Vascular escape from vasoconstriction and post-stimulatory hyperemia in the superior mesenteric artery of the cat

1988 ◽  
Vol 66 (9) ◽  
pp. 1174-1180 ◽  
Author(s):  
W. Wayne Lautt ◽  
Dallas J. Legare ◽  
Leslie K. Lockhart
Keyword(s):  
Superior Mesenteric Artery ◽  
Adenosine Receptors ◽  
Mesenteric Artery ◽  
Vascular Tone ◽  
Low Dose ◽  
Data Interpretation ◽  
High Dose ◽  
Partial Recovery ◽  
Sympathetic Nerve Stimulation

Vascular escape is seen as a partial recovery from initial vasoconstriction despite continued constrictor stimuli. Escape in the feline intestine (superior mesenteric artery) occurred for i.a. norepinephrine (NE) infusions (56% escape for low dose, 40% for high dose NE) and for sympathetic nerve stimulation (SNS) (65% for 1 Hz, 49% for 3 Hz, 44% for 9 Hz). Adenosine infusion or blockade of adenosine receptors (8-phenyltheophylline) did not alter the escape, showing that endogenous adenosine levels are unlikely to play any role in the mechanism of escape. Other aspects of escape were studied: equiconstrictor doses of NE given i.a. or i.v. lead to similar degrees of escape; propranolol and ouabain did not alter escape; the degree of escape was significantly greater for the low dose NE and the 1-Hz SNS than for higher intensities of stimulation, however, escape did not inversely correlate significantly with the initial degree of vasoconstriction when all data were pooled. Post-stimulatory hyperemia occurs upon cessation of vasoconstrictor stimuli, reaches a peak conductance within 1 min, and returns to baseline within about 3 min. Hyperemia was quantitated from the peak vasodilation and from the area under the flow–hyperemia curve. The hyperemias were not related to NE dose or SNS frequency nor did they correlate with initial vasoconstriction or extent of vascular escape. Contrary to the hypothesis that adenosine may mediate hyperemia, adenosine infusions reduced the response and adenosine receptor antagonism tended to elevate the response. Propranolol and ouabain did not produce significant effects on post-stimulatory hyperemia. A discussion of the merits of using vascular resistance or conductance to assess vascular tone and vascular escape concludes that in the in vivo systems in which changes in vascular tone result mainly in changes in blood flow, the use of resistance is unacceptable and may lead to serious error in data interpretation.

Adenosine modulation of vasoconstrictor responses to stimulation of sympathetic nerves and norepinephrine infusion in the superior mesenteric artery of the cat

1988 ◽  
Vol 66 (7) ◽  
pp. 937-941 ◽  
Author(s):  
W. Wayne Lautt ◽  
Leslie K. Lockhart ◽  
Dallas J. Legare
Keyword(s):  
Superior Mesenteric Artery ◽  
Nerve Stimulation ◽  
Adenosine Receptors ◽  
Mesenteric Artery ◽  
Sympathetic Nerves ◽  
Sympathetic Nerve Stimulation ◽  
Vascular Bed ◽  
Norepinephrine Infusion ◽  
Resistance Vessels ◽  
Stimulation Of

Vasoconstriction induced by sympathetic nerve stimulation and by norepinephrine infusion in the superior mesenteric artery of cats anesthetized with pentobarbital was inhibited by adenosine infusions in a dose-related way. The responses to nerve stimulation were not inhibited to a greater extent than the responses to norepinephrine, thus suggesting no presynaptic modulation of sympathetic nerves supplying the resistance vessels of the feline intestinal vascular bed. Blockade of adenosine receptors using 8-phenyltheophylline did not alter the degree of constriction induced by nerve stimulation or norepinephrine infusion, indicating that in the fasted cat, endogenous adenosine co-released or released subsequent to constriction does not affect the peak vasoconstriction reached. Isoproterenol caused similar degrees of vasodilation as adenosine but did not show significant antagonism of the pooled responses to nerve stimulation or norepinephrine infusion; there was no tendency for the degree of dilation induced by isoproterenol to correlate with the inhibition of constrictor responses. Thus, the effect of adenosine on nerve- and norepinephrine-induced constriction is not secondary to nonspecific vasodilation.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

Nonprotein sulfhydryl compounds in canine gastric mucosa: effects of PGE2 and ethanol

1985 ◽  
Vol 249 (1) ◽  
pp. G137-G144 ◽  
Author(s):  
T. A. Miller ◽  
D. Li ◽  
Y. J. Kuo ◽  
K. L. Schmidt ◽  
L. L. Shanbour
Keyword(s):  
Gastric Mucosa ◽  
Low Dose ◽  
Mucosal Damage ◽  
Gastric Mucosal Damage ◽  
High Dose ◽  
Mucosal Protection ◽  
Gastric Mucosal Protection ◽  
Sulfhydryl Compounds ◽  
Mild Irritants

By use of an in vivo canine chambered stomach preparation in which the gastric mucosa was partitioned into two equal halves, the effect of topical 16,16-dimethyl PGE2 (DMPGE2) (1 microgram/ml of perfusate) and 8% and 40% ethanol on tissue levels of nonprotein sulfhydryl compounds was assessed. Both DMPGE2 and 8% ethanol significantly increased (P less than 0.005) mucosal levels of nonprotein sulfhydryls when compared with corresponding mucosa bathed with saline alone. In contrast, mucosa bathed with 40% ethanol showed significantly decreased levels. If mucosa was bathed with DMPGE2 or 8% ethanol prior to exposing the stomach to 40% ethanol, this depletion in sulfhydryl compounds was not observed. Since other experimental observations have shown that exogenously administered prostaglandins and mild irritants (such as low-dose alcohol) can prevent gastric mucosal damage by necrotizing agents (such as high-dose alcohol), our findings are consistent with the hypothesis that nonprotein sulfhydryls may play a role in mediating gastric mucosal protection.

scholarly journals 735 Identification of a small molecule that prevents T cell exhaustion using machine learning algorithms paired with high-resolution single cell RNAseq

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A766-A766
Author(s):  
Isabelle Le Mercier ◽  
Sunny Sun ◽  
Dongmei Xiao ◽  
Laura Isacco ◽  
Daniel Treacy ◽  
...  
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Machine Learning Algorithms ◽  
High Dose ◽  
T Cell Exhaustion ◽  
Tcr Signaling ◽  
Compound A ◽  
Cell Exhaustion

BackgroundT cell responses are tightly regulated and require a constant balance of signals during the different stages of their activation, expansion, and differentiation. As a result of chronic antigen exposure, T cells become exhausted in solid tumors, preventing them from controlling tumor growth.MethodsWe identified a transcriptional signature associated with T cell exhaustion in patients with melanoma and used our proprietary machine learning algorithms to predict molecules that would prevent T cell exhaustion and improve T cell function. Among the predictions, an orally available small molecule, Compound A, was highly predicted.ResultsCompound A was tested in an in vitro T cell Exhaustion assay and shown to prevent loss of proliferation and expression of immune checkpoint receptors. Transcriptionally, Compound A-treated cells looked indistinguishable from conventionally expanded, non-exhausted T cells. However, when assessed in a classical T cell activation assay, Compound A demonstrated dose dependent activity. At low dose, Compound A was immuno-stimulatory, allowing cells to divide further by preventing activation induced cell death. At higher doses, Compound A demonstrated immuno-suppressive activity preventing early CD69 upregulation and T cell proliferation. All together, these observations suggest that Compound A prevented exhaustion with a mechanism of action involving TCR signaling inhibition. While cessation of TCR signaling or rest has been recently associated with improved CAR-T efficacy by preventing or reversing exhaustion during the in vitro manufacturing phase, it is unclear if that mechanism would translate in vivo.Compound A was evaluated in the CT26 and MC38 syngeneic mouse models alongside anti-PD1. At low dose Compound A closely recapitulated anti-PD1 mediated cell behavior changes by scRNA-seq and flow cytometry in CT26 mice. At high dose, Compound A led to the accumulation of naive cells in the tumor microenvironment (TME) confirming the proposed mechanism of action. Low dose treatment was ineffective in MC38 mouse model but a pulsed treatment at high dose also recapitulated anti-PD1 activity in most animals. Importantly, we identified a new T cell population responding to anti-PD1 that was particularly increased in the MC38 mouse model; Compound A treatment also impacted this population.ConclusionsThese data confirm that mild TCR inhibition either suboptimal or fractionated can prevent exhaustion in vivo. However, this approach has a very limited window of activity between immuno-modulatory and immuno-suppressive effects, thereby limiting potential clinical benefit. Finally, these results demonstrate that our approach and platform was able to predict molecules that would prevent T cell exhaustion in vivo.

scholarly journals Comparison of the in-vivo Effect of Two Tranexamic Acid Doses on Fibrinolysis Parameters in Adults Undergoing Valvular Cardiac Surgery with Cardiopulmonary Bypass - A Pilot Investigation

2020 ◽  
Author(s):  
Zhen-feng ZHOU ◽  
Wen Zhai ◽  
Li-na YU ◽  
Kai SUN ◽  
Li-hong SUN ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Placebo Group ◽  
Cardiopulmonary Bypass ◽  
Plasminogen Activator ◽  
Dose Group ◽  
Low Dose ◽  
High Dose Group ◽  
High Dose ◽  
Pai 1

Abstract Background: The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB, which has not been systematically elucidated.Methods: A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T1), 5 min after the TXA bolus (T2), 5 min after the initiation of CPB (T3), 5 min before the end of CPB (T4) and 5 min after the protamine administration (T5). A Thrombelastography (TEG) and standard coagulation test were also performed.Results: Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (p <0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (p <0.05); TAFI concentrations also decreased at the T5 in low-dose group (p <0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. No significant differences were observed in the levels of the coagulation proteins at any points between the groups.Conclusions: The vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass, and we recommend a low dose TXA regimen for those patients.Clinical trial number and registry URL: ChiCTR-IPR-17010303; http://www.chictr.org.cn, Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.

scholarly journals Επικεκαλυμμένες ενδαγγειακές προθέσεις και επαναστένωση μετά από αγγειοπλαστική

2014 ◽  
Author(s):  
Δημήτριος Λυσίτσας
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Low Dose ◽  
High Dose ◽  
Hsp 70

Εισαγωγή: Η υπερπλασία του έσω χιτώνα παίζει μείζων ρόλο στην επαναστένωση (in-stentrestenosis). Στην παρούσα μελέτη αξιολογήσαμε in vitro την επίδραση της D-24851(κυτταροτοξική ουσία που σταματά τον κυτταρικό κύκλο στο στάδιο G2-M) στονπολλαπλασιασμό των λείων μυϊκών κυττάρων και μελετήσαμε την ασφάλεια και τηνδραστικότητα μίας ενδαγγειακής πρόθεσης (stent) επικαλυμμένης με πολυμερή ουσία πουαπελευθερώνει την D-24851, στην αναστολή της υπερπλασίας του έσω χιτώνα χωρίς ναεμποδίζει την αναγεννητική ικανότητα του ενδοθηλίου σε in vivo πειραματικό μοντέλο.Υλικό και Μέθοδοι: Γυμνά μεταλλικά stent (n=6), stent επικαλυμμένα μόνο με πολυμερήουσία (polymer-coated, n=7) και stent επικαλυμμένα με πολυμερή ουσία πουαπελευθερώνουν 31±1μg (low-dose, n=7), 216±8 μg (high-dose, n=6) ή 1774±39 μg(extreme-dose, n=5) της D-24851 εμφυτεύτηκαν στις μηριαίες αρτηρίες λευκών New Zealandκουνελιών. Τα πειραματόζωα θυσιάστηκαν στις 28 ημέρες για ιστομορφομετρική ανάλυση.Για την αξιολόγηση της ενδοθηλιακής αναγέννησης στις 90 ημέρες, 12 πειραματόζωαχρησιμοποιήθηκαν για την τοποθέτηση polymer-coated (n=3), low dose (n=3), high dose(n=3) or extreme dose (n=3) ενδαγγειακών προθέσεων.Αποτελέσματα: In vitro η D-24851 αναστέλλει την υπερπλασία των λείων μυϊκών κυττάρωνκαι επάγει την απόπτωση τους χωρίς να αυξάνει την επαγωγή της heat shock protein 70(HSP-70), μία κυτταροπροστατευτική και αντι-αποπτωτική πρωτεΐνη. Η θεραπεία με lowdoseD-24851 stents συνδυάστηκε με 38% (P=0.029) μείωση της υπερπλαστικής περιοχήςτου έσω χιτώνα και 35% (P=0.003) μείωση της επι τοις εκατό στένωσης του αυλού σεσύγκριση με τα γυμνά μεταλλικά stents. Ο τραυματισμός και η φλεγμονή του αρτηριακού τοιχώματος δεν παρουσίασαν σημαντικές διαφορές μεταξύ των ομάδων. Τα επικαλυμμέναμόνο με πολυμερή ουσία stents εμφάνισαν παρόμοια ανάπτυξη νεοιστού σε σύγκριση με ταγυμνά μεταλλικά stents. Ωστόσο, όλες οι ομάδες των stents με D-24851 παρουσίασαν ατελήενδοθηλιοποίηση συγκρινόμενα με τα polymer-coated stents.Συμπεράσματα: Οι επικεκαλυμμένες ενδαγγειακές προσθέσεις με πολυμερή ουσία καιχαμηλη δόση D-24851 μειώνουν σημαντικά την υπερπλασιά του έσω χιτώνα. Λόγω τηςατελούς ενδοθηλιοποίησης, μακράς διάρκειας μελέτες είναι απαραίτητες για ναπιστοποιήσουν ότι η αναστολή του νεοιστού παραμένει και μετά τις 28 ημέρες.

scholarly journals Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

2009 ◽  
Vol 77 (12) ◽  
pp. 5612-5622 ◽  
Author(s):  
T. Eoin West ◽  
Thomas R. Hawn ◽  
Shawn J. Skerrett
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
High Dose ◽  
Tlr Signaling ◽  
Necrosis Factor Alpha ◽  
Airborne Infection ◽  
Essential Components ◽  
High Doses

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

Low-dose prostacyclin has potent capillary permeability-reducing effect in cat skeletal muscle in vivo

1997 ◽  
Vol 273 (1) ◽  
pp. H200-H207 ◽  
Author(s):  
A. D. Moller ◽  
P. O. Grande
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Vascular Tone ◽  
Low Dose ◽  
Capillary Permeability ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

The dose-response effects of intravenous infusion of prostacyclin on capillary permeability (the capillary filtration coefficient technique), hydrostatic capillary pressure, transcapillary filtration, and vascular tone were analyzed in vivo on cat skeletal muscle from a normal and an increased permeability level. Increased permeability was accomplished by intra-arterial infusion of tumor necrosis factor-alpha or histamine. Permeability effects of bradykinin were also analyzed. Prostacyclin decreased capillary permeability by 8% at a dose of 0.1 ng.kg-1.min-1 and at most by 30% below control attained at 2 ng.kg-1.min-1, also with no effect on vascular tone and hydrostatic capillary pressure. The permeability increase by tumor necrosis factor-alpha and histamine (by 54 and 73%) was more than counteracted by the simultaneous infusion of prostacyclin at 2 ng.kg-1.min-1. The vasodilator effect of tumor necrosis factor-alpha was also restituted. Indomethacin (prostacyclin inhibitor)-induced increase in capillary permeability (25%) was more than restituted by prostacyclin at 2 ng.kg-1.min-1. Surprisingly, bradykinin decreased capillary permeability. We conclude that endogenous prostacyclin may be a physiological regulator of capillary permeability and that low-dose prostacyclin infusion may have clinical relevance in states of increased permeability.

Effects of acetylsalicylic acid on pulmonary vascular tone and membrane permeability in blood-perfused dog lung

1993 ◽  
Vol 75 (6) ◽  
pp. 2561-2569 ◽  
Author(s):  
K. Kambara ◽  
M. Arakawa ◽  
T. Segawa ◽  
F. Ando ◽  
M. Ohno ◽  
...  
Keyword(s):  
Acetylsalicylic Acid ◽  
Extravascular Lung Water ◽  
Vascular Tone ◽  
Low Dose ◽  
Pressor Response ◽  
Plasma Concentrations ◽  
High Dose ◽  
Constant Flow ◽  
Lung Water ◽  
Pulmonary Vasoconstriction

We studied the effects of acetylsalicylic acid (ASA) on pressor response, microvascular filtration coefficient (Kf), extravascular lung water, and plasma concentrations of cyclooxygenase- and 5-lipoxygenase-derived products in 21 blood-perfused dog lungs with constant flow. The lungs were perfused for 1 h with an intrapulmonary injection of saline as vehicle (n = 5), a low dose of ASA [136 +/- 25 (SD) micrograms/ml perfusate; n = 5], a high dose of ASA (1,006 +/- 278 micrograms/ml perfusate; n = 6), or alloxan (1,000 mg; n = 5). Alloxan significantly increased Kf and extravascular lung water, whereas neither the low nor high dose of ASA increased Kf or extravascular lung water. The ASA-induced increase in vascular resistance did not correlate with the extent of the decrease in perfusate 6-keto-prostaglandin F1 alpha or the ratio of perfusate 6-ketoprostaglandin F1 alpha to thromboxane B2. Moreover, ASA did not enhance the generation of perfusate leukotrienes B4, D4, or E4. We conclude that pulmonary microvascular permeability is unaltered by ASA and that neither the decrease in plasma prostacyclin nor the increase in plasma sulfidopeptide leukotrienes may account for ASA-induced pulmonary vasoconstriction.

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