Biomedical subjects

Jamil Assreuy

Publications and source records attributed to Jamil Assreuy.

17 recordsLinked to original sources

PubMed2006

Nitric oxide and cardiovascular dysfunction in sepsis.

Sepsis and septic shock are the major causes of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction involving chemical mediators such as cytokines and chemokines and inflammatory cells such as the polymorphonuclear neutrophil and macrophage takes place. In addition to this systemic inflammatory process, sepsis and septic shocks cause a profound decrease in the peripheral vasomotor tone leading to a great decrease in the peripheral resistance. This event is central to derangement of hemodynamic and perfusion parameters. Nitric oxide (NO) is produced by several cell types and has been implicated in a wide range of physiological and pathological processes, with both detrimental and beneficial effects. There is a wealth of data implicating NO as a key player in all cardiac, vascular, renal and pulmonary derangements of sepsis and septic shock. Clinical assays trying to improve sepsis by inhibiting NO formation by NO synthases have met with failure, probably due to the lack of selectivity of inhibitors towards NOS isoforms. Notwithstanding the search for selective inhibitors, a better understanding of the NO molecular effector mechanisms may provide new opportunities for therapy development. Some of these NO effector mechanisms are discussed, including guanylate cyclase, nitrosothiols, potassium channels, reactive oxygen species and gene expression in the context of sepsis. Thus, more research on the relationship between NO and sepsis is clearly needed and warranted and may provide new therapeutic targets to treat sepsis and septic shock.

Animals↗

PubMed2005

Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity.

We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 micromol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier. Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.

Animals↗

PubMed2005

Comparative study of respiratory burst induced by phorbol ester and zymosan in human granulocytes.

OBJECTIVES: We have comparatively evaluated respiratory burst and some steps of its signaling in human granulocytes towards different stimuli. MATERIALS AND METHODS: An alternative method to remove erythrocytes by dextran differential sedimentation was employed. Respiratory burst (RB) was assessed in a flow cytometer by the oxidation of a fluorescent probe (dichlorodihydrofluorescein). Stimuli were phorbol ester (PMA) and zymosan. RESULTS: Granulocytes obtained with dextran sedimentation mounted a normal RB for the two stimuli but cells obtained by erythrocyte lysis were ineffective to respond to zymosan (P < 0.05). EGTA did not affect PMA-induced, but inhibited zymosan-induced RB (P < 0.05). PMA-induced RB was blocked by a protein kinase C inhibitor (P < 0.05), whereas zymosan was not. Microfilament integrity was essential for zymosan but not for PMA, whereas microtubule depolymerization does not seem to be essential for both stimuli. Granulocytes obtained from recently diagnosed leukemia patients responded relatively well to both stimuli but after chemotherapy, the response to zymosan was increased whereas cells were unable to respond to PMA. CONCLUSION: The use of the proposed method allows the study of both RB and phagocytosis, making it useful to study these granulocyte responses in the clinical and experimental settings.

Adult↗

PubMed2005

Involvement of NF-kappaB and glutathione in cytotoxic effects of nitric oxide and taxol on human leukemia cells.

Nitric oxide (NO) has been shown to be cytotoxic for normal and transformed cell lines. One of the intracellular targets for NO action is glutathione (GSH). GSH determinates cellular redox potential and modulates several biological events. During oxidative and nitrosative stress, glutathione system imbalance is associated with the upregulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, which is mediated by nuclear factor kappaB (NF-kappaB). Our previous studies demonstrated a cytotoxic effect of NO and taxol on human lymphoblastic leukemia cells triggered by inhibition of NF-kappaB activity. In this study, we have demonstrated the involvement of GSH in taxol- and NO-induced cytotoxic effects on human CEM leukemia cells. NO- and taxol-induced a depletion of GSH levels in CEM cells, which was potentialized by l-buthionine-S,R-sulfoximine (BSO), an inhibitor of gamma-GCS. BSO induced an increase in nuclear translocation of NF-kappaB. However, when cells were treated with NO or taxol in association with BSO, these compounds inhibited the constitutive activity of NF-kappaB. These results suggest that oxidative and nitrosative damage in lymphoblastic leukemia cells shall be mediated by NO- and taxol-induced GSH depletion as a consequence of preventing GSH synthesis.

Buthionine Sulfoximine↗

PubMed2005

Multiple potassium channels mediate nitric oxide-induced inhibition of rat vascular smooth muscle cell proliferation.

Several nitric oxide (NO) effects in the cardiovascular system are mediated by soluble guanylate cyclase (sGC) activation but potassium channels (KC) are also emerging as important effectors of NO actions. We investigated the relationship among vascular smooth muscle cell proliferation, NO, cyclic GMP, and KC using the A7r5 smooth muscle cell line derived from rat aorta. NO donors (two nitrosothiols, S-nitroso-acetyl-d,l-penicillamine, SNAP, and S-nitroso-glutathione, GSNO, and an organic nitrate, glyceryl trinitrate, GTN; 1-1000 microM) dose-dependently inhibited cell proliferation. ODQ (a selective inhibitor of sGC; 0.1 and 1 microM) and KT5823 (a selective inhibitor of cGMP-dependent protein kinase, 1 microM) prevented NO effects, confirming that sGC is a key target. In this report, we show that tetraethylammonium (TEA, a non-selective blocker of KC, 300 microM), and 4-aminopyridine (a selective blocker of voltage-dependent KC, 100 microM) prevented SNAP inhibitory effects on cell proliferation, whereas glibenclamide (a selective blocker of ATP-dependent KC, 1 microM) was ineffective. Iberiotoxin (a selective blocker of high conductance calcium-activated KC, 100 nM), as well charybdotoxin (a blocker of high and intermediate conductance calcium-activated KC, 100 nM) and apamine (a selective blocker of small conductance calcium-activated KC, 100 nM), blocked the antiproliferative effect induced by SNAP. NS1619 (an opener of high conductance calcium-activated KC, 1-100 microM), inhibited cell proliferation. In addition, sub-effective concentrations of ODQ (100 nM) and TEA (10 microM) synergized in blocking SNAP antiproliferative effects. Thus, voltage-dependent and calcium-activated but not ATP-dependent KC appear to have a prominent role, besides sGC activation, in NO-induced inhibition of vascular smooth muscle cell proliferation.

Adenosine Triphosphate↗

PubMed2005

The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. Adenosine-triphosphate (ATP)-sensitive potassium (K(ATP)) channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a K(ATP) channel blocker, in renal I/R injury in rats. METHODS: The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-10] 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na(+), and K(+) levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia. RESULTS: Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-alpha levels and nuclear factor-kappaB (NF-kappaB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours. CONCLUSION: Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.

Adenosine Triphosphate↗

PubMed2005

Corticosterone modulates noradrenaline-induced melatonin synthesis through inhibition of nuclear factor kappa B.

In chronically inflamed animals, adrenal hormones exert a positive control on the secretion of melatonin by the pineal gland. In this paper, the mechanism of corticosterone as a modulator of melatonin and N-acetylserotonin (NAS) was determined. Rat pineal glands in culture, stimulated for 5 hr with noradrenaline (10 nm), were previously incubated with corticosterone (1.0 nm-1.0 microm) for 48 hr in the presence or absence of the glucocorticoid receptor (GR) antagonist, mifepristone (1.0 microm), the proteasome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN, 12.5 microm) or the antagonist of the nuclear factor kappa B (NFkappaB), pyrrolidinedithiocarbamate (PDTC, 12.5 microm). Corticosterone potentiated noradrenaline-induced melatonin and NAS production in a bell-shaped manner. The increase in NAS (12.9 +/- 2.7, n=6 versus 34.3 +/- 8.3 ng per pineal) and melatonin (16.3 +/- 2.0, n=6 versus 44.3 +/- 12.9 ng per pineal) content induced by 1 microm corticosterone was blocked by mifepristone, and mimicked by ALLN and PDTC. The presence of GRs was shown by [3H]-dexamethasone binding (0.30 +/- 0.09 pmol/mg protein) and corticosterone inhibition of NFkappaB nuclear translocation was demonstrated by electromobility shift assay. Therefore, corticosterone potentiates noradrenaline-induced melatonin and NAS production through GR inhibition of NFkappaB nuclear translocation. To the best of our knowledge, this is the first time that this relevant pathway for passive and acquired immune response is shown to modulate melatonin production in pineal gland.

Animals↗

PubMed2004

Involvement of guanylate cyclase and potassium channels on the delayed phase of mouse carrageenan-induced paw oedema.

Previous studies from this laboratory have shown that administration of nitric oxide (NO) donors reduces the early phase (which peaks at 4 h) of carrageenan-induced paw oedema. The aim of this study was to investigate the influence of NO donors on the delayed phase of the mouse paw oedema, which peaks 48 h after carrageenan injection. Treatment of animals with sodium nitroprusside (1.5, 5 and 10 micromol/kg, subcutaneously (s.c.)) 8 h after the subplantar carrageenan injection (300 microg/paw), reduced ( approximately 50%) the delayed phase of paw oedema and the delayed increase in plasma leakage, as assessed by Evans Blue extravasation. Two other NO donors, S-nitroso-N-acetyl-dl-penicillamine (SNAP) or glyceril trinitrate (both at 28 micromol/kg) yielded an inhibition in paw oedema similar to that of sodium nitroprusside. NO-induced inhibition of the delayed phase of paw oedema was reversed when animals were treated with 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1 (ODQ, a soluble guanylate cyclase inhibitor, 11 micromol/kg, s.c.) or with tetraethylammonium (TEA, a nonselective potassium channel blocker, 300 micromol/kg, s.c.), 30 min before the prophylactic dose of sodium nitroprusside. In conclusion, our results show that a brief exposure to NO donors, even when made several hours after the inflammatory reaction has been triggered, is still able to cause an important reduction on the delayed phase of carrageenan-induced mouse paw oedema and fluid leakage. Moreover, this long-lasting NO antiinflammatory effect appears to be dependent on guanylate cyclase and potassium channels.

Animals↗

PubMed2004

Prostaglandin E2 and dexamethasone regulate eosinophil differentiation and survival through a nitric oxide- and CD95-dependent pathway.

Apoptosis, involving both CD95/CD95L interactions and their modulation by nitric oxide (NO), is central to regulation of mature eosinophil numbers. However, its role in regulating eosinophil production from bone-marrow precursors is unknown. We examined the effects of prostaglandin E2 (PGE2) and dexamethasone on eosinophil differentiation and survival in murine bone-marrow cultures, and their relationship to: NO production as well as CD95/CD95L-dependent apoptosis. Bone-marrow cultures were established with IL-5, alone or in association with PGE2, dexamethasone or both. PGE2 (10(-7)M) inhibited eosinophil differentiation by selectively inducing apoptosis in developing eosinophils. Dexamethasone (10(-7)M) protected developing eosinophils from PGE2-induced apoptosis. Since dexamethasone prevents induction of nitric oxide synthase (NOS), we evaluated the role of NO in the effects of both PGE2 and dexamethasone. NO donors (SNAP and SNP) down-modulated eosinophil precursor responses to IL-5. SNAP induced apoptosis through a dexamethasone-resistant mechanism. The NOS inhibitors, Nomega-nitro-L-arginine and aminoguanidine, blocked the effects of PGE2 on developing eosinophils. PGE2 was ineffective in bone-marrow from knockout mice lacking inducible NOS. PGE2 up-regulated CD95 and CD95L expression in developing eosinophils. Neither PGE2 nor SNAP were effective in cultures from CD95L-deficient gld mice. These data suggest that PGE2 induces apoptosis in developing eosinophils through inducible NOS, leading to NO-dependent activation of the CD95L/CD95 pathway, while dexamethasone antagonizes the effects of PGE2 on the same targets.

Animals↗

PubMed2004

Caffeic acid derivatives: in vitro and in vivo anti-inflammatory properties.

Caffeic acid and some of its derivatives such as caffeic acid phenetyl ester (CAPE) and octyl caffeate are potent antioxidants which present important anti-inflammatory actions. The present study assessed the in vitro and in vivo effects of five caffeic acid derivatives (caffeic acid methyl, ethyl, butyl, octyl and benzyl esters) and compared their actions to those of CAPE. In the model of LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages, the pre-incubation of all derivatives inhibited nitrite accumulation on the supernatant of stimulated cells, with mean IC50 (microM) values of 21.0, 12.0, 8.4, 2.4, 10.7 and 4.80 for methyl, ethyl, butyl, octyl, benzyl and CAPE, respectively. The effects of caffeic acid derivatives seem to be related to the scavenging of NO, as the compounds prevented SNAP-derived nitrite accumulation and decreased iNOS expression. In addition, butyl, octyl and CAPE derivatives significantly inhibited LPS-induced iNOS expression in RAW 264.7 macrophages. Extending the in vitro results, we showed that the pre-treatment of mice with butyl, octyl and CAPE derivatives inhibited carrageenan-induced paw edema and prevented the increase in IL-1beta levels in the mouse paw by 30, 24 and 36%, respectively. Butyl, octyl and CAPE derivatives also prevented carrageenan-induced neutrophil influx in the mouse paw by 28, 49 and 31%, respectively. Present results confirm and extend literature data, showing that caffeic acid derivatives exert in vitro and in vivo anti-inflammatory actions, being their actions mediated, at least in part by the scavenging of NO and their ability to modulate iNOS expression and probably that of other inflammatory mediators.

Animals↗

PubMed2004

Inhibition of glucocorticoid receptor binding by nitric oxide in endotoxemic rats.

OBJECTIVE: Nitric oxide is an important participant in septic shock. For example, it causes profound vasodilation and hypotension. Despite their potent antiinflammatory properties, glucocorticoids are not routinely used in septic shock. Some studies show that antiinflammatory doses of glucocorticoids can be beneficial, but other studies do not indicate their use in this situation. We have previously shown the inhibitory effect of nitric oxide on glucocorticoid receptor binding in vitro. Nitric oxide donors decreased the binding of immunoprecipitated glucocorticoid receptor obtained from mouse L929 fibroblasts. These in vitro findings prompted us to study whether in vivo manipulations of the nitric oxide system would interfere with the glucocorticoid receptor binding. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university. SUBJECTS: Female Wistar rats. INTERVENTIONS: Injection of bacterial lipopolysaccharide, anesthesia, cardiovascular perfusion, and organ removal for biochemical assays. MEASUREMENTS AND MAIN RESULTS: Following lipopolysaccharide injection, plasma nitrate + nitrite increased and inducible nitric oxide synthase activity was stimulated in several organs, the highest rates being in the lung and spleen. If dexamethasone was injected before lipopolysaccharide, it completely blocked inducible nitric oxide synthase induction and the increase in plasma nitrate + nitrite. On the other hand, if dexamethasone was injected after lipopolysaccharide, it failed to affect both inducible nitric oxide synthase induction and increased plasma nitrate + nitrite levels. Lipopolysaccharide also caused an inhibition of glucocorticoid receptor binding in lung and spleen. Previous administration of a nitric oxide synthase inhibitor prevented both lipopolysaccharide-induced decrease in glucocorticoid receptor binding and the increase in plasma nitrate + nitrite. Injection of a nitric oxide donor into naive animals significantly decreased glucocorticoid receptor binding activity and prevented dexamethasone-induced increase in liver tyrosine aminotransferase activity. CONCLUSIONS: The results indicate that the failure of glucocorticoids to exhibit their antiinflammatory effects when administered to endotoxemic rats may be explained, at least in part, by the nitric oxide-induced inhibition of glucocorticoid receptor binding ability, thus precluding the expression of the antiinflammatory effects of both exogenous and endogenous corticosteroids.

Animals↗

PubMed2003

Trypanocidal and leishmanicidal properties of substitution-containing chalcones.

Ten chalcones were synthesized and tested as potential leishmanicidal and trypanocidal agents. All tested compounds caused concentration-dependent inhibition of the in vitro growth of Leishmania braziliensis and Trypanosoma cruzi with no significant toxic effect towards host macrophages. Our results show that the positions of the substituents seem to be critical for their antiprotozoal activities.

Amphotericin B↗

PubMed2002

Involvement of nitric oxide and potassium channels in the bradykinin-induced vasodilatation in the rat kidney perfused ex situ.

The role of nitric oxide (NO), K(+) channels, and arachidonic acid metabolism, via cytochrome P450 and cyclooxygenase pathways, in the renal vasodilatory effect of bradykinin was examined in the isolated rat kidney perfused ex situ with a blood-free solution. Bradykinin (BK, 0.25-1.0 microM) induced a dose-dependent reduction of 10-35% in the relative renal vascular resistance (rRVR) of isolated kidneys preconstricted with phenylephrine (PHE, 0.17-0.35 microM). The vasodilating effect of 0.5 microM bradykinin was significantly inhibited by the nitric oxide synthase inhibitors, N(G)-nitro-L-arginine (95% inhibition) and N(G)-nitro-L-arginine methyl ester (45-75% inhibition). Clotrimazole, an inhibitor of cytochrome P450 pathway but not indomethacin, a cyclooxygenase inhibitor, reduced the renal vasodilator response to bradykinin by 84%. The nonspecific K(+) channel inhibitor, tetraethylammonium ion (TEA) and the selective inhibitor of Ca(2+)-activated K(+) channels, charybdotoxin (ChTX) greatly attenuated the vasodilator response to bradykinin by approximately 84% and 79%, respectively. These two K(+) channel inhibitors showed similar effects on vasodilatation induced by S-nitroso-acetyl-D,L-penicillamine (1 microM), a nitric oxide donor. The results suggest that bradykinin releases nitric oxide which, by opening potassium channels specifically the Ca(+)-dependent type, mediates the renal vasodilator response to bradykinin in the isolated kidney perfused ex situ.

Animals↗

PubMed2002

Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain.

The study of inbred strains of rodents that differ for specific behaviours can help us to understand the biological mechanisms underlying complex psychological traits. Lewis (LEW) and SHR inbred rat strains, for example, have been recently proposed as a genetic model for the study of anxiety. Our goal was to characterise two Brazilian substrains of LEW and SHR rats, that have never been compared before, behaviourally and/or pharmacologically, in order to evaluate their potential contribution to studies on anxiety and pain. Male and female LEW and SHR rats were submitted after 8 weeks of age to five anxiety/emotionality tests: the open field (7 or 260 lux), the elevated plus-maze, the elevated T-maze and the black/white box. Rats of all groups were also submitted to the formalin test of nociception and measurement of blood pressure. Significant strain differences (P<0.05) were observed in both sexes for all indices of anxiety and also for measures of pain and blood pressure. SHRs, compared with LEWs, explored more the aversive environments of all anxiety tests, showed less nociceptive responses and were hypertensive. All differences in experimental anxiety parameters agree with previous differences reported between two French LEW and SHR substrains, suggesting that LEWs are more anxious than SHRs, thus consolidating these strains as a useful genetic model for the study of anxiety and pain. The possible involvement of tachykinergic mechanisms is discussed.

Animals↗

PubMed2002

Differential involvement of guanylate cyclase and potassium channels in nitric oxide-induced hyporesponsiveness to phenylephrine in endotoxemic rats.

This study evaluated the involvement of nitric oxide (NO), guanylate cyclase, and potassium channels in the long-lasting vascular hyporesponsiveness to phenylephrine induced by Escherichia coli lipopolysaccharide (LPS) in vitro and in vivo. Experiments in rat aorta rings with endothelium incubated with LPS (10 microg/mL) for 12 h showed that the hyporesponsiveness depends on guanylate cyclase activity and tetraethylammonium-sensitive, but not voltage- or ATP-dependent, potassium channels. Pressor responses to phenylephrine were reduced by 50% in rats injected 8 and 24 h before with LPS (10 mg/kg, intraperitoneally). Pretreatment with NO synthase inhibitors (iNOS; Nomega-nitro-L-arginine methyl ester [L-NAME], 55 micromol/kg or aminoguanidine, 244 micromol/kg, intraperitoneally) fully prevented LPS-induced hyporesponsiveness. When administered just before phenylephrine, L-NAME (11 micromol/kg, intravenously) reversed the hyporesponsiveness in rats injected 8 h, but not in those injected 24 h before with LPS, whereas 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1 (ODQ, 11 micromol/kg, intravenously) reversed the hyporesponsiveness in animals injected 24 h, but not in those injected 8 h before with LPS. Tetraethylammonium (360 micromol/kg, intravenously) reestablished normal responses to phenylephrine in rats injected 8 and 24 h before with LPS. Again, neither voltage- nor ATP-dependent potassium channels appears to be involved. Western blot showed that iNOS expression peaked at 8 h, decreasing to low levels 24 h after LPS injection. Therefore, NO is important in initiating LPS-induced hyporesponsiveness to vasoconstrictors, but not in maintaining it for long periods. Once NO has exerted its effects and even when iNOS expression is minimal, the long-lasting hyporesponsiveness appears to depend on a complex interplay between guanylate cyclase and potassium channel activation.

Animals↗

PubMed2002

The role of ATP-sensitive potassium channels in neutrophil migration and plasma exudation.

Neutrophil activation and migration during an inflammatory response is preceded or accompanied by plasma membrane electrical changes. Besides changes in calcium currents, neutrophils have a high permeability to potassium, mainly through potassium channels. However, the significance of potassium channels in neutrophil physiology is still unclear. Here, we show that the treatment of rats with the ATP-sensitive potassium channel blocker glibenclamide (4, 20, or 40 micromol/kg) dose dependently decreased carrageenan-, N-formyl-methionyl-leucyl-phenylalanine (fMLP)-, and lipopolysaccharide-induced neutrophil influx and fluid leakage into the interpleural space. On the other hand, minoxidil (an ATP-sensitive potassium channel opener; 25, 50, and 100 micromol/kg) increased both neutrophil influx and fluid leakage induced by a submaximal dose of carrageenan. In addition, in vitro human neutrophil chemotaxis induced by leukotriene B4 or fMLP (both 1 microM) was fully blocked by glibenclamide (10, 30, and 100 microM) or tetraethylammonium (a nonselective potassium channel blocker; 1, 3, and 10 mM). Thus, our results disclose the possibility that ATP-sensitive potassium channels may have a role in neutrophil migration and chemotaxis and plasma exudation in the inflammatory response.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

The presence of the endothelial layer reduces nitric oxide-induced hyporesponsiveness to phenylephrine in rat aorta.

A single exposure to nitric oxide (NO) donors produces a long-lasting hyporesponsiveness to phenylephrine (HRP) in rat aorta rings. Here the authors investigate the role of the endothelial layer in the development of NO-induced HRP and the putative role of endothelium-derived vasoconstrictors in counteracting it. The NO donor S-nitrosoacetyl-D,L-penicillamine (SNAP) induced a dose-dependent reduction in the maximal effect (Emax) of phenylephrine. In rings without endothelium, Emax dropped to 60%, 25%, and 10% of control values 1 h after a 30-min incubation with SNAP (2, 20, and 200 microM, respectively). In contrast, the presence of endothelium prevented the HRP induced by 2 microM SNAP and significantly reduced the HRP elicited by 20 and 200 microM SNAP (Emax reductions of 50% and 65%, respectively), thereby characterizing the endothelium protective effect. Superoxide dismutase (SOD; 100 IU/mL), MnTBAP (a nonenzymatic SOD mimetic; 100 microM), captopril (10 microM), MK886 (a lipoxygenase inhibitor; 10 microM) and BQ 123 (endothelin receptor A antagonist; 1 microM) did not change the endothelium protective effect. Therefore, increased release of vasoconstrictors that would counteract NO-induced loss in phenylephrine responses cannot account for the protective effect of endothelium. In contrast, oxidation of sulphydryls with DTNB prevented the onset of SNAP-induced HRP. A better understanding of mechanisms by which the endothelial layer (or protein sulphydryl groups present in it) exerts its protective effect towards the NO-induced loss in physiological vasoconstriction is likely to be of value in cardiovascular conditions such as ischemia/reperfusion and septic shock.

Animals↗