Faculty Opinions recommendation of Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo.

ABSTRACT In lactating rats and rabbits the mode of antagonism of sympathomimetics, angiotensin or pain toward oxytocin-induced milk-ejection was investigated. In rats intra-arterial (intrafemoral) doses of 0.01–0.02 μg or intravenous (iv) doses of 0.1–0.5 μg of either epinephrine, isoproterenol, norepinephrine, angiotensin or 10 μg of phenylephrine injected simultaneously with, or 30 seconds before an oxytocin dose (10 μU intrafemoral, 300 μU iv) greatly inhibited or suppressed the oxytocin response. A 15 second pain stimulus caused moderate inhibition. With alpha-receptor blockade pain, epinephrine, isoproterenol, norepinephrine, phenylephrine and angiotensin inhibition were, respectively, 70%, 75%, 100%, 40%, 0% and 100%. Under beta-receptor blockade the corresponding values were 14%, 40%, 0%, 70%, 100% and 100%; with simultaneous intrafemoral injections neither catecholamine was inhibitory toward oxytocin. In corresponding rabbit experiments approximately 10-fold higher iv drug dosages were applied and similar results were observed. In both species, combined alpha and beta-receptor blockade nearly eliminated the antagonistic actions of sympathomimetics toward oxytocin, whereas angiotensin inhibition persisted unchanged. The results indicate: 1) Mammary myoepithelial cells contain beta-adrenergic receptors but no alpha-receptors; 2) Inhibition of oxytocin-induced milk-ejection by isoproterenol and phenylephrine is meditated through stimulation of myoepithelial beta-receptors (myoepithelial relaxation) and vascular alpha-receptors (vasoconstriction), respectively; 3) Epinephrine and norepinephrine inhibition of milk-ejection is due to stimulation of vascular alpha-receptors and myoepithelial beta-receptors; 4) Angiotensin effects are unrelated to adrenergic receptor mechanisms; 5) Administration of both alpha and beta-adrenergic blockers is desirable for stabilizing the sensitivity of the oxytocin milk-ejection assay preparation against interference from endogenous or exogenous catecholamines; 6) Other than using adrenergic blockers, pharmacologic doses of oxytocin can correct nursing difficulties in animals and man with hyperfunction of the adrenal-sympathetic system.

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The adrenergic beta-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial beta-receptor

Diabetes ◽

10.2337/diabetes.32.12.1110 ◽

1983 ◽

Vol 32 (12) ◽

pp. 1110-1116 ◽

Cited By ~ 18

Author(s):

O. Gotzsche

Keyword(s):

Adenylate Cyclase ◽

Diabetic Rats ◽

Adenylate Cyclase System ◽

Beta Receptor ◽

Streptozotocin Diabetic Rats

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Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

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Effect of Beta-Receptor Blockade on Anxiety with Reference to the Three-Systems Model of Phobic Behavior

Neuropsychobiology ◽

10.1159/000118186 ◽

1985 ◽

Vol 13 (4) ◽

pp. 187-193 ◽

Cited By ~ 10

Author(s):

Olov Fagerström ◽

Kenneth Hugdahl ◽

Nils Lundström

Keyword(s):

Receptor Blockade ◽

Beta Receptor ◽

Systems Model ◽

Beta Receptor Blockade

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Effects of central venous blood volume shifts on arterial baroreflex control of heart rate

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1981.241.4.h571 ◽

1981 ◽

Vol 241 (4) ◽

pp. H571-H575 ◽

Cited By ~ 5

Author(s):

G. E. Billman ◽

D. T. Dickey ◽

K. K. Teoh ◽

H. L. Stone

Keyword(s):

Heart Rate ◽

Blood Volume ◽

Volume Expansion ◽

Body Position ◽

Venous Blood ◽

Receptor Blockade ◽

Baroreflex Control ◽

Beta Receptor ◽

Blood Volume Expansion ◽

Beta Receptor Blockade

The purpose of this study was to investigate the effects of anesthesia, body position, and blood volume expansion on baroreflex control of heart rate. Five male rhesus monkeys (7.0-10.5 kg) were given bolus injection of 4.0 micrograms/kg phenylephrine during each of the following situations: awake sitting, anesthetized (AN) (10 mg/kg ketamine-HCl) sitting, AN recumbent, AN 90 degrees head down tilt, and AN 50% blood volume expansion with normal saline. beta-Receptor blockade was also performed on each treatment after anesthesia. Four additional animals were similarly treated after 20% blood volume expansion. R-R interval was plotted against systolic aortic pressure, and the slope was determined by linear regression. Baroreflex slope was significantly (P less than 0.05) reduced by 90 degrees head down tilt and 50% volume expansion both before and after beta-receptor blockade. A similar trend was seen after 20% volume expansion. These data are consistent with the thesis that baroreflex control of heart rate is reduced by central blood volume shifts.

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