Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the hypothesis that adaptations in peripheral arterial vasoreactivity are induced by exercise training. Male rats were trained to run on a treadmill at 30 m/min (15 degrees incline) for 1 h/day 5 days/wk for 10-12 wk. Efficacy was indicated by a 51% increase (P < 0.05) in citrate synthase activity in soleus muscle of exercise-trained (ET) rats compared with that of sedentary (SED) control rats. Responses to vasoactive compounds were examined in vitro using rings of abdominal aorta. Maximal isometric contractile tension evoked by KCl, norepinephrine (NE), and phenylephrine were not different between groups; sensitivity to phenylephrine was also not different between groups. However, sensitivity was lower for both KCl and NE in vessels from ET animals. Endothelium removal did not influence KCl sensitivity but did abolish the difference in NE sensitivity of vessel segments between ET and SED animals. Maximal vasodilator responses induced by acetylcholine (ACh; NE or prostaglandin F2 alpha preconstriction) were greater in vessel rings from ET rats. However, dilatory responses by sodium nitroprusside (NE or prostaglandin F2 alpha preconstriction) and forskolin (NE preconstriction) were not different between groups, indicating that the augmented ACh-induced dilatory response resulted from an adaptation of the endothelium. Blockade of nitric oxide synthase activity diminished ACh-induced vasodilation by 79 and 100% in SED and ET rats, respectively. These results indicate that training alters vasomotor function in rat abdominal aortas through adaptations of both endothelium and smooth muscle.
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PMID:Exercise training alters endothelium-dependent vasoreactivity of rat abdominal aorta. 822 51

Previous work has demonstrated that 10 wk of exercise training enhances the responsiveness of rat abdominal aortas to acetylcholine (ACh), an endothelium-dependent vasodilator. The purpose of this study was to determine the time course for this training-induced adaptation of vascular endothelium. Additionally, the contribution of the cyclooxygenase and nitric oxide synthase mechanisms to the enhanced endothelium-mediated relaxation were examined. Male rats were divided into sedentary (SED) and exercise groups. Exercised animals were further subdivided into postexercise (POST-EX), 1 DAY, 1 WK, 2 WK, 4 WK and 10 WK groups. Exercise consisted of treadmill running at 30 m.min-1 (15 degrees incline) for 1 h.d-1 (5 d.wk-1 for the 1 WK, 2 WK, 4 WK, and 10 WK groups). Maximal vasodilator responses induced by 10(-4) M ACh (10(-7) M norepinephrine preconstriction) were determined on abdominal aortic rings in vitro immediately after a single exercise bout in POST-EX rats and 24 h after a single bout of exercise in 1 DAY animals. Maximal 10(-4) M ACh-induced dilation of aortas from 1 WK, 2 WK, 4 WK, and 10 WK animals was determined 24 h after the last exercise bout. Soleus muscle citrate synthase activity was greater in 2 WK (31 +/- 1 mumol.min-1.g wet wt-1), 4 WK (34 +/- 2), and 10 WK (36 +/- 1 mumol.min-1.g wet wt-1) rats than in SED (27 +/- 1 mumol.min-1.g wet wt.-1) animals. Maximal ACh-induced relaxation was greater in aorta from 4 WK (72 +/- 2%) and 10 WK (79 +/- 1%) rats than SED (61 +/- 2%) rats. ACh-mediated dilatory responses remained enhanced in the presence of the cyclooxygenase blocker indomethacin (10(-5) M), but were abolished by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (300 microM). In addition, the expression of endothelial nitric oxide synthase (ecNOS) protein in aortas from 4 WK (P = 0.057) and 10 WK (P < 0.05) rats was greater than in aortas from SED animals. These data indicate that the enhanced endothelium-dependent, ACh-mediated dilation of the rat aorta is present by 4 wk of endurance exercise training. This adaptation appears to be mediated primarily through the nitric oxide synthase pathway and is associated with an increased expression of ecNOS.
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PMID:Time course of enhanced endothelium-mediated dilation in aorta of trained rats. 937 82

The possible role of nitric oxide (.NO) in brain energy metabolism during perinatal asphyxia in the rat was studied. Exposure of early neonates to 5 min of anoxia significantly inhibited brain mitochondrial complex II-III activity by 25%, without affecting complex I, complex IV or citrate synthase activities. This insult was accompanied by ATP depletion (54%) and increased concentration of nitrites plus nitrates (1.4-fold), suggesting enhanced .NO synthesis. Administration of Nomega-nitro-L-arginine monomethyl ester (L-NAME) to the mothers inhibited neonatal brain .NO synthase activity, as reflected by the decreased (23%) cyclic GMP concentration. These L-NAME-treated neonates showed complete resistance to anoxic-mediated brain mitochondrial complex II-III damage. Our results suggest that brain mitochondrial dysfunction leading to energy deficiency during perinatal asphyxia is a .NO-mediated process.
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PMID:Nitric oxide mediates brain mitochondrial damage during perinatal anoxia. 951 75

The effects of exercise training were investigated on the vascular responses in the isolated guinea-pig saphenous artery. Exercising animals swam 5 days week-1 for 6 weeks (60 min day-1 for weeks 1 and 2; 75 min day-1 for weeks 3 and 4; 90 min day-1 for weeks 5 and 6), while control animals were placed into shallow water for the same duration. Trained animals had significantly higher ventricular:body weight ratios, increased citrate synthase activity in the latissimus dorsi, and enhanced Na+ pump concentrations in the latissimus dorsi and gastrocnemius muscles (P < 0.05). In vitro isometric techniques were used to measure constriction and relaxation responses of saphenous artery rings from trained and control animals. There were no significant differences in the constriction responses to KCl (50 mm) and phenylephrine (0.3-100 microM) in arterial rings from control versus trained animals. Relaxation responses to acetylcholine (10 microM; ACh-relaxation), following preconstriction with phenylephrine (10 microM), were significantly enhanced in rings from trained animals (P < 0.05). Acetylcholine relaxed the vessels to 47 +/- 6% (control) and 18 +/- 3% (trained) of the preconstriction responses to phenylephrine. The nitric oxide synthase inhibitor N G-nitro-L-arginine (L-NA; 50 microM) significantly attenuated the ACh-relaxation in control and trained animals (P < 0.05). The effect of L-NA on the ACh-relaxation was significantly larger in trained (change in ACh-relaxation with L-NA = 29 +/- 9%) than control (14 +/- 3%) animals (P < 0.05). In conclusion, exercise training enhanced the ACh-relaxation of the isolated guinea-pig saphenous artery. Inhibition of nitric oxide synthase attenuated the ACh-relaxation of rings from control and trained animals, but this effect was significantly larger in the vessels from trained animals. These results are consistent with the idea that nitric oxide could contribute to the enhanced ACh-relaxation of the saphenous artery with exercise training.
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PMID:Exercise training enhances relaxation of the isolated guinea-pig saphenous artery in response to acetylcholine. 1066 99

Activation of murine microglial and macrophage cell lines with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) resulted in the induction of the inducible form of nitric oxide synthase (NOS) and the release of micromolar amounts of NO into the surrounding medium. The synthesis of NO was associated with increased cellular membrane damage as assessed by trypan blue dye exclusion and the leakage of lactate dehydrogenase into the cell culture medium. However, the synthesis and release of cytokines was largely unaffected. NO-mediated cell damage was also accompanied by a marked decrease in the intracellular levels of reduced glutathione and ATP. In addition, significant inhibition of mitochondrial respiratory chain enzyme activities was seen following cellular activation. However, citrate synthase activity (a mitochondrial matrix enzyme) was not detectable in the extracellular supernatants, suggesting preservation of the integrity of the mitochondrial inner membrane following activation. These effects were largely prevented by the addition of the NOS inhibitor, N-guanidino monomethyl L-arginine during the activation period. Our observations demonstrate that induction of NOS activity in microglia results in damage to the plasma membrane leading to a loss of glutathione, complex-specific inhibition of the mitochondrial electron transport chain and depletion of cellular ATP. Our data suggest that pharmacological modulation of NOS activity in activated microglia in vivo may prevent cellular damage to bystander cells such as neurons, astrocytes and oligodendrocytes, as well as to microglia themselves.
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PMID:Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function. 1116 60

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. We have previously demonstrated that chronic stress induced an increase in nitric oxide (NO) production via an expression of inducible NO synthase (iNOS) in brain. Since it has been demonstrated that NO regulates mitochondrial function, we sought to study the susceptibility of the mitochondrial respiratory chain complexes to chronic restrain stress exposure in brain cortex. In adult male rats, stress (immobilization for six hours during 21 days) inhibits the activities of the first complexes of the mitochondrial respiratory chain (inhibition of 69% in complex I-III and of 67% in complex II-III), without affecting complex IV activity, ATP production and oxygen consumption. The mitochondrial marker citrate synthase is not significantly affected by stress after 21 days, indicating that at this time the mitochondrial structure is still intact. Moreover, the administration of the preferred inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (400 mg/kg i.p. daily from days 7 to 21 of stress) protects against the inhibition of the activity of complexes of the mitochondrial respiratory chain as well as prevents NO(x)(-) accumulation, lipid peroxidation and glutathione depletion induced by stress. These results suggest that a sustained overproduction of NO via iNOS is responsible, at least in part, of the inhibition of mitochondrial respiratory chain caused by stress and that this pathway also accounts for the oxidative stress found in this situation.
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PMID:Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. 1118 37

The present study examined in vitro vasomotor function and expression of enzymes controlling nitric oxide (NO) bioavailability in thoracic aorta of adult male normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that either remained sedentary (Sed) or performed 6 wk of moderate aerobic exercise training (Ex). Training efficacy was confirmed by elevated maximal activities of both citrate synthase (P = 0.0024) and beta-hydroxyacyl-CoA dehydrogenase (P = 0.0073) in the white gastrocnemius skeletal muscle of Ex vs. Sed rats. Systolic blood pressure was elevated in SHR vs. WKY (P < 0.0001) but was not affected by Ex. Despite enhanced endothelium-dependent relaxation to 10(-8) M ACh in SHR vs. WKY (P = 0.0061), maximal endothelium-dependent relaxation to 10(-4) M ACh was blunted in Sed SHR (48 +/- 12%) vs. Sed WKY (84 +/- 6%, P = 0.0067). Maximal endothelium-dependent relaxation to 10(-4) M ACh was completely restored in Ex SHR (93 +/- 9%) vs. Sed SHR (P = 0.0011). N(omega)-nitro-l-arginine abolished endothelium-dependent relaxation in all groups (P </= 0.0001) and caused equal vasocontraction to maximal ACh in Sed SHR and Ex SHR. Endothelium-independent relaxation to sodium nitroprusside was similar in all groups. Protein levels of endothelial NO synthase were higher in SHR vs. WKY (P = 0.0157) and in Ex vs. Sed (P = 0.0536). Protein levels of the prooxidant NAD(P)H oxidase subunit, gp91phox, were higher in SHR vs. WKY (P < 0.0001) and were diminished in Ex vs. Sed (P = 0.0557). Levels of the antioxidant SOD-1, -2, and catalase enzymes were lower in SHR vs. WKY (all P </= 0.0005) but were not altered by Ex. Thus elevated gp91phox-dependent oxidative stress and reduced antioxidant capacity likely contributed to impaired endothelium-dependent vasorelaxation in Sed SHR. Furthermore, reduced gp91phox-dependent oxidative stress and enhanced endothelial NO synthase-derived NO likely contributed to restored endothelium-dependent vasorelaxation in Ex SHR.
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PMID:Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. 1475 24

The polyamines (spermine, putrescine, and spermidine) can have neurotoxic or neuroprotective properties in models of neurodegeneration. However, assessment in a model of hypoxia-ischemia (HI) has not been defined. Furthermore, the putative mechanisms of neuroprotection have not been elucidated. Therefore, the present study examined the effects of the polyamines in a rat pup model of HI and determined effects on key enzymes involved in inflammation, namely, nitric oxide synthase (NOS) and arginase. In addition, effects on mitochondrial function were investigated. The polyamines or saline were administered i.p. at 10mg/kg/day for 6 days post-HI. Histological assessment 7 days post-HI revealed that only spermine significantly (P<0.01) reduced infarct size from 46.14 +/- 10.4 mm3 (HI + saline) to 4.9 +/- 2.7 mm3. NOS activity was significantly increased following spermine treatment in the left (ligated) hemisphere compared with nonintervention controls (P<0.01) and HI + saline (P<0.05). In contrast, spermine decreased arginase activity compared with HI + saline but was still significantly elevated in comparison to nonintervention controls (P<0.01). Assessment of mitochondrial function in the HI + saline group, revealed significant and extensive damage to complex-I (P<0.01) and IV (P<0.001) and loss of citrate synthase activity (P<0.05). No effect on complex II-III was observed. Spermine treatment significantly prevented all these effects. This study has therefore confirmed the neuroprotective effects of spermine in vivo. However, for the first time, we have shown that this effect may, in part, be due to increased NOS activity and preservation of mitochondrial function.
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PMID:Neuroprotective effects of spermine following hypoxic-ischemic-induced brain damage: a mechanistic study. 1513 86

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.
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PMID:Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. 1535 Aug 50

Endurance exercise training (Ex) has been shown to increase maximal skeletal muscle blood flow. The purpose of this study was to test the hypothesis that increased endothelium-dependent vasodilation is associated with the Ex-induced increase in muscle blood flow. Furthermore, we hypothesized that enhanced endothelium-dependent dilation is confined to vessels in high-oxidative muscles that are recruited during Ex. To test these hypotheses, sedentary (Sed) and rats that underwent Ex (30 m/min x 10% grade, 60 min/day, 5 days/wk, 8-12 wk) were studied using three experimental approaches. Training effectiveness was evidenced by increased citrate synthase activity in soleus and vastus lateralis (red section) muscles (P < 0.05). Vasodilatory responses to the endothelium-dependent agent acetylcholine (ACh) in situ tended to be augmented by training in the red section of gastrocnemius muscle (RG; Sed: control, 0.69 +/- 0.12; ACh, 1.25 +/- 0.15; Ex: control, 0.86 +/- 0.17; ACh, 1.76 +/- 0.27 ml x min(-1) x 100 g(-1) x mmHg(-1); 0.05 < P < 0.10 for Ex vs. Sed during ACh). Responses to ACh in situ did not differ between Sed and Ex for either the soleus muscle or white section of gastrocnemius muscle (WG). Dilatory responses of second-order arterioles from the RG in vitro to flow (4-8 microl/min) and sodium nitroprusside (SNP; 10(-7) through 10(-4) M), but not ACh, were augmented in Ex (vs. Sed; P < 0.05). Dilatory responses to ACh, flow, and SNP of arterioles from soleus and WG muscles did not differ between Sed and Ex. Content of the endothelial isoform of nitric oxide synthase (eNOS) was increased in second-order, fourth-order, and fifth-order arterioles from the RG of Ex; eNOS content was similar between Sed and Ex in vessels from the soleus and WG muscles. These findings indicate that Ex induces endothelial adaptations in fast-twitch, oxidative, glycolytic skeletal muscle. These adaptations may contribute to enhanced skeletal muscle blood flow in endurance-trained individuals.
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PMID:Nonuniform effects of endurance exercise training on vasodilation in rat skeletal muscle. 1544 26


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