitrite, which was taken as an index of NO production, was concentration-dependently increased by preferential inhibitors of cyclic AMP-dependent phosphodiesterases (rolipram and trequinsin). This effect was reproduced by a specific activator of the cyclic AMP-dependent protein kinase(s) A, Sp-8-CPT-cAMPS (10(-4) M) but was prevented by a specific inhibitor of cyclic AMP-dependent protein kinase(s) A, Rp-8-CPT-cAMPS (10(-4) M). These compounds alone [rolipram (10(-6) M), trequinsin (3 x 10(-6) M) and Sp-8-CPT-cAMPS (10(-4) M)] slightly but significantly increased the release of nitric oxide while Rp-8-CPT-cAMPS elicited no such effect. 4. Inducible NOS protein was expressed in IL-1 beta (30 u ml-1, 24 h)-stimulated smooth muscle cells as assessed by Western blot analysis. The level of iNOS protein was markedly increased in smooth muscle cells which had been exposed to IL-1 beta in combination with either rolipram (3 x 10(-6) M) or Sp-8-CPT-cAMPS (10(-4) M) but was reduced in those exposed to IL-1 beta and Rp-8-CPT-cAMPS (10(-4) M). A weak expression of iNOS protein was found in smooth muscle cells which had been exposed to either Sp-8-CPT-cAMPS or rolipram alone for 24 h while Rp-8-CPT-cAMPS elicited no such effect. 5. Exposure of smooth muscle cells to IL-1 beta (30 u ml-1) for 30 min increased the level of NF-kappa B-DNA complexes in nuclear extracts as detected by electrophoretic mobility shift assay. Similar levels of NF-kappa B-DNA complexes were found in cells which had been exposed to IL-1 beta in combination with either Sp-8-CPT-cAMPS (10(-4) M), trequinsin (10(-6) M) or rolipram (10(-6) M). None of the modulators alone affected the basal level of NF-kappa B binding activity. 6. NO-donors [sodium nitroprusside (SNP) 10(-4) M; dinitrosyl-iron-di-L-cysteine-complex (DNIC), 10(-4) M; 3-morpholino-sydnonimine (SIN-1), 10(-4) M] and atrial natriuretic factor (10(-6) M) significantly increased the IL-1 beta (30 or 60 u ml-1, 24 h)-stimulated expression of iNOS protein and activity as assessed indirectly by the conversion of oxyhaemoglobin to methaemoglobin. In the absence of IL-1 beta, SNP (10(-4) M, 24 h) but not the other cyclic GMP-dependent vasodilators caused a modest expression of iNOS protein. No such effect was found in smooth muscle cells exposed to SNP in combination with Rp-8-CPT-cAMPS (10(-4) M) while an increased level of iNOS protein was found in those exposed to SNP in combination with either Sp-8-CPT-cAMPS (10(-4) M) or rolipram (3 x 10(-6) M). 7. Exposure of vascular smooth muscle cells to either S-nitroso-L-cysteine (Cys-SNO, 10(-4) M), SNP (10(-4) M) or SIN-1 (10(-4) M) for 35 min affected minimally the basal activation of NF-kappa B but abolished that evoked by IL-1 beta (30 u ml-1 added during the last 30 min). However, addition of Cys-SNO following the stimulation with IL-1 beta (during the last 5 min of the 30 min exposure period) reduced the level of NF-kappa B-DNA complexes only slightly. 8. These data indicate that the cyclic AMP-dependent pathway plays a decisi
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PMID:Effect of cyclic GMP-dependent vasodilators on the expression of inducible nitric oxide synthase in vascular smooth muscle cells: role of cyclic AMP. 890 45

There is ample evidence that nitric oxide (NO) is an important neurotransmitter in many tissues of the urogenital tract. The aim of the present study was to examine the possible role of NO in ureteral relaxation. Human ureteral rings were mounted in organ bath chambers and precontracted in KCl. Increasing doses of the NO donor linsidomine (SIN-1) were added with and without prior blockade of the NO/cGMP pathway by methylene blue and protein kinase (PK) inhibitors Rp-8-pCPT-cGMPS and RP-8-CPT-cAMPS. Electrical filed stimulation (EFS) was done before and after incubation with L-NOARG (NG-nitro-L-arginine) and TTX (tetratodoxin). For detection of neuronal NO synthase (NOS), ureters were stained immunohistochemically. Ureteral strips were dose dependently relaxed by SIN-1; preincubation with methylene blue and protein kinase G inhibitor significantly reduced the SIN-1-induced relaxations. No effects of L-NOARG and TTX on EFS-induced tone alterations were found. NOS-positive neuronal axons and nerve-ending-like structures were found in the muscular layers. Our in vitro findings suggest that ureteral relaxation may involve the NO pathway.
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PMID:A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro. 900 25