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Biomedical subjects

S Moncada

Publications and source records attributed to S Moncada.

At least 55 records · Page 3Linked to original sources
PubMed1998

Persistent induction of nitric oxide synthase in tumours from mice treated with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid.

An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours. This pattern of induction is distinct from that caused by agents such as endotoxin, muramyl dipeptide or Corynebacterium parvum. The induction of NOS (iNOS) in the tumour was more persistent (maximal at 3 days) than in other tissues (maximal at 12 h). Immunohistochemical staining suggested that iNOS was located in macrophages and endothelial cells within and around the tumour. Treatment with 5,6-MeXAA also caused substantial increases in plasma nitrite and nitrate (NOx) concentrations that peaked at 8-12 h after 5,6-MeXAA. The increase in plasma NOx was prevented by a NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), indicating that it was due to enhanced production of NO. Tumour-bearing mice were more responsive than controls to 5,6-MeXAA both in their plasma NOx increase and in their lower maximally tolerated dose. L-NIO was unable to prevent the complete tumour necrosis and regression caused by 5,6-MeXAA at a dose that substantially inhibited the increase of plasma NOx. In conclusion, the experimental anti-tumour agent 5,6-MeXAA induced NO synthesis in tumour-associated macrophages and in immunologically active tissues in parallel with its effects on tumour growth. The experiments with a non-selective NOS inhibitor L-NIO, however, suggest that NO is not a significant component in the mechanism of the anti-tumour action of 5,6-MeXAA in this particular model.

Animals↗
PubMed1998

Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse.

1. The release of cytokines following administration of endotoxin and the contribution of nitric oxide (NO) to the subsequent haemodynamic profile were investigated in the conscious mouse. 2. Administration of endotoxin (E. Coli, 026:B6, 12.5 mg kg(-1), i.v.) elevated the concentration of tumour necrosis factor-alpha (TNF-alpha) in the plasma within 0.5 h, reaching a maximum at 2 h and returning to control concentrations by 4 h. In addition, the concentration of interleukin-6 (IL-6) in the plasma was also elevated within 1 h, reaching a maximum at 3 h and remaining elevated throughout the 12 h of study. 3. Endotoxin (12.5 mg kg(-1), i.v.) induced the expression of a Ca2+-independent (inducible) NO synthase in the mouse heart and elevated the concentrations of nitrite and nitrate in the plasma within 4 h, reaching a maximum at 12 h. This was accompanied by a progressive fall in blood pressure over the same period. 4. The vasopressor effect of noradrenaline (0.5-4 microg kg(-1) min(-1), i.v.) administered as a continuous infusion was significantly attenuated 7 h after endotoxin (12.5 mg kg(-1), i.v). 5. The NO synthase inhibitor NG-monomethyl-L-arginine HCl (L-NMMA; 1-10 mg kg(-1), i.v. bolus) reversed the fall in blood pressure when administered 7 h after endotoxin (12.5 mg kg(-1), i.v.). 6. In an attempt to maintain a constant blood concentration, L-NMMA was administered as a continuous infusion (10 mg kg(-1) h(-1), i.v.), beginning 4 h after a lower dose of endotoxin (6 mg kg(-1), i.v.). Such treatment prevented the fall in blood pressure and the elevation of nitrite and nitrate in the plasma throughout the 18 h of observation. 7. The fall in blood pressure following endotoxin (3 mg kg(-1), i.v.) was significantly reduced throughout the 18 h of observation in homozygous mutant mice lacking the inducible NO synthase. 8. In summary, we have developed a model of endotoxin shock in the conscious mouse in which an overproduction of NO by the inducible NO synthase is associated with the haemodynamic disturbances. This model, which exhibits many of the characteristics of septic shock in man, will enable the study of the pathology of this condition in more detail and aid the investigation of potential therapeutic agents both as prophylactics and, more importantly, as treatments.

Adrenergic alpha-Agonists↗
PubMed1998

Nitrergic neurotransmission mediates the non-adrenergic non-cholinergic responses in the clitoral corpus cavernosum of the rabbit.

The corpus cavernosum is the erectile tissue in the penis and clitoris. Although nitrergic neurotransmission has been characterized in detail in the penile corpus cavernosum, functional studies on the inhibitory non-adrenergic non-cholinergic (NANC) transmission in the clitoral corpus cavernosum have been lacking. Here we demonstrate that electrical field stimulation (EFS) induces NANC relaxation responses in the clitoral corpus cavernosum of the rabbit. These responses were inhibited by NG-nitro-L-arginine methylester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) or tetrodotoxin. The inhibitory effect of L-NAME was partially reversed by L-arginine but not by D-arginine. EFS-induced relaxations were enhanced by an inhibitor of type V cyclic GMP phosphodiesterase, zaprinast. These results suggest that nitrergic neurotransmission is responsible for the NANC relaxation responses in the clitoral corpus cavernosum of the rabbit.

Animals↗
PubMed1998

S-nitrosoglutathione inhibits platelet activation and deposition in coronary artery saphenous vein grafts in vitro and in vivo.

OBJECTIVE: To investigate platelet activation and deposition in human saphenous vein and internal mammary artery grafts following coronary artery bypass in vitro and in vivo, as well as inhibition of activation by the platelet selective nitric oxide donor S-nitrosoglutathione (GSNO). DESIGN: Controlled in vitro and in vivo studies. SETTING: Tertiary cardiac centre. PATIENTS: 24 patients undergoing coronary artery bypass surgery requiring vein and artery grafts. INTERVENTIONS: In vitro: human platelet rich plasma was perfused through segments of vein and artery, with or without GSNO 10(-6) M, and the platelet count was measured in the effluent. In vivo: indium-111 labelled antibody against the platelet alpha granule protein GMP-140 was injected at the end of coronary bypass grafting and gamma counts were compared between vein and artery grafts with or without systemic infusion of GSNO (40 nmol/min). RESULTS: In vitro: platelet count in perfused vein (< 70% of baseline) decreased more than in artery segments (89-94% of baseline) (p < 0.001). The platelet count was unchanged with GSNO in vein and artery segments. In vivo: gamma counts were greater at all time points over vein than artery grafts (p < 0.05), and were reduced by infusion of GSNO (p < 0.05). CONCLUSIONS: Platelet activation is greater in vein than in artery grafts in vitro and in vivo. Activation, which contributes to early vein graft failure, was inhibited by GSNO.

Aged↗
PubMed1998

[Occupational accidents in Barcelona (Spain), from 1992 to 1993].

INTRODUCTION: The statistics related to labor accidents as with any other notification system ought to be the basis for programs and policies with a view to the adoption of preventive measures. In order to establish preventive norms, however, the health system needs data from researchers focussing on the dynamics of and the pitfalls revealed by specific events. Within this context the main objective of this study is to proceed with an in-depth analysis of the labor accidents verified in Barcelona (Spain) using for this purpose a descriptive statistics model to test variables such as type of accident, economic sector, economic enterprise and type of labor contract. METHOD: The data source utilized was the notification system for labor accidents with grave consequences such as death of the victim registered in Barcelona during the period 1992-1993. Labor accidents registered for male workers numbered 848. A log-linear model was applied to this data base. RESULTS AND CONCLUSIONS: The results show a positive association between traumatic accidents with the construction, traffic and services sectors. A positive association was also found between traumatic accidents and the size of the company concerved the small ones being the worse type in terms of worker's injuries. Regarding the nontraumatic accidents, the study showed a positive correlation between large-sized enterprises and type of temporary worker and the civil construction sector as compared to workers with long term work contracts within industry and services. There was some evidence, also, of a positive association between small and medium sized companies and temporary work and the occurrence of work accidents.

Accidents, Occupational↗
PubMed1998

[Role of nitric oxide in cell respiration].

Nitric oxide (NO) synthesized in a constitutive manner by a cell, acts on effector cells as a physiological regulator of the vascular tone, of platelet inhibition and of neuron-neuron interaction. By contrast, the release for longer periods of time of higher amounts of inducible NO, transforms NO from a physiological mediator into a cytostatic and cytotoxic molecule. The presence of NO synthetase in mitochondria suggests that physiological small amounts of NO could be involved in cellular respiration regulation by inhibition of cytochrome oxidase. Long exposure of cells to NO results in an irreversible inhibition of cellular respiration not dependent on a generalized superoxide or peroxynitrite formation. Cellular respiration inhibition could be reverted by either analyzing complex IV alone, by blocking Complex I or by the addition of gluthation. Therefore, our hypothesis is that suppression of complex IV is a normal physiological effect dependent on NO concentration. When cells are exposed to NO for longer periods of time, thiol groups are nitrosilated in complex I while gluthation transnitrosilates until its level drops to critical values. At this point, cellular respiration is blocked and this could be the pathway by which NO is transformed from a physiological mediator into a pathological molecule. We also believe that thiol nitrosilation and transnitrosilation by gluthation is a critical mechanism involved in oxidative stress prevention.

Cell Respiration↗
PubMed1997

Nitrergic control of peripheral sympathetic responses in the human corpus cavernosum: a comparison with other species.

Noradrenergic contractions induced by electrical field stimulation (EFS) of the rabbit anococcygeus muscle and the human and rabbit corpus cavernosum did not occur until termination of stimulation, even when EFS was applied for long periods (10 min). After treatment with a nitric oxide synthase inhibitor, a scavenger of NO, or a specific inhibitor of the soluble guanylate cyclase, EFS-induced contraction began as soon as stimulation commenced and its magnitude and duration were increased. In the presence of a cGMP-phosphodiesterase inhibitor, the lag period between the end of EFS and the onset of contraction was longer, and the response was smaller. Even when the concentration of endogenous noradrenaline was increased with cocaine, the contraction still did not occur during EFS and the lag period was unchanged, although the response was enhanced. When tissue tone was elevated, relaxation occurred during EFS followed by a contraction. After blockade of neuronal noradrenaline release with guanethidine, contractions of the tissues to increasing concentrations of exogenous noradrenaline were significantly reduced by EFS, an effect that was reversible by inhibition of NO synthase. In contrast, in the rat and mouse anococcygeus muscles contraction began immediately with EFS, and nitrergic stimulation by EFS did not affect the responses elicited by high concentrations of exogenous noradrenaline. These results suggest that the human and rabbit genitourinary organs have a powerful nitrergic innervation that does not merely modulate, but actually controls, the sympathetic responses. Our observations may increase understanding of the balance between nitrergic and sympathetic systems in humans, disruption of which may contribute to certain pathological conditions.

Animals↗
PubMed1997

Subcellular localization of nitric oxide synthase in the cerebral ventricular system, subfornical organ, area postrema, and blood vessels of the rat brain.

The distribution of neuronal nitric oxide synthase (nNOS) has been studied in the more rostral portion of the lateral ventricle, subfornical organ, area postrema and blood vessels of the rat central nervous system. nNOS was located by means of a specific polyclonal antibody, by using light and electron microscopy. Light microscopy showed immunoreactive varicose nerve fibers and terminal boutons-like structures in the lateral ventricle, positioned in supra- and subependimal areas. The spatial relationships between immunoreactive neuronal processes and the wall of the intracerebral blood vessels were studied. Electron microscopy showed numerous nerve fibers in the wall of the lateral ventricle; many were nNos-immunoreactive and established very close contact with ependymal cells. Immunoreactive neurons and processes were found in the subependymal plate of the ventricular wall, the subfornical organ, the area postrema, and the circularis nucleus of the hypothalamus. In these last three areas, the immunoreactive neurons were found close to the perivascular space of fenestrated and nonfenestrated blood vessels. The nNOS immunoreactivity was localized to the endoplasmic reticulum, cisterns, ribosomes, neurotubules, and in the inner part of the external membrane. In the terminal boutons, the reaction product was found surrounding the vesicle membranes. This distribution showed nNOS as a predominantly membrane-bound protein. The nitrergic nerve fibers present in the wall of the ventricular system might regulate metabolic functions as well as neurotransmission in the subfornical organ, area postrema and circularis nucleus of the hypothalamus.

Animals↗
PubMed1997

Visualisation of nitric oxide released by nerve stimulation.

We have visualised nitric oxide (NO) released from the electrically stimulated myenteric plexus and hypogastric nerve. NO was visualised by a reaction with luminol and hydrogen peroxide to generate photons which were counted using a microscope coupled to a photon counting camera. Electrical stimulation of the tissues induced an increase in photon counts which was frequency-dependent and prevented by inhibition of the NO synthase or by tetrodotoxin. The light emitted during nerve stimulation was not only observed at the nerve terminals but also at the axon and soma. Our results indicate that NO released from the whole nerve cell may affect target cells surrounding all parts of the nitrergic neuron. Thus, NO functions as a unique mechanism of synaptic and non-synaptic communication in the nervous system.

Animals↗
PubMed1997

Modulation of noradrenergic responses by nitric oxide from inducible nitric oxide synthase.

The effect of lipopolysaccharide (LPS) treatment on noradrenergic responses elicited by electrical field stimulation (EFS) was investigated in the rabbit anococcygeus muscle. In the absence of LPS, EFS-induced contractions were enhanced and nitrergic relaxations were inhibited by NG-nitro-L-arginine (L-NOARG) but not by NG-monomethyl-L-arginine (L-NMMA). Administration of L-NMMA prior to L-NOARG inhibited the enhancement of EFS-induced contractions by L-NOARG and reversed the inhibitory effect of L-NOARG on nitrergic relaxations. Treatment with LPS induced a time-dependent loss of phenylephrine-induced tone which was inhibited by cycloheximide, dexamethasone, L-NMMA, or L-NOARG. Treatment of the anococcygeus muscle with LPS also resulted in a time-dependent loss in the magnitude of EFS-induced contractions and an increase in the delay of onset of contractions. These effects were reversible by pretreatment with cycloheximide or by treatment with L-NMMA. These results suggest that LPS induces a loss of tone and of noradrenergic responses through expression of the inducible NO synthase in the rabbit anococcygeus muscle. L-NMMA blocks these effects but does not affect nitrergic transmission, while L-NOARG is active against both.

Animals↗
PubMed1997

Receptor specificity and trigemino-vascular inhibitory actions of a novel 5-HT1B/1D receptor partial agonist, 311C90 (zolmitriptan).

1. 311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone) is a novel 5-HT1B/1D receptor agonist with proven efficacy in the acute treatment of migraine. Here, we describe the receptor specificity of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. 2. At the "5-HT1B-like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A50] = 6.79 +/- 0.06) partial agonist achieving 77 +/- 4% of the maximum effect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A50] = 6.48 +/- 0.04) was half as potent as 311C90 and produced 97 +/- 2% of the 5-HT maximum effect. Studies in which receptor inactivation methods were used to estimate the affinity (pKA) and efficacy relative to 5-HT (tau rel) for each agonist confirmed that 311C90 exhibits higher affinity than sumatriptan (pKA = 6.63 +/- 0.04 and 6.16 +/- 0.03, respectively) and that both drugs are partial agonists relative to 5-HT (tau rel = 0.61 +/- 0.03 and 0.63 +/- 0.10, respectively, compared to 5-HT = 1.0). 3. Consistent with its effects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A50] = 6.92 +/- 0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2-3 fold higher than for sumatriptan (p[A50] = 6.46 +/- 0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A50] = 7.3 +/- 0.1 and 6.7 +/- 0.1, respectively), but maximum effects relative to 5-HT were lower (37 +/- 8% and 35 +/- 7%, respectively). In both types of vessel, the inability of 5-HT1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT2A receptors. 4. 311C90 displayed high affinity at human recombinant 5-HT1D (formerly 5-HT1D alpha) and 5-HT1B (formerly 5-HT1D beta) receptors in transfected CHO-K1 cell membranes (pIC50 values = 9.16 +/- 0.12 and 8.32 +/- 0.09, respectively). In intact cells, the drug produced concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase (p[A50] = 9.9 and 9.5, respectively) achieving the same maximum effect as 5-HT. Excepting human recombinant 5-HT1A and 5-ht1F receptors at which the drug behaved as an agonist with modest affinity (pIC50 = 6.45 +/- 0.11 and 7.22 +/- 0.12, respectively), 311C90 exhibited low, or no detectable affinity (pKi or pKB < or = 5.5) at numerous other monoamine receptors, including other 5-HT receptor subtypes. 5. When administered to anaesthetized guinea-pigs ten minutes before unilateral electrical stimulation of the trigeminal ganglion (1.2 mA, 5 Hz, 5 ms, 5 min), 311C90 (3-30 micrograms kg-1, i.v.) caused a dose-dependent inhibition of [125I]-albumin extravasation within the ipsilateral dura mater. At the same doses, the drug also produced dose-dependent falls in cranial vascular conductance (32.3 +/- 7.5% at 30 micrograms kg-1), as measured in the ear by laser doppler flowmetry. 6. These results show that 311C90, a novel member of the 5-HT1B/1D agonist drug class, exhibits a high degree of pharmacological specificity. Its potent partial agonist action at "5-HT1B-like' receptors in intracranial arteries, coupled with potent agonism at 5-HT1D and 5-HT1B receptors and an ability to inhibit neurogenic plasma protein extravasation in the dura, are consistent with its utility as an effective acute treatment for migraine.

Animals↗
PubMed1997

Nitrergic modulation of cholinergic responses in the opossum lower oesophageal sphincter.

1. Electrical field stimulation (EFS) of the superfused lower oesophageal sphincter from opossum (Monodelphis domestica) elicited biphasic responses. The first phase (relaxation) was strictly dependent on the duration of the EFS. The second phase (contraction) started following termination of the EFS (< or = 15 Hz). EFS at frequencies above 15 Hz led only to contraction, which started immediately upon initiation of the stimulation. 2. In the presence of NG-nitro-L-arginine (L-NOARG; 0.1-300 microM), the relaxation phase was abolished and the contractile response started with the initiation of EFS (at all frequencies) and was greater in magnitude. The contractile response to EFS was completely blocked with scopolamine (10 microM). 3. Exogenous acetylcholine (1-100 microM) elicited concentration-dependent contractions of the sphincter in the presence of botulinum toxin. These contractions were abolished when EFS was applied during administration of acetylcholine. This inhibitory effect of EFS was completely reversed when the tissue was treated with L-NOARG (100 microM). 4. These results suggest that the cholinergic response in the opossum lower oesophageal sphincter is under nitrergic control.

Acetylcholine↗