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Biomedical subjects

R Levi

Publications and source records attributed to R Levi.

At least 19 recordsLinked to original sources
PubMed1992

Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle.

Nitric oxide (NO) synthesis is induced in vascular smooth muscle cells by lipopolysaccharide (LPS) where it appears to mediate a variety of vascular dysfunctions. In some cell types tetrahydrobiopterin (BH4) synthesis has also been found to be induced by cytokines. Because BH4 is a cofactor for NO synthase, we investigated whether BH4 synthesis is required for LPS-induced NO production in rat aortic smooth muscle cells (RASMC). The total biopterin content (BH4 and more oxidized states) of untreated RASMC was below our limit of detection. However, treatment with LPS caused a significant rise in biopterin levels and an induction of NO synthesis; both effects of LPS were markedly potentiated by interferon-gamma. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I, the rate-limiting enzyme for de novo BH4 synthesis, completely abolished the elevated biopterin levels induced by LPS. DAHP also caused a concentration-dependent inhibition of LPS-induced NO synthesis. Inhibition of NO synthesis by DAHP was reversed by sepiapterin, an agent which circumvents the inhibition of biopterin synthesis by DAHP by serving as a substrate for BH4 synthesis via the pterin salvage pathway. The reversal by sepiapterin was overcome by methotrexate, an inhibitor of the pterin salvage pathway. Sepiapterin, and to a lesser extent BH4, dose-dependently enhanced LPS-induced NO synthesis, indicating that BH4 concentration limits the rate of NO production by LPS-activated RASMC. Sepiapterin also caused LPS-induced NO synthesis to appear with an abbreviated lag period phase, suggesting that BH4 availability also limits the onset of NO synthesis. In contrast to the stimulation of LPS-induced NO synthesis, observed when sepiapterin was given alone, sepiapterin became a potent inhibitor of NO synthesis in the presence of methotrexate. This is attributable to a direct inhibitory action of sepiapterin on GTP cyclohydrolase I, an activity which is only revealed after blocking the metabolism of sepiapterin to BH4. Further studies with sepiapterin, methotrexate, and N-acetylserotonin (an inhibitor of the BH4 synthetic enzyme, sepiapterin reductase) indicated that the BH4 is synthesized in RASMC predominantly from GTP; however, a lesser amount may derive from pterin salvage. We demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by LPS in vascular smooth muscle. Our findings also suggest that pterin synthesis inhibitors may be useful for the therapy of endotoxin- and cytokine-induced shock.

Amino Acid Oxidoreductases↗
PubMed1992

Nitric oxide synthase in macula densa regulates glomerular capillary pressure.

Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.

Amino Acid Oxidoreductases↗
PubMed1992

Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.

BACKGROUND: Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension. PURPOSE: The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension. METHODS: Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine. RESULTS: Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA. CONCLUSIONS: Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors. IMPLICATIONS: Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Amino Acid Oxidoreductases↗
PubMed1992

Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice.

The influenza virus haemagglutinin epitope 91-108, which is a conserved amino acid sequence in all type A H3 strains, was expressed in Salmonella flagellin, to evaluate its potential as a vaccine. For that purpose, a synthetic oligonucleotide comprising 54 bases coding for the corresponding sequence was inserted into the plasmid pLS408 and transformed into Escherichia coli JM101. Colonies containing the recombinant plasmid were used to transform Salmonella typhimurium LB5000 and were then transduced to a flagellin negative 'live vaccine' aroA mutant of Salmonella dublin. Rabbits immunized either with the live recombinant S. dublin or with the flagellin isolated from it, showed significant levels of IgG response against the synthetic peptide 91-108 as well as against the intact A/Texas/77 influenza virus. Mice immunized with the same preparations developed influenza-specific IgG antibodies in the blood and secreted IgA antibodies in their lungs. Furthermore, these mice showed about 50% protection against challenge infection with the virus. The most successful results were achieved by intranasal immunization with the isolated recombinant flagellin, when employed without the aid of adjuvant.

Amino Acid Sequence↗
PubMed1992

Peptide binding to class I molecules of the major histocompatibility complex on the surface of living target cells.

Molecules encoded by the class I major histocompatibility genes bind short (nonameric) peptides produced by intracellular proteolysis of antigens. These complexes formed intracellularly are then expressed on membranes of target cells and recognized by the antigen receptor of cytolytic T cells. No binding of externally added peptides could so far be monitored directly on the antigen presenting cells, although cytotoxicity experiments and indirect binding assays provided evidence for its existence. Here we report experiments where specific binding to class I molecules, of externally added peptides, has been monitored on living cells. N-terminal biotin-labelled Kd-restricted peptides (residues 147-155, residues 147-158, and an analogue lacking the arginine at position 156, derived from the sequence of the influenza A virus nucleoprotein) were incubated with murine H-2Kd mastocytoma cells (line P815) at 4 degrees C. The binding on surface of live, intact cells was then demonstrated fluorometrically via the interaction of a streptavidin-phycoerythrin conjugate with the biotin-labelled peptides. Thus, this binding does not involve processing, and its specificity in terms of peptide structure was established by competition with the respective unmodified peptides. The specificity of binding to class I molecules was demonstrated by blocking experiments using monoclonal antibodies specific for H-2Kd. Finally, a correlation was observed between the results of peptide binding measurements and those of cytotoxicity assays.

Amino Acid Sequence↗
PubMed1992

Episodic cluster headache. I: Personality and some neuropsychological characteristics in male patients.

The etiology and pathogenesis of cluster headache remain largely unknown. Some previous studies have focused on personality characteristics in cluster headache. However, no consistent personality profile has been found. The present study applied two personality inventories, the Karolinska Scales of Personality (KSP) and the Heart and Lifestyle Type A Measure (HALTAM), that have not previously been used in the context of cluster headache. A correlation has been suggested between left-handedness and early learning difficulties, and cluster headache. Thus, these variables were included and measured by inventory techniques. Forty-nine out of 51 consecutive male patients with episodic cluster headache participated in the present study. As compared to controls, the cluster headache patients were significantly more anxiety-prone (higher scores in the KSP Somatic anxiety and Muscular tension subscales), less successfully socialized (low scores in the KSP Socialization scale), and had a more hostile attitude towards others (higher scores in the HALTAM Hostility scale). No relationships between left-handedness or early learning difficulties, and cluster headache disease were found. The implications of the personality differences for the etiology of cluster headache disease are discussed.

Adult↗
PubMed1992

Episodic cluster headache. II: High tobacco and alcohol consumption in males.

Forty-nine out of 51 consecutive male patients with episodic cluster headache were studied with regard to their smoking and drinking habits in general and in relation to cluster headache periods. Questionnaires were constructed for data regarding tobacco intake. Situation-related smoking behavior was registered according to Frith (1971). Screening for alcohol over-consumption was made using the Malmö modification of the brief Michigan Alcoholism Screening Test (Mm-MAST). Eighty-three percent of the patients used tobacco on a regular basis at the time of the study, with an average consumption of 20 cigarettes per day. Only 3% had never used tobacco regularly. The smoking-related desire to smoke in different situations was consistent with what is found in a general population of smokers. Sixty-seven percent of the patients had scores on the Mm-MAST indicative of alcohol over-consumption (i.e. heavy social drinking or alcoholism). During active headache periods 79% decreased their alcohol intake, whereas no consistent change in tobacco consumption was reported for the group as a whole. These findings were further corroborated by the fact that alcohol, but not tobacco intake, was reported by the majority of patients to elicit headache attacks during periods. Thus, our study showed high alcohol and tobacco consumption to be prominent features in male patients with episodic cluster headache. Since neither alcohol nor tobacco appear to have properties of ameliorating headache periods or attacks, the addictive behavior in our patients more likely reflects certain personality characteristics.

Adolescent↗
PubMed1992

NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone?

Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.

Animals↗
PubMed1992

Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites.

Hypoxia is a potent coronary-vasodilating signal; its mechanisms are still controversial. We have assessed the possible role of nitric oxide (NO) in hypoxic coronary vasodilatation (HCVD) in isolated guinea pig hearts perfused at constant pressure. HCVD was elicited by a 1-minute 100% N2 exposure; coronary flow doubled within 1 minute of hypoxia (early phase) and returned to baseline within 40 seconds after reoxygenation (late phase). The early phase of HCVD was associated with a rapid approximately eightfold increase in cGMP overflow, an indication of NO release. The specific NO synthase inhibitor N omega-methyl-L-arginine (NMA, 0.1-1 mM) antagonized HCVD and the associated increase in cGMP spillover (maximum inhibition, approximately 65%); excess arginine (1.2 mM) prevented both effects. The late phase of HCVD was associated with an increase in adenosine overflow and was attenuated by the adenosine receptor antagonist BW A1433 (1 microM; maximum inhibition, approximately 45%). Indomethacin (10 microM) inhibited HCVD in spontaneously beating hearts by approximately 35% but had no effect in hearts paced at faster rates. NMA and BW A1433 were more effective in combination than alone (maximum inhibition, approximately 72%). However, irrespective of the concentrations used, there was no synergism among the anti-HCVD effects of NMA, BW A1433, and indomethacin, nor was HCVD completely inhibited by the antagonists, whether alone or in combination. Our findings indicate that NO is an important mediator of the early phase of HCVD, whereas additional mechanisms and/or factors, including adenosine and vasodilatatory prostaglandins, contribute to the late phase.

Adenosine↗
PubMed1992

A central nervous system action of nitric oxide in blood pressure regulation.

We had reported that the systemic administration of N omega-methyl-L-arginine (L-NMA), a specific inhibitor of nitric oxide (NO) synthesis from L-arginine (ARG), raises arterial blood pressure (BP) while paradoxically enhancing central sympathetic outflow. Cervical spinal cord transection abolishes the increase in sympathetic outflow and attenuates the pressor effect of L-NMA. Thus, in addition to lowering BP by direct vasorelaxation, NO may also act in the central nervous system to reduce vascular sympathetic tone. To test this hypothesis we have injected L-NMA directly into the central nervous system in anesthetized rats. Intracisternally (i.c.), L-NMA elicited a small pressor response accompanied by a marked increase in sympathetic renal nerve activity (RNA). In contrast, the inactive stereoisomer N omega-methyl-D-arginine had neither pressor nor neural effects. The increases in RNA and BP elicited by i.c. L-NMA were abolished by spinal cord transection at C1 to C2 and by the i.v. administration of ARG. When administered i.c., ARG also abolished the increase in RNA elicited by i.v. L-NMA and significantly attenuated the pressor response. Thus, our findings indicate that L-NMA acts centrally by an ARG-reversible mechanism in the anesthetized rat to stimulate sympathetic nerve activity. Inasmuch as centrally synthesized NO has been postulated to play a second messenger and/or neurotransmitter role, our findings suggest that one such function would be the central regulation of sympathetic outflow and hence, BP.

Animals↗
PubMed1991

Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages.

We have previously reported that cultured murine brain endothelial cells (MBE) produce large quantities of nitric oxide (NO) after activation with interferon-gamma in combination with any of several immunoactivators including: bacterial endotoxin, tumor necrosis factor and interleukin-1. Since endothelial cells are the first example of a cell-type which may possess both a constitutive and an inducible type of NO synthase, it was of interest to compare the requirements of these two enzyme activities. Induction of NO synthesis in MBE by cytokines was abolished by the protein synthesis inhibitor, cycloheximide, and by 2,4-diamino-6-hydroxypyridine (DAHP), a selective inhibitor of GTP cyclohydrolase I, the rate-limiting enzyme for de novo synthesis of tetrahydrobiopterin (THB). In the presence of DAHP, NO synthesis was restored by sepiapterin (SEP), a substrate for the alternative pathway of THB synthesis occurring via pterin salvage. Moreover, SEP increased NO synthesis to greater than 150% of control values, suggesting that THB availability is rate-limiting for NO synthesis by cytokine-induced MBE. Methotrexate, an inhibitor of the pterin salvage pathway of THB synthesis, completely reversed the stimulation of NO synthesis by sepiapterin. Thus, cytokine-induced MBE NO synthase appears to have an absolute requirement for THB as cofactor. In additional studies we found that NO synthesis by cytokine-activated MBE was inhibited by NG-monosubstituted arginine analogs with a rank-order of potency NH2 greater than CH3 greater than NO2, in contrast with the rank-order of NO2 greater than NH2 greater than CH3 previously described for inhibition of the constitutive endothelial cell enzyme. Using a kinetic assay for NO synthase activity, based on oxidation of myoglobin heme-iron, we have found that these rank orders of potency also apply to cytosol preparations of cytokine-induced and untreated endothelial cells, respectively. Further differences between constitutive and cytokine-induced NO synthase were observed with regard to calmodulin requirements. Whereas constitutive NO synthase was potently inhibited by the calmodulin antagonists mellitin and trifluoperazine, cytokine-induced NO synthase was unaffected. In summary, NO synthesis by cytokine-activated MBE is THB-dependent, calmodulin-independent and inhibited by NG-substituted arginine analogs with a rank-order profile distinct from that for untreated endothelial cells but identical to that for cytokine-activated macrophages.

Amino Acid Oxidoreductases↗
PubMed1991

Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs.

The cofactor requirements of macrophage nitric oxide (NO.) synthase suggest involvement of an NADPH-dependent flavoprotein. This prompted us to test the effect of the flavoprotein inhibitors diphenyleneiodonium (DPI), di-2-thienyliodonium (DTI), and iodoniumdiphenyl (ID) on the NO. synthases of macrophages and endothelium. DPI, DTI, and ID completely inhibited NO. synthesis by mouse macrophages, their lysates, and partially purified macrophage NO. synthase. Inhibition of NO. synthase by these agents was potent (IC50's 50-150 nM), irreversible, dependent on time and temperature, and independent of enzyme catalysis. The inhibition by DPI was blocked by NADPH, NADP+, or 2'5'-ADP, but not by NADH. Likewise, FAD or FMN, but not riboflavin or adenosine 5-diphosphoribose, protected NO. synthase from inhibition by DPI. Neither NADPH nor FAD reacted with DPI. Once NO. synthase was inhibited by DPI, neither NADPH nor FAD could restore its activity. DPI also inhibited acetylcholine-induced relaxation of norepinephrine-preconstricted rabbit aortic rings (IC50 300 nM). Inhibition of acetylcholine-induced relaxation persisted for at least 2 h after DPI was washed out. In contrast, DPI had no effect on norepinephrine-induced vasoconstriction itself nor on vasorelaxation induced by the NO.-generating agent sodium nitroprusside. These results suggest that NO. synthesis in both macrophages and endothelial cells depends on an NADPH-utilizing flavoprotein. As a new class of NO. synthase inhibitors, DPI and its analogs are likely to prove useful in analyzing the physiologic and pathophysiologic roles of NO(.).

Amino Acid Oxidoreductases↗
PubMed1991

Increase in concanavalin A cap formation on lymphoma cells following interaction with inactive influenza viruses.

Binding of the lectin Con A to its ligand on the cell surface of normal circulating lymphocytes induces capping in 28-32% of these cells. This Con A cap formation is markedly decreased in malignant cells from the human hematopoietic system. Among others, the human lymphoma Daudi cell line exhibit a cap formation with Con A in only 5-10% of the cells. In this study, we found that inactivated influenza viruses induced changes in the cell surface membrane of Daudi cells resulting in an increased percentage of Con A cap forming cells (30-40%). This phenomenon occurred independently of viral replication and was initiated by adsorption of inactivated viral particles or isolated hemagglutinin and neuraminidase viral glycoproteins. This phenomenon may be due to the binding of Con A molecules to viral receptors and to cell receptors leading to crosslinking of Con A receptors that will induce their mobility and the formation of a cap. Alternatively, experiments performed with cytochalasin B and colchicine suggest that the viral interaction with the cell membrane may have induced changes in the cytoskeleton at the level of microtubules. These changes induced increased lateral movement of the Con A receptors resulting into formation of a cap.

Adsorption↗
PubMed1990

[Malignant skin neoplasms].

Malignant skin neoplasms of the auricle and peri-auricular region constitute only 6% of all skin cancers. However, rates of recurrence and metastasis are higher than for other cutaneous malignancies. Of 81 patients with malignant skin neoplasms of the auricle, 53.1% had basal cell carcinoma, 39.5% squamous cell carcinoma and 7.4% malignant melanoma. The neoplasms were 4 times more common in men (more than in other series), and more common in those of Ashkenazi origin (75% of the patients) and in the elderly (peak incidence in the 7th decade). All patients were treated surgically, and 21 were also irradiated. In 4 with cervical metastases neck dissection was performed. The recurrence rate for all neoplasms was 12.4% and the rate of metastases to regional lymph nodes from squamous cell carcinoma, 12.5%. There was a marked correlation between positive margins after surgical excision and rates of recurrence and regional metastases. Malignant skin neoplasms of the auricle should be regarded as high risk lesions which often recur and/or metastasize. Therefore, it is recommended to excise the tumors adequately so as to get negative margins, and to follow-up with careful, frequent evaluation.

Adolescent↗
PubMed1990

Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis.

Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.

Animals↗
PubMed1990

Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine.

Many cell types are known to synthesize nitric oxide (NO.) from L-arginine. There appear to be at least two forms of NO. synthase: an inducible, tetrahydrobiopterin- and flavin-dependent activity exemplified by the macrophage enzyme and a constitutive, Ca+(+)-dependent activity exemplified by the endothelial cell enzyme. L-NG-methylarginine inhibits NO. synthesis by both cell types. We now report that L-NG-aminoarginine and L-NG-nitroarginine are about 100-fold more potent than NG-methylarginine in blocking endothelial cell NO. synthesis. In contrast, NG-aminoarginine and NG-methylarginine are about equipotent with macrophages whereas NG-nitroarginine is much less potent. Since macrophage and endothelial cell NO. synthesis are differentially sensitive to the inhibitors, the panel of inhibitors can be used in complex biological systems to determine if macrophage-like or endothelial-like cells are the predominant source of NO.. Indeed, all three inhibitors elicit a strong pressor response in the anesthetized guinea pig, a result consistent with the view that endothelial cells continually produce vasodilatory NO(.).

Animals↗