Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Results from previous studies suggest that alveolar macrophages must be exposed to inflammatory stimuli to produce nitric oxide (.NO). In this study, we report that naive unstimulated rat alveolar macrophages do produce .NO and attempt to characterize this process. Western blot analysis demonstrates that the enzyme responsible is an endothelial nitric oxide synthase (eNOS). No brain or inducible NOS can be detected. The rate of .NO production is approximately 0.07 nmol.10(6) cells-1.h-1, an amount that is less than that produced by the eNOS found in alveolar type II or endothelial cells. Alveolar macrophage .NO formation is increased in the presence of extracellular L-arginine, incubation medium containing magnesium and no calcium, a calcium ionophore (A-23187), or methacholine. .NO production is inhibited by NG-nitro-L-arginine methyl ester (L-NAME) but not by NG-nitro-L-arginine, L-N5-(1-iminomethyl)ornithine hydrochloride, or aminoguanidine. Incubation with ATP, ADP, or histamine also inhibits .NO formation. Some of these properties are similar to and some are different from properties of eNOS in other cell types. Cellular .NO levels do not appear to be related to ATP or lactate content. Alveolar macrophage production of .NO can be increased approximately threefold in the presence of lung surfactant or its major component, dipalmitoyl phosphatidylcholine (DPPC). The DPPC-induced increase in .NO formation is time and concentration dependent, can be completely inhibited by L-NAME, and does not appear to be related to the degradation of DPPC by alveolar macrophages. These results demonstrate that unstimulated alveolar macrophages produce .NO via an eNOS and that lung surfactant increases .NO formation. This latter effect may be important in maintaining an anti-inflammatory state in vivo.
 ...
PMID:Constitutive nitric oxide production by rat alveolar macrophages. 953 Jan 71

The effects of sodium nitroprusside on the electrical and mechanical properties of the smooth muscle of the guinea-pig vas deferens, and its responses to transmitter substances, have been investigated by use of the sucrose-gap technique. Isolated longitudinal segments of guinea-pig vas deferens contracted in response to electrical field stimulation (100 V, 0.04-0.1 ms, 1-5 Hz, 10 s train every 60 s) and application of ATP (1 mM) or noradrenaline (10 microM). Sodium nitroprusside (0.1 mM) did not affect resting tension but did enhance contractions evoked by electric-field stimulation but not by ATP or noradrenaline. The sodium nitroprusside-induced enhancement was unaffected by the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME) (0.1 mM). Conversely, electrically evoked contractions were unaffected by the nitric oxide precursor L-arginine (1 mM) or the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) (0.1 mM). The amplitudes of electrically evoked excitatory junction potentials (EJPs) were not affected by application of sodium nitroprusside, although it caused a small depolarization of 0.7+/-0.3 mV. Similarly, the depolarization caused by exogenous application of ATP or noradrenaline was unaffected by the presence of sodium nitroprusside. L-NAME, L-arginine and SNAP did not affect EJP amplitude or baseline membrane potential. It is concluded that sodium nitroprusside enhances electrically evoked contractions of the guinea-pig vas deferens by reducing the threshold voltage for action potential firing in smooth-muscle cells.
 ...
PMID:Sodium nitroprusside enhances contractions of the guinea-pig isolated vas deferens. 953 Sep 89

The role of mitochondrial energy metabolism in glutamate mediated neurotoxicity was studied in rat neurones in primary culture. A brief (15 min) exposure of the neurones to glutamate caused a dose-dependent (0.01-1 mM) increase in cyclic GMP levels together with delayed (24 h) neurotoxicity and ATP depletion. These effects were prevented by either the nitric oxide (.NO) synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (NAME; 1 mM) or by the N-methyl-D-aspartate (NMDA) glutamate-subtype receptor antagonist D-(-)-2-amino-5-phosphonopentanoate (APV; 0.1 mM). Glutamate exposure (0.1 mM and 1 mM) followed by 24 h of incubation caused the inhibition of succinate-cytochrome c reductase (20-25%) and cytochrome c oxidase (31%) activities in the surviving neurones, without affecting NADH-coenzyme-Q1 reductase activity. The rate of oxygen consumption was impaired in neurones exposed to 1 mM glutamate, either with glucose (by 26%) or succinate (by 39%) as substrates. These effects on the mitochondrial respiratory chain and neuronal respiration, together with the observed glutathione depletion (20%) by glutamate exposure were completely prevented by NAME or APV. Our results suggest that mitochondrial dysfunction and impairment of antioxidant status may account for glutamate-mediated neurotoxicity via a mechanism involving .NO biosynthesis.
 ...
PMID:Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion. 959 99

1. The role of endothelial factors and potassium channels in the action of the pineal hormone melatonin to potentiate vasoconstrictor responses was investigated in the isolated perfused tail artery of the rat. 2. Melatonin (100 nM) potentiated contractile responses to both adrenergic nerve stimulation and alpha1-adrenoceptor stimulation by phenylephrine. After removal of the endothelium, melatonin no longer caused potentiation. 3. The potentiating effect of melatonin was also lost when nitric oxide synthase was inhibited with L-NAME (10 nM). Thus potentiating effects depend on the presence of nitric oxide released by the endothelium. However, melatonin did not affect relaxation responses to acetylcholine in endothelium-intact arteries, nor did melatonin modulate relaxing responses to sodium nitroprusside in endothelium-denuded arteries. While melatonin does not appear to modulate agonist-induced release of nitric oxide nor its effect, melatonin may modulate nitric oxide production induced by flow and shear stress. 4. When the Ca2+-activated K+ channel opener, NS 1619 (10 microM), was present, potentiating effects of melatonin were restored in endothelium-denuded vessels. However, addition of the opener of ATP-sensitive K+ channels, cromakalim (3 microM), did not have the same restorative effect. Furthermore, addition of a blocker of Ca2+-activated K+ channels, tetraethylammonium (1 mM), significantly attenuated potentiating effects of melatonin. These findings support the hypothesis that melatonin inhibits the activity of large conductance Ca2+-activated K+ channels to produce its potentiating effects. 5. Thus in the rat perfused tail artery, potentiation of constriction by melatonin depends on the activity of both endothelial factors and Ca2+-activated K+ channels. Our findings suggest that melatonin inhibits endothelial K+ channels to decrease flow-induced release of nitric oxide as well as block smooth muscle K+ channels to enhance vascular tone.
 ...
PMID:Effect of melatonin in the rat tail artery: role of K+ channels and endothelial factors. 960 58

1. We have used the isolated, buffer-perfused, superior mesenteric arterial bed of male and female rats to assess the relative contributions of nitric oxide (NO) and the endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxations to carbachol. 2. Carbachol caused dose-related relaxations of methoxamine-induced tone in mesenteric vascular beds from male rats described by an ED50(M) of 0.43+/-0.15 nmol and a maximum relaxation (Rmax(M) of 89.6+/-1.2% (n=28) which were not significantly different from those observed in mesenteries from female rats (ED50(F)=0.72+/-0.19 nmol and Rax(F)=90.7+/-0.9%; n=22). 3. In the males, the addition of 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused the dose-response curve to carbachol to be significantly (P<0.001) shifted to the right 15 fold (ED50(M)=6.45+/-3.53 nmol) and significantly (P<0.01) reduced Rmax(M) (79.7+/-2.8%, n=13). By contrast, L-NAME had no effect on vasorelaxation to carbachol in mesenteries from female rats (ED50(f)= 0.89+/-0.19 nmol, Rmax(F)=86.9+/-2.3%, n=9). 4. Raising tone with 60 mM KCl significantly reduced the maximum relaxation to carbachol in mesenteries from male rats 2 fold (Rmax(M)=40.3+/-9.2%, n=4; P<0.001) and female rats by 1.5 fold (Rmax(F)=55.3+/-3.3%, n=6; P<0.001), compared with methoxamine-induced tone. The potency of carbachol was also significantly reduced 1.2 fold in preparations from males (ED50(M)=0.87+/-0.26 nmol; P<0.01) but not the females (ED50(F)=4.04+/-1.46 nmol). In the presence of both 60 mM KCl and L-NAME, the vasorelaxation to carbachol was completely abolished in mesenteries from both groups. 5. The cannabinoid receptor antagonist SR141716A (1 microM), which is also a putative EDHF antagonist, had no significant effect on the responses to carbachol in mesenteries from males or females (ED50(M)=1.41+/-0.74 nmol, Rmax(M)=89.4+/-2.5%, n=7; ED50(F)=2.17+/-0.95 nmol, Rmax(F)=89.9+/-1.8%, n=9). In mesenteries from male rats, in the presence of 100 microM L-NAME, SR141716A significantly (P<0.05) shifted the dose-response curve to carbachol 8 fold further to the right than that seen in the presence of L-NAME alone (ED50(M)= 53.8+/-36.8 nmol) without affecting Rmax(M) (72.4+/-4.8%, n=10). In mesenteries from female rats, the combined presence of L-NAME and SR141716A, significantly (P < 0.01) shifted the dose-response curve to carbachol 7.5 fold, (ED50(F)=6.66+/-2.46 nmol), as compared to L-NAME alone and significantly (P<0.001) decreased Rmax(F) (70.1+/-5.5%, n=8). 6. Vasorelaxations to the nitric oxide donor sodium nitroprusside (SNP), to the endogenous cannabinoid, anandamide (a putative EDHF) and to the ATP-sensitive potassium channel activator, levcromakalim, did not differ significantly between male and female mesenteric vascular beds. 7. The continuous presence of sodium nitroprusside (SNP; 20-60 nM) had no effect on vasorelaxation to carbachol in mesenteries from either males or females. In the presence of L-NAME, SNP significantly (P<0.05) reduced the potency of carbachol 6 fold, without affecting the maximal relaxation in mesenteries from male rats (ED50(M)=40.9+/-19.6 nmol, Rmax(M)=79.4+/-2.5%, n=11). Similarly in mesenteries from female rats, the ED50(F) was also significantly (P<0.01) increased 7 fold (6.24+/-2.02 nmol), while the Rmax(F) was unaffected (81.9+/-11.0%; n=4). 8 The results of the present investigation demonstrate that the relative contributions of agonist-stimulated NO and EDHF to endothelium-dependent relaxations in the rat isolated mesenteric arterial bed, differ between males and females. Specifically, although both NO and EDHF appear to contribute towards endothelium-dependent relaxations in males and females, blockade of NO synthesis alone has no effect in the female. This suggests that EDHF is functionally more important in females; one possible explanation for this is that in the absence of NO, the recently identified ability of EDHF to compensate for the loss of NO, is functio
 ...
PMID:Sex differences in the relative contributions of nitric oxide and EDHF to agonist-stimulated endothelium-dependent relaxations in the rat isolated mesenteric arterial bed. 960 78

To explore the role of calcitonin gene-related peptide (CGRP) in rat pregnancy, we determined the density of myometrial CGRP-encoded nerve fibre terminals and examined, in an organ bath, the relaxant effect of the peptide on uterine strips near parturition. Comparisons were made with the uterus and aorta of nonpregnant rats. In the myometrium, CGRP immunoreactive nerve fibers were abundant in nonpregnant rats and scarce at the parturient stage. In the aorta there was no variation in the density of CGRP fibres with gestation. In nonpregnant rats only, CGRP relaxed spontaneous and tetrodotoxin (TTX)-sensitive electrically-evoked uterine contractions (EC50 40 nM, Emax 80%). The effect was antagonized by CGRP[8-37] (pKB 6.47) but was not affected by either blockers of nitricoxid synthase or ATP-sensitive potassium channels. CGRP was also able to relax contractions evoked by direct depolarization of the cells (TTX-insensitive contractions) (EC50, 2 nM, Emax 70%). In aorta contracted with arginine vasopressin, CGRP-induced relaxation was the same in nonpregnant and parturient animals. It was antagonized by CGRP [8-371 (pKB 6.90) and was abolished in presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Amylin neither relaxed the uterus nor the aorta. In pregnant rats, the relaxant effect of CGRP on the uterus was limited on day 21 and was totally absent on day 22 of gestation. We conclude that the primary relaxant effect of CGRP on the uterus occurs at the level of myometrial smooth muscle cells. In the myometrium, gestation decreases CGRP innervation and impairs the relaxant responses to CGRP. Such changes are not observed in vascular tissues like aorta.
 ...
PMID:Relaxant effect of the calcitonin gene-related peptide (CGRP) on the nonpregnant and pregnant rat uterus. Comparison with vascular tissue. 960 32

Endomorphin 1 and 2, newly discovered endogenous ligands for the mu-opioid receptor, have vasodepressor activity in the rat. In the present study, the mechanism mediating hemodynamic responses to endomorphin 2 and the endomorphin analog [D-Ala2]endomorphin 2 (TAPP) was investigated in the rat. Intravenous injections of TAPP and endomorphin 2 produced similar dose-dependent decreases in systemic arterial pressure and were approximately 10-fold more potent than Met-enkephalin. TAPP and endomorphin 2 decreased heart rate, cardiac output, and total peripheral resistance. Under constant-flow conditions, injections of TAPP and endomorphin 2 into the perfusion circuit produced decreases in hindquarter perfusion pressure, and vasodilator responses were attenuated by the opioid receptor antagonist naloxone. Hindquarter vasodilator responses to TAPP and endomorphin 2 were attenuated by the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg iv), whereas responses to the endothelium-independent vasodilators calcitonin gene-related peptide, diethylamine/nitric oxide, and isoproterenol were not changed. Hindquarter vasodilator responses to TAPP and endomorphin 2 were not altered by the cyclooxygenase inhibitor sodium meclofenamate, the ATP-dependent K+ channel antagonist U-37883A, or the presence of a time-delay coil in the perfusion circuit. These results indicate that vasodilator responses to TAPP and endomorphin 2 are mediated by the activation of a naloxone-sensitive opioid receptor and the release of nitric oxide from the endothelium within the hindquarter vascular bed of the rat.
 ...
PMID:D-[Ala2]endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats. 961 81

1. We have previously demonstrated that adenosine-5'-O-(2-thiodiphosphate) (ADPbetaS), a potent P2Y-purinoceptor agonist, relaxed pancreatic vasculature not only through prostacyclin (PGI2) and nitric oxide (NO) release from the endothelium but also through other mechanism(s). In this study, we investigated the effects of an inhibitor of the Na+/K+ pump, of ATP-sensitive K+ (K(ATP)) channels and of small (SK(Ca)) or large (BK(Ca)) conductance Ca2+-activated K+ channels. Experiments were performed at basal tone and during the inhibition of NO synthase and cyclo-oxygenase. 2. In control conditions, ADPbetaS (15 microM) induced an initial transient vasoconstriction followed by a progressive and sustained vasodilatation. In the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME, 200 microM) the transient vasoconstriction was reversed into a one minute vasodilator effect, which was then followed by a progressive and sustained vasodilatation similar to that observed with ADPbetaS alone. The addition of indomethacin (10 microM) did not significantly modify the profile of ADPbetaS-induced vasodilatation. 3. Ouabain (100 microM) decreased basal pancreatic flow rate and did not modify ADPbetaS-induced relaxation. This inhibitor of the Na+/K+ pump increased the pancreatic vasoconstriction induced by L-NAME or by the co-administration of L-NAME and indomethacin. Ouabain did not modify either the L-NAME or the L-NAME/indomethacin resistant part of the ADPbetaS vasodilatation. 4. The K(ATP) inhibitor tolbutamide (185 microM) did not significantly modify basal pancreatic flow rate and ADPbetaS-induced relaxation. This inhibitor which did not change L-NAME-induced vasoconstriction, significantly diminished the L-NAME resistant part of ADPbetaS-induced vasodilatation. Tolbutamide intensified the vasoconstriction induced by the co-administration of L-NAME and indomethacin. In contrast, the L-NAME/indomethacin resistant part of ADPbetaS vasodilatation was not changed by the closure of K(ATP). 5. The SK(Ca) inhibitor apamin (0.1 microM) did not significantly change pancreatic vascular resistance whatever the experimental conditions (in the absence or in presence of L-NAME or L-NAME/indomethacin). In the presence of L-NAME, the closure of SK(Ca) channels changed the one minute vasodilator effect of ADPbetaS into a potent vasoconstriction and thereafter modified only the beginning of the second part of the L-NAME-resistant part of the ADPbetaS-induced vasodilatation. In contrast, the L-NAME/indomethacin resistant part of ADPbetaS-induced relaxation remained unchanged in the presence of apamin. 6. Charybdotoxin (0.2 microM), an inhibitor of BK(Ca), increased pancreatic vascular resistance in the presence of L-NAME/indomethacin. In the presence of L-NAME, the closure of BK(Ca) channels reversed the one minute vasodilator effect of ADPbetaS into a potent vasoconstriction and drastically diminished the sustained vasodilatation. In contrast the L-NAME/indomethacin resistant part of ADPbetaS-induced relaxation was not modified by the presence of charybdotoxin. Under L-NAME/indomethacin/charybdotoxin/apamin infusions, ADPbetaS evoked a drastic and transient vasoconstriction reaching a maximum at the second minute, which was followed by a sustained increase in the flow rate throughout the ADPbetaS infusion. The maximal vasodilator effect of ADPbetaS observed was not modified by the addition of apamin. 7. The results suggest that the L-NAME-resistant relaxation induced by ADPbetaS in the pancreatic vascular bed involves activation of BK(Ca), K(ATP) and to a lesser extent of SK(Ca) channels, but the L-NAME/indomethacin resistant part of ADPbetaS-induced relaxation is insensitive to the closure of K(ATP), SK(Ca) and BK(Ca) channels.
 ...
PMID:Involvement of K+ channel permeability changes in the L-NAME and indomethacin resistant part of adenosine-5'-O-(2-thiodiphosphate)-induced relaxation of pancreatic vascular bed. 963 Mar 54

We investigated the effects of increases in the extracellular potassium concentration on the function of the rabbit corpus cavernosum. The resting tissue tension increased as the potassium concentration was increased from 4.7 mM to 20 mM or 30 mM. The maximum contraction induced by 200 microM phenylephrine was significantly decreased in the presence of 30 mM potassium compared with 4.7 mM potassium. After precontraction was induced with 200 microM phenylephrine, the magnitude of field-stimulated relaxation increased significantly as the potassium concentration was increased from 4.7 mM to 10 or 20 mM, but was almost completely abolished at 30 mM potassium. There was no difference in the suppressive effect of L-NAME on field-stimulated relaxation between specimens treated with 4.7 mM or 20 mM potassium. ATP- and bethanechol-induced relaxation was not affected by increases in the extracellular potassium concentration. A high-dose potassium solution (124 mM) induced contraction of the corpus cavernosum. In tissue precontracted with phenylephrine, a high-dose potassium solution that contained phenylephrine induced relaxation of corpus cavernosum; this relaxation was completely suppressed by L-NAME. These findings suggest that small increases in the extracellular potassium concentration increase field-stimulated relaxation of the corpus cavernosum and that this relaxation is not related to the effects of nitric oxide. Relaxation induced by high-dose potassium in tissue precontracted with phenylephrine is probably the result of release of nitric oxide.
 ...
PMID:Does potassium induce the release of nitric oxide in the rabbit corpus cavernosum? 963 47

In the current investigation, the role of basal nitric oxide (NO) in modulating the vasorelaxant responses to pinacidil and levcromakalim was examined in goat isolated coronary artery. Pinacidil (10(-8) 10(-4) M) elicited concentration-dependent relaxations of the coronary artery ring segments (with intact endothelium) constricted with 30 mM K+ saline solution. The EC50 of the vasodilator was 2.57 x 10(-6) M (95% CL, 1.9-3.46 x 10(-6) M). The removal of endothelium by mechanical rubbing caused a rightward shift in the concentration-response curve of pinacidil with a corresponding increase in EC50 value (1.90 x 10(-5) M; 95% CL, 1.12-3.23 x 10(-5) M). Similar to endothelium removal, treatment of endothelium-intact rings either with the NO synthesis inhibitor L-NAME (NG-nitro-L-arginine methyl ester; 3 x 10(-5) M) or the guanylate cyclase inhibitor, methylene blue (3 x 10(-6) M) resulted in a marked inhibition in the relaxant responses to pinacidil. Hence, the EC50 values of the potassium channel opener were significantly higher in tissues treated either with L-NAME (7.41 x 10(-6) M; 95% CL, 6.02-9.12 x 10(-6) M) or methylene blue (2.29 x 10(-5) M; 95% CL, 1.58-3.31 x 109-5) M) as compared to untreated controls. The ATP-sensitive potassium (KATP) channel blocker glibenclamide, which caused a significant rightward shift in the concentration-relaxation curve of pinacidil in control tissues, was found to be less potent in antagonising the relaxant responses of the KATP channel opener in endothelium-denuded rings and in rings with intact endothelium but treated with either L-NAME or methylene blue. In contrast to the observations made with pinacidil, the vasodilator responses to another KATP channel opener, levcromakalim, were potentiated in the absence of basal NO. Thus, the EC50 of levcromakalim was 1.33 x 10(-8) M (95% CL, 0.8-2.21 x 10(-8) M) in control tissues with intact endothelium, which was significantly higher than those obtained in endothelium-deprived rings (4.81 x 10(-9) M; 95% CL, 4.04-5.73 x 10(-9) M) or endothelium intact rings treated either with L-NAME (2.63 x 10(-9) M; 95% CL, 1.58-4.36 x 10(-9) M) or methylene blue (2.82 x 10(-9) M; 95% CL, 1.7-4.68 x 10(-9) M). The selective modulation by basal NO of the arterial relaxations elicited with the KATP channel openers was evident from the findings that papaverine-induced relaxations were not affected in the absence of basal NO. Taken together, the results of the present study suggest that basal NO differentially modulates the interaction of pinacidil and levcromakalim with the KATP channels in goat coronary artery through a cGMP-dependent pathway.
 ...
PMID:Basal nitric oxide release differentially modulates vasodilations by pinacidil and levcromakalim in goat coronary artery. 965 Aug 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>