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S Moncada

Publications and source records attributed to S Moncada.

At least 307 records · Page 17Linked to original sources
PubMed1989

Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase.

A soluble enzyme obtained from rat forebrain catalyzes the NADPH-dependent formation of nitric oxide (NO) and citrulline from L-arginine. The NO formed stimulates the soluble guanylate cyclase and this stimulation is abolished by low concentrations of hemoglobin. The synthesis of NO and citrulline is dependent on the presence of physiological concentrations of free Ca2+ and is inhibited by NG-monomethyl-L-arginine, but not by its enantiomer NG-monomethyl-D-arginine or by L-canavanine. L-Homoarginine, L-arginyl-L-aspartate, or L-arginine methyl ester can replace L-arginine as substrates for the enzyme. These results indicate that NO is formed from L-arginine in the brain through an enzymic reaction similar to that in vascular endothelial cells, neutrophils, and macrophages, adding support to our hypothesis that the formation of NO from L-arginine is a widespread transduction mechanism for the stimulation of the soluble guanylate cyclase.

Animals↗
PubMed1989

Role of endothelium-derived nitric oxide in the regulation of blood pressure.

The role of endothelium-derived nitric oxide in the regulation of blood pressure in the anesthetized rabbit was studied with N omega-monomethyl-L-arginine (L-NMMA), a specific inhibitor of its formation from L-arginine. L-NMMA (3-100 mg.kg-1), but not its D-enantiomer, induced a dose-dependent long-lasting (15-90 min) increase in mean systemic arterial blood pressure. L-NMMA (100 mg.kg-1) also inhibited significantly the hypotensive action of acetylcholine, without affecting that of glyceryl trinitrate. Both these actions of L-NMMA were reversed by L-arginine (300 mg.kg-1), but not by D-arginine (300 mg.kg-1), indomethacin (1 mg.kg-1), prazosin (0.3 mg.kg-1), or by vagotomy. The effects of L-NMMA in vivo were associated with a significant inhibition of the release of nitric oxide from perfused aortic segments ex vivo. This inhibition was reversed by infusing L-arginine through the aortic segments. These results indicate that nitric oxide formation from L-arginine by the vascular endothelium plays a role in the regulation of blood pressure and in the hypotensive actions of acetylcholine.

Acetylcholine↗
PubMed1989

Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.

Endothelium derived relaxing factor (EDRF) has been identified as nitric oxide, synthesised from the amino acid L-arginine, a process which is inhibited by the L-arginine analogue NG-monomethyl L-arginine (L-NMMA). We have studied the effect of local infusions of L-NMMA on venous reactivity in healthy volunteers. Studies were performed using the veins on the back of the hand. The diameter of a single dorsal hand vein was measured in healthy subjects who had taken 600 mg of aspirin 30 min before the experiment. Changes in diameter were recorded during local infusions of noradrenaline, bradykinin, acetylcholine, glyceryl trinitrate, L- and D-arginine and its NG-monomethyl derivatives. L-NMMA (100 nmol.min-1) stereospecifically inhibited vasodilatation induced by acetylcholine and bradykinin (p less than 0.02) but not that induced by the endothelium independent vasodilator glyceryl trinitrate. L-NMMA (100 nmol.min-1) potentiated the venoconstrictor effect of a high dose of acetylcholine (100 nmol.min-1) without affecting the action of noradrenaline and without having a direct venoconstrictor effect in doses up to 10 mumol.min-1. These results show that the venous effects of certain vasodilators in man are mediated through the release of nitric oxide (EDRF) synthesised from L-arginine. They also highlight differences in basal and stimulated production of nitric oxide between arteries and veins.

Adult↗
PubMed1989

A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation.

1. The role of L-arginine in the basal and stimulated generation of nitric oxide (NO) for endothelium-dependent relaxation was studied by use of NG-monomethyl L-arginine (L-NMMA), a specific inhibitor of this pathway. 2. L-Arginine (10-100 microM), but not D-arginine (100 microM), induced small but significant endothelium-dependent relaxations of rings of rabbit aorta. In contrast, L-NMMA (1-300 microM) produced small, endothelium-dependent contractions, while its enantiomer NG-monomethyl-D-arginine (D-NMMA; 100 microM) had no effect. 3. L-NMMA (1-300 microM) inhibited endothelium-dependent relaxations induced by acetylcholine (ACh), the calcium ionophore A23187, substance P or L-arginine without affecting the endothelium-independent relaxations induced by glyceryl trinitrate or sodium nitroprusside. 4. The inhibition of endothelium-dependent relaxation by L-NMMA (30 microM) was reversed by L-arginine (3-300 microM) but not by D-arginine (300 microM) or a number of close analogues (100 microM). 5. The release of NO induced by ACh from perfused segments of rabbit aorta was also inhibited by L-NMMA (3-300 microM), but not by D-NMMA (100 microM) and this effect of L-NMMA was reversed by L-arginine (3-300 microM). 6. These results support the proposal that L-arginine is the physiological precursor for the basal and stimulated generation of NO for endothelium-dependent relaxation.

Acetylcholine↗
PubMed1989

Local opioid-sensitive afferent sensory neurones in the modulation of gastric damage induced by Paf.

1. The role of local sensory neurones in modulating the extent of gastric mucosal damage induced by close-arterial infusion of platelet-activating factor (Paf 50 ng kg-1 min-1 for 10 min) has been investigated in the anaesthetized rat. 2. Local intra-arterial infusion of the neurotoxin, tetrodotoxin (TTX), substantially augmented the mucosal damage induced by Paf, as assessed by both macroscopic and histological techniques. 3. In rats pretreated with capsaicin 2 weeks prior to study, to induce a functional ablation of primary afferent neurones, gastric damage induced by Paf was significantly augmented. 4. Administration of morphine (0.75-3 mg kg-1 i.v.) or its peripherally acting quaternary analogue, N-methyl morphine (15 mg kg-1 i.v.), also significantly enhanced the gastric damage induced by Paf. 5. The potentiation by morphine of Paf-induced gastric damage was inhibited by administration of the opioid antagonists, naloxone (1 mg kg-1 i.v.) or the peripherally acting N-methyl nalorphine (3 mg kg-1 i.v.). 6. Administration of TTX or morphine alone, or pretreatment with capsaicin did not induce any detectable mucosal damage, suggesting that interference with local sensory neuronal activity itself does not directly induce mucosal disruption. 7. These results indicate that peripheral opiate-sensitive afferent sensory neurones play a physiological defensive role in the mucosa, attenuating the extent of gastric damage induced by Paf.

Animals↗
PubMed1989

Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit.

1. The role of nitric oxide (NO) in the regulation of the vascular tone of the coronary circulation of the Langendorff-perfused rabbit heart was investigated. 2. NG-monomethyl-L-arginine (L-NMMA; 10-100 microM), a specific inhibitor of NO formation from L-arginine (L-Arg), but not its D-enantiomer (D-NMMA; 100 microM) produced a dose-related, sustained increase in the coronary perfusion pressure (CPP). In addition, L-NMMA inhibited the vasodilator responses of acetylcholine (ACh), unmasking in some instances its direct vasoconstrictor effect. These effects of L-NMMA were attenuated by L-Arg. 3. L-NMMA (10 and 30 microM), but not D-NMMA (30 microM), caused a long-lasting inhibition of NO formation which was reversed by L-Arg (30 and 100 microM), but not by D-Arg (100 microM). 4. This study indicates that the formation of NO from L-Arg in the coronary circulation of the rabbit plays a role both as a regulator of vascular tone and as a mediator of the vasodilatation induced by ACh.

Acetylcholine↗
PubMed1988

L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation.

The formation of nitric oxide (NO) from L-arginine by vascular endothelial cells and its relationship to endothelium-dependent relaxation of vascular rings was studied. The release of NO, measured by bioassay or chemiluminescence, from porcine aortic endothelial cells stimulated with bradykinin was enhanced by infusions of L-, but not D-arginine. The release of 15NO, determined by high resolution mass spectrometry, from L-guanidino 15N (99%) arginine was also observed, indicating that NO is formed from the terminal guanidino nitrogen atom(s) of L-arginine. L-NG-monomethyl arginine (L-NMMA), but not D-NMMA, inhibited both the generation of NO by endothelial cells in culture and the endothelium-dependent relaxation of rabbit aortic rings. Both these effects were reversed by L-arginine. These data indicate that L-arginine is the physiological precursor for the formation of NO which mediates endothelium-dependent relaxation.

Animals↗
PubMed1988

Actions of nitric oxide on the release of prostacyclin from bovine endothelial cells in culture.

Endothelial cells release the potent vasodilator prostacyclin, as well as the highly labile endothelium-derived relaxing factor (EDRF) which mediates vascular relaxation induced by some vasodilators including acetylcholine and bradykinin. EDRF has recently been characterised as nitric oxide (NO). The effects of NO on prostacyclin release, measured as 6-keto-PGF1 alpha, from endothelial cells obtained from bovine thoracic aorta, have now been investigated. Incubation of endothelial cells in culture with bradykinin (10-100 nM) stimulated the release of 6-keto-PGF1 alpha. Pre-incubation (0.5-2 min) with NO (13-130 microM) caused a significant dose-dependent inhibition of 6-keto-PGF1 alpha release, reaching a maximum of 29 +/- 4% inhibition. Pre-incubation with superoxide dismutase (30 units ml-1) which prevents the breakdown of NO, significantly augmented the degree of inhibition, as did the selective inhibitor of cyclic GMP phosphodiesterase, M & B 22948 (5 microM), reaching 51 +/- 2% inhibition. The potentiation by M & B 22948 suggests that this inhibitory effect of high concentrations of NO is brought about by elevation of intracellular cyclic GMP levels following activation of guanylate cyclase. Whether endogenous NO is produced by endothelial cells under physiological conditions in sufficient quantities to modulate prostacyclin release remains to be established.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Vascular endothelial cells synthesize nitric oxide from L-arginine.

Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue and for the inhibition of platelet aggregation and platelet adhesion attributed to endothelium-derived relaxing factor. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay, chemiluminescence or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.

Animals↗
PubMed1988

Effect of SKF 525A on the release of nitric oxide and prostacyclin from endothelial cells.

The effect of SKF 525A on the endothelium-dependent relaxation of rabbit aortic rings and on the release of nitric oxide and prostacyclin from porcine aortic endothelial cells in culture was examined. SKF 525A (10-30 microM) inhibited acetylcholine- but not the calcium ionophore A23187-induced endothelium-dependent relaxation without affecting the release of endothelium-derived relaxing factor from endothelial cells stimulated with bradykinin. Higher concentrations of SKF 525A (30-200 microM) caused transient endothelium-dependent relaxation of rabbit aortic rings and the release of nitric oxide and prostacyclin from the endothelial cells without inducing release of lactate dehydrogenase. The mechanism whereby SKF 525A releases nitric oxide and prostacyclin from endothelial cells requires further investigation.

Acetylcholine↗
PubMed1988

Isolation and washing of human platelets with nitric oxide.

Nitric oxide (NO) was compared with prostacyclin as an inhibitor of the activation of human platelets during isolation, washing and storage. The use of NO throughout the procedure prevented the activation of platelets. The morphology and behaviour of NO-washed platelets was similar to that of prostacyclin-washed platelets when stored at 4 degrees C for up to 24 h. Prolonged storage resulted in deterioration of the platelets which occurred earlier in the NO-washed than in the prostacyclin-washed platelets. The protective effect of NO was potentiated by the selective cGMP phosphodiesterase inhibitor M & B 22948, suggesting that it is mediated by the activation of guanylate cyclase.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1988

Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator.

1. Acetylcholine (ACh, 0.03-3.0 microM) induced a dose-dependent vasodilatation in the isolated Langendorff-perfused heart of the rabbit. The vasodilatation was mimicked by exogenous nitric oxide (NO, 0.045-4.5 nmol). 2. There was no detectable vascular relaxing activity in the cardiac effluent when these concentrations of ACh or NO were injected through the heart, even in the presence of an infusion of superoxide dismutase (SOD). 3. Acetylcholine (0.03-3.0 microM), however, induced the release into the cardiac effluent of a material which produced a chemiluminescent signal when reacted with ozone, a response which could be mimicked with exogenous NO (0.045-4.5 nmol) injected through the heart. 4. The effects of ACh, but not those of NO, were antagonized by atropine (2 microM). Prostacyclin (1 microM) injected through the heart induced vasodilatation without the release of a biologically active or chemiluminescent material. 5. During passage through the heart, greater than 99% of the biological activity of exogenous NO disappeared, whereas there was approximately 50% reduction of its chemiluminescent response. This indicates complete transformation into a mixture containing approximately 50% NO2- and 50% of other non-chemiluminescent material(s), presumably NO3-. 6. This study suggests that ACh induces endothelium-dependent vasodilatation in the coronary circulation through the release of the endogenous nitrovasodilator, NO, which is rapidly converted to NO2- and NO3-.

Acetylcholine↗