Interaction between norepinephrine and hypoxia on carotid body chemoreception in rabbits

The effects of both bolus injection and constant infusion of various levels of norepinephrine (NE) on the activity of single-carotid chemoreceptor nerve fibers was studied in pentobarbital-anaesthetized rabbits under normoxic and hypoxic conditions. All animals were paralyzed and artificially ventilated. The dominant effect of NE was to excite carotid body chemoreceptor fibers in a dose-dependent fashion. There was an inverse relationship between the effect of NE on afferent fiber discharge and arterial O2 tension at all levels of exogenous NE above threshold levels. Propranolol (PROP) in sufficient dosage abolished the chemoreceptor response to NE and also markedly reduced the chemoreceptor response to hypoxia. These results support suggestions that beta-adrenergic receptors may be an integral part of the O2 chemosensory mechanism. They also demonstrate a nonadditive interaction between the effects of NE and hypoxia on the chemoreceptor afferent fibers. A reduction in resting discharge levels after infusion of PROP further suggests that endogenous catecholamines may contribute to carotid body chemoreceptor activity even under normoxic normocapnic conditions.

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Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Journal of Applied Physiology ◽

10.1152/japplphysiol.01167.2000 ◽

2002 ◽

Vol 92 (2) ◽

pp. 780-788 ◽

Cited By ~ 78

Author(s):

Martin Berghoff ◽

Madeera Kathpal ◽

Sonja Kilo ◽

Max J. Hilz ◽

Roy Freeman

Keyword(s):

Nerve Fibers ◽

Axon Reflex ◽

Doppler Flowmetry ◽

Relative Contribution ◽

C Fibers ◽

Cutaneous Microcirculation ◽

C Fiber ◽

Dose Dependent Fashion ◽

Cutaneous Perfusion ◽

Dose Dependent

The relative contribution of endothelial vasodilating factors to acetylcholine (ACh)-mediated vasodilation in the forearm cutaneous microcirculation is unclear. The aims of this study were to investigate the contributions of prostanoids and cutaneous C fibers to basal cutaneous blood flow (CuBF) and ACh-mediated vasodilation. ACh was iontophoresed into the forearm, and cutaneous perfusion was measured by laser-Doppler flowmetry. To inhibit the production of prostanoids, four doses of acetylsalicylic acid (ASA; 81, 648, 972, and 1,944 mg) were administered orally. Cutaneous nerve fibers were blocked with topical anesthesia. Cyclooxygenase inhibition did not change basal CuBF or endothelium-mediated vasodilation to ACh. In contrast, ASA (972 and 1,944 mg) significantly reduced the C-fiber-mediated axon reflex in a dose-dependent fashion. Blockade of C-fiber function significantly reduced axon reflex-mediated vasodilation but did not affect basal CuBF or endothelium-dependent vasodilation. The findings suggest that prostanoids do not contribute significantly to basal CuBF or endothelium-dependent vasodilation in the forearm microcirculation. In contrast, prostanoids are mediators of the ACh-provoked axon reflex.

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Plasminogen Interactions with Immobilized Fibrinogen

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647121 ◽

1989 ◽

Vol 62 (04) ◽

pp. 1078-1082 ◽

Cited By ~ 5

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.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653872 ◽

1995 ◽

Vol 73 (05) ◽

pp. 805-811 ◽

Cited By ~ 12

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.

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Faculty Opinions recommendation of CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120832.577093 ◽

2008 ◽

Author(s):

Andrew Weinberg

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Ctla4 Blockade ◽

Dose Dependent Fashion ◽

Dose Dependent

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Nerve growth factor and glutamate increase the density and expression of substance P-containing nerve fibers in healthy human masseter muscles

Scientific Reports ◽

10.1038/s41598-021-95229-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Abdelrahman M. Alhilou ◽

Akiko Shimada ◽

Camilla I. Svensson ◽

Peter Svensson ◽

Malin Ernberg ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Nmda Receptors ◽

Masseter Muscle ◽

Temporomandibular Disorder ◽

Nerve Fibers ◽

Receptor Subtype ◽

Nerve Growth ◽

Afferent Fibers ◽

Pain Characteristics

AbstractNocifensive behavior induced by injection of glutamate or nerve growth factor (NGF) into rats masseter muscle is mediated, in part, through the activation of peripheral NMDA receptors. However, information is lacking about the mechanism that contributes to pain and sensitization induced by these substances in humans. Immunohistochemical analysis of microbiopsies obtained from human masseter muscle was used to investigate if injection of glutamate into the NGF-sensitized masseter muscle alters the density or expression of the NMDA receptor subtype 2B (NR2B) or NGF by putative sensory afferent (that express SP) fibers. The relationship between expression and pain characteristics was also examined. NGF and glutamate administration increased the density and expression of NR2B and NGF by muscle putative sensory afferent fibers (P < 0.050). This increase in expression was greater in women than in men (P < 0.050). Expression of NR2B receptors by putative sensory afferent fibers was positively correlated with pain characteristics. Results suggest that increased expression of peripheral NMDA receptors partly contributes to the increased pain and sensitivity induced by intramuscular injection of NGF and glutamate in healthy humans; a model of myofascial temporomandibular disorder (TMD) pain. Whether a similar increase in peripheral NMDA expression occurs in patients with painful TMDs warrants further investigation.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.440 ◽

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; < 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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.270.6.g897 ◽

1996 ◽

Vol 270 (6) ◽

pp. G897-G901 ◽

Cited By ~ 3

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.

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Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors

Science Signaling ◽

10.1126/scisignal.aay9452 ◽

2019 ◽

Vol 13 (615) ◽

pp. eaay9452 ◽

Cited By ~ 9

Author(s):

Alejandro Moreno-Domínguez ◽

Patricia Ortega-Sáenz ◽

Lin Gao ◽

Olalla Colinas ◽

Paula García-Flores ◽

...

Keyword(s):

Ion Channels ◽

Carotid Body ◽

Acute Hypoxia ◽

Mechanistic Explanation ◽

Nerve Fibers ◽

Adaptive Responses ◽

Glomus Cells ◽

Adult Mice ◽

Genes Encoding ◽

Regulation Of Breathing

Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α (Epas1) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia.

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

AJP Renal Physiology ◽

10.1152/ajprenal.1991.261.5.f873 ◽

1991 ◽

Vol 261 (5) ◽

pp. F873-F879 ◽

Cited By ~ 3

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.

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