scholarly journals Rate of NO scavenging alters effects of recombinant hemoglobin solutions on pulmonary vasoreactivity

2002 ◽  
Vol 93 (4) ◽  
pp. 1327-1336 ◽  
Author(s):  
Thomas C. Resta ◽  
Benjimen R. Walker ◽  
Mark R. Eichinger ◽  
Michael P. Doyle
Keyword(s):  
First Generation ◽  
Microvascular Permeability ◽  
Human Hemoglobin ◽  
Oxygen Carriers ◽  
No Donor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Hemodynamic ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Many hemoglobin-based oxygen carriers (HBOCs) produce systemic and pulmonary hypertension and may increase microvascular permeability as a consequence of nitric oxide (NO) scavenging. In this study, we examined the effects of two recombinant human hemoglobin solutions, rHb1.1 and rHb2.0 for injection (rHb2.0), with different rates of NO scavenging on vasoconstrictor reactivity and vascular permeability in isolated, saline-perfused rat lungs. We hypothesized that rHb1.1, a first-generation HBOC with an NO scavenging rate similar to that of native human hemoglobin, would exacerbate pulmonary vasoconstriction and permeability and that rHb2.0, a second-generation HBOC with an NO scavenging rate ∼20- to 30-fold lower than that of rHb1.1, would minimally influence these responses. Consistent with this hypothesis, rHb1.1 enhanced pulmonary vasoconstrictor reactivity to both hypoxia and thromboxane mimetic U-46619 in a dose-dependent fashion. In contrast, rHb2.0 produced little or no change in reactivity to these stimuli. Furthermore, whereas rHb1.1 abrogated pulmonary vasodilation to the NO-donor S-nitroso- N-acetyl-penicillamine (SNAP), dose-dependent responses to SNAP were preserved, albeit attenuated, in lungs treated with rHb2.0. Finally, the capillary filtration coefficient was unaltered by either rHb1.1 or rHb2.0. We conclude that pulmonary hemodynamic responses to rHb2.0 are greatly reduced compared with those observed with rHb1.1, consistent with rHb2.0 having a diminished capacity to scavenge NO. In addition, neither hemoglobin solution measurably altered microvascular permeability in this preparation.

Cardiac depressant and circulatory effects of prostaglandin D2 in developing lambs

1987 ◽  
Vol 252 (2) ◽  
pp. H374-H383 ◽  
Author(s):  
W. H. Drummond ◽  
R. L. Carter
Keyword(s):  
Pressor Response ◽  
High Dose ◽  
Prostaglandin D2 ◽  
Pulmonary Vasodilation ◽  
Circulatory Effects ◽  
Pulmonary Vasoconstriction ◽  
Cardiac Depression ◽  
Pulmonary Vasodilator ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Pulmonary and systemic vascular and cardiac effects of intravenous prostaglandin D2 (PGD2), given at 0.1, 1.0, and 10 micrograms/kg, were measured in chronically instrumented lambs during normoxia and hypoxia at ages 2–3, 9–14, and greater than or equal to 21 days. During normoxia, PGD2 was not a pulmonary vasodilator at low dose and caused mild pulmonary vasoconstrictor changes at 10 micrograms/kg in young lambs; normoxic older lambs had pulmonary vasoconstriction at both 1 microgram/kg and 10 micrograms/kg doses. With hypoxemia, PGD2 caused mild pulmonary vasodilation at all doses in the youngest lambs, converted the normoxic 9–14-day-old lambs' pressor response to a nonresponse, and attenuated the high-dose pulmonary vasoconstriction in the greater than or equal to 21 day lambs. PGD2 was a directly dose-related systemic pressor (+5-20 mmHg) at all ages during both normoxia and hypoxia. Heart rate and cardiac output decreased in a dose-dependent fashion during both normoxia and hypoxia. The PGD2-induced cardiac depression was unaltered by age or ventilatory hypoxemia. PGD2 response of the lamb pulmonary circulation changes from marginal dilation to constriction during the late postnatal development. During the same period, PGD2 dose-related systemic pressor and cardiac depressant effects remain stable. Thus, the circulatory effects of PGD2 are complexly interrelated with age, dose, and presence of hypoxemia.

Plasminogen Interactions with Immobilized Fibrinogen

1989 ◽  
Vol 62 (04) ◽  
pp. 1078-1082 ◽  
Author(s):  
Burt Adelman ◽  
Patricia Ouynn
Keyword(s):  
Immunosorbent Assay ◽  
Aminocaproic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Binding Regions ◽  
Dose Dependent Fashion ◽  
Epsilon Aminocaproic Acid ◽  
Dose Dependent

SummaryThis report describes the binding of plasminogen to fibrinogen adsorbed onto polystyrene wells. Binding was determined by enzyme linked immunosorbent assay. Both glu- and lys-plasminogen bound to immobilized fibrinogen in a dose-dependent fashion. However, more lys- than glu-plasminogen bound when equal concentrations of either were added to immobilized fibrinogen. Plasminogen binding was inhibited by epsilon aminocaproic acid indicating that binding was mediated via lysine-binding regions of plasminogen. Soluble fibrinogen added in excess of immobilized fibrinogen did not compete for plasminogen binding but fibrinogen fragments produced by plasmin digestion of fibrinogen did. Treatment of immobilized fibrinogen with thrombin caused a small but significant (p <0.01) increase in plasminogen binding. These studies demonstrate that immobilized fibrinogen binds both glu- and lys-plasminogen and that binding is mediated via lysine-binding regions. These interactions may facilitate plasminogen binding to fibrinogen adsorbed on to surfaces and to cells such as platelets which bind fibrinogen.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

scholarly journals IMMU-09. CONCURRENT DEXAMETHASONE LIMITS THE CLINICAL BENEFIT OF IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii106-ii106
Author(s):  
Bryan Iorgulescu ◽  
Prafulla Gokhale ◽  
Maria Speranza ◽  
Benjamin Eschle ◽  
Michael Poitras ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Innate Immune Responses ◽  
Dose Dependent Fashion ◽  
Dexamethasone Therapy ◽  
Clinical Correlate ◽  
Dose Dependent

Abstract BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; &lt; 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

Linkage of [Ca2+]i in single isolated D cells to somatostatin secretion induced by cholecystokinin

1996 ◽  
Vol 270 (6) ◽  
pp. G897-G901 ◽  
Author(s):  
J. DelValle ◽  
J. Wakasugi ◽  
H. Takeda ◽  
T. Yamada
Keyword(s):  
Channel Blocker ◽  
Gastric Fundus ◽  
Initial Transient ◽  
Somatostatin Secretion ◽  
Phospholipid Signaling ◽  
Dose Dependent Fashion ◽  
Direct Linkage ◽  
D Cells ◽  
Transient Elevation ◽  
Dose Dependent

The Ca2+/inositol phospholipid signaling cascade has been implicated in the mechanism by which cholecystokinin (CCK) stimulates gastric somatostatin release, but a direct linkage between intracellular events in gastric D cells and somatostatin secretion has not been established. To address this problem we developed a method for correlating somatostatin release with the measurement of intracellular Ca2+ concentration ([Ca2+]i) in isolated D cells. Resting [Ca2+]i in single D cells was 100 +/- 5.7 nM (means +/- SE, n = 41), and CCK induced a rise in [Ca2+]i in a dose-dependent fashion, producing a maximal stimulatory effect (243 +/- 15% of control, n = 12) at a peptide concentration of 2 x 10(-8) M. The CCK-mediated increase in [Ca2+]i was biphasic, with a rapid, initial transient elevation followed by a sustained plateau. The rise in [Ca2+]i was accompanied by a concomitant increase in release of somatostatin-like immunoreactivity (SLI). Removal of extracellular Ca2+ had no effect on the initial transient elevation in [Ca2+]i induced by CCK but abolished both the sustained plateau in [Ca2+]i and the release of SLI. The selective CCK antagonist L-364, 718 (10(-7) M) inhibited the effects of CCK on both [Ca2+]i and SLI release. The nonspecific Ca2+ channel blocker NiCl2 (10(-3) M) and the L-type Ca2+ channel blocker nifedipine inhibited the sustained rise in [Ca2+]i and the release of SLI but left the initial transient increase in [Ca2+]i unaltered. These results indicate that CCK-stimulated release of SLI from D cells in the gastric fundus is linked to influx of extracellular Ca2+ via L-type Ca2+ channels.

scholarly journals Vasoactive intestinal peptide stimulates mucus secretion, but nitric oxide has no effect on mucus secretion in the ferret trachea

2006 ◽  
Vol 101 (2) ◽  
pp. 486-491 ◽  
Author(s):  
Jung-Soo Kim ◽  
Kosuke Okamoto ◽  
Shinobu Arima ◽  
Bruce K. Rubin
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Vasoactive Intestinal Peptide ◽  
Mucus Secretion ◽  
Cell Secretion ◽  
Mucin Secretion ◽  
No Donor ◽  
Peptide Analog ◽  
Dose Dependent ◽  
Vip Receptor

Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are neurotransmitters involved in the regulation of bronchial and pulmonary vascular tone. Published studies of the effects of VIP on airway mucus secretion have yielded conflicting results. The purpose of this study was to determine the effect of VIP on mucus secretion in the ferret trachea and if this effect was influenced by NO. We used a sandwich enzyme-linked lectin assay to measure mucin secretion and a turbidimetric assay to measure lysozyme (serous cell) secretion from ferret tracheal segments. VIP (10−7 M) increased mucin secretion over 2 h. VIP (10−9 to 10−5 M) stimulated mucin secretion in a dose-dependent fashion. VIP-induced mucin secretion was partially blocked by a VIP receptor antagonist (a chimeric VIP-pituitary adenylate cyclase-activating peptide analog, VIP receptor antagonist) at a 10-fold excess concentration. At all concentrations tested, neither NG-nitro-l-arginine methyl ester, an inhibitor of NO synthase, nor S-nitroso- N-acetyl-penicillamine, an NO donor, had any significant effect on constitutive or VIP-induced mucus secretion. We conclude that VIP-stimulated mucin and lysozyme secretion was both time dependent and dose dependent and that NO neither stimulates nor inhibits mucus secretion in the ferret trachea.

11-Dehydrocorticosterone, a glucocorticoid metabolite, inhibits aldosterone action in toad bladder

1991 ◽  
Vol 261 (5) ◽  
pp. F873-F879 ◽  
Author(s):  
A. S. Brem ◽  
K. L. Matheson ◽  
J. L. Barnes ◽  
D. J. Morris
Keyword(s):  
Sodium Transport ◽  
Cell Layer ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Hydroxysteroid Dehydrogenase ◽  
Toad Bladder ◽  
Compound A ◽  
Dose Dependent Fashion ◽  
Epithelial Cell Layer ◽  
Dose Dependent

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes glucocorticoid hormones and diminishes their ability to induce sodium transport. In these studies, we determined the location of this enzyme in toad bladder and assessed the biological role for its 11-dehydro end product. Employing a polyclonal antibody directed toward 11 beta-OHSD and immunofluorescence techniques, we located the enzyme in the epithelial cell layer of the toad bladder. Although corticosterone (10(-7) M) can partially suppress aldosterone (10(-7) M)-stimulated short-circuit current (SCC), a clear excess of corticosterone (10(-6) M) did not inhibit the aldosterone-induced induced (10(-8) M) rise in SCC (n = 6). The 11-dehydro product of corticosterone, 11-dehydrocorticosterone (compound A) added to the serosal bath suppressed aldosterone (10(-8) M) peak SCC (360 min) in a dose-dependent fashion reaching 46 +/- 5% of control values at 10(-5) M (n = 6; P less than 0.001). Compound A (10(-5) M) in the mucosal bath also was capable of partially inhibiting the peak aldosterone rise in SCC to 63 +/- 7% of control values with aldosterone at 10(-8) M (n = 6; P less than 0.01) and to 64 +/- 10% of control values with aldosterone at 10(-7) M (n = 9; P less than 0.01). Compound A alone at 10(-5) M did not have any effect on SCC. Isolated toad bladders were not able to transform compound A (at 10(-8) and 10(-5) M) back to corticosterone. Thus the 11-dehydro end product of 11 beta-OHSD (compound A) may play a biologic role by regulating a component of mineralocorticoid-induced sodium transport.

scholarly journals Annexin A5 prevents post-interventional accelerated atherosclerosis development in a dose-dependent fashion in mice

2012 ◽  
Vol 221 (2) ◽  
pp. 333-340 ◽  
Author(s):  
M.M. Ewing ◽  
J.C. Karper ◽  
M.L. Sampietro ◽  
M.R. de Vries ◽  
K. Pettersson ◽  
...  
Keyword(s):  
Annexin A5 ◽  
Accelerated Atherosclerosis ◽  
Dose Dependent Fashion ◽  
Atherosclerosis Development ◽  
Dose Dependent

E-MYRCENOL: A NEW PHEROMONE FOR THE PINE ENGRAVER, IPS PINI (SAY) (COLEOPTERA: SCOLYTIDAE)

1990 ◽  
Vol 122 (3) ◽  
pp. 401-406 ◽  
Author(s):  
D.R. Miller ◽  
G. Gries ◽  
J.H. Borden
Keyword(s):  
Sex Ratio ◽  
Pest Management ◽  
Lodgepole Pine ◽  
Ips Pini ◽  
Ethanol Solution ◽  
Forest Pest ◽  
Pine Engraver ◽  
Forest Pest Management ◽  
Dose Dependent Fashion ◽  
Dose Dependent

AbstractE-Myrcenol reduced catches of the pine engraver, Ips pini (Say), to ipsdienol-baited, multiple-funnel traps in a dose-dependent fashion. The sex ratio was unaffected by E-myrcenol treatments. Lures containing E-myrcenol in ethanol solution failed to protect freshly cut logs of lodgepole pine from attack by I. pini. Rather, I. pini preferentially attacked logs treated with devices releasing E-myrcenol and ethanol, over nontreated, control logs. Our results demonstrate that E-myrcenol is a new pheromone for I. pini, and emphasize the importance of understanding basic pheromone biology before utilisation of a semiochemical in forest pest management.

Sign in / Sign up

Export Citation Format

Share Document