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Chinese Medical Journal Nov 2018
Topics: Adrenal Gland Neoplasms; Catecholamines; Humans; Magnetic Resonance Imaging; Male; Middle Aged; PAX8 Transcription Factor; Phenoxybenzamine; Pheochromocytoma
PubMed: 30381598
DOI: 10.4103/0366-6999.244126 -
The Journal of Physiology Oct 19681. The pattern and control of sweating in one breed of goat and six breeds of sheep have been studied.2. Heat exposure of both sheep and goats resulted in periodic...
1. The pattern and control of sweating in one breed of goat and six breeds of sheep have been studied.2. Heat exposure of both sheep and goats resulted in periodic discharges of moisture on to the surface of the skin of the shorn mid-side. The frequency of discharge showed considerable variation between individual animals, varying from less than 1/hr to 14/hr. Approximate counts of the number of active sweat glands suggested that the same glands were involved at each discharge.3. The amount of moisture produced at each discharge declined upon continued heat exposure. The rate of decline was independent of the frequency of discharge.4. Adreno-medullary denervation had no effect on the pattern of sweating in either the sheep or the goat.5. Intravenous adrenaline administration (5 mug/kg body wt.) caused the sweat glands to discharge, but noradrenaline had no effect at the same dose.6. Thermal sweating was inhibited by bethanidine and phenoxybenzamine but not by propranolol. Sweating induced by intravenous adrenaline administration was blocked by phenoxybenzamine but not by bethanidine or propranolol.7. It is concluded that sweating on the mid-side of the sheep and goat is controlled by an adrenergic mechanism, that secretion from the adrenal medulla under conditions of mild heat stress does not stimulate the glands and that sweating is mediated by adrenergic alpha-receptors.
Topics: Adrenal Medulla; Animals; Denervation; Epinephrine; Female; Goats; Guanidines; Hot Temperature; Male; Norepinephrine; Phenoxybenzamine; Propranolol; Sensory Receptor Cells; Sheep; Sweat Glands; Sweating
PubMed: 5685286
DOI: 10.1113/jphysiol.1968.sp008623 -
British Journal of Pharmacology Nov 2009Nitric oxide (NO) controls numerous physiological processes by activation of its receptor, guanylyl cyclase (sGC), leading to the accumulation of 3'-5' cyclic guanosine...
BACKGROUND AND PURPOSE
Nitric oxide (NO) controls numerous physiological processes by activation of its receptor, guanylyl cyclase (sGC), leading to the accumulation of 3'-5' cyclic guanosine monophosphate (cGMP). Ca(2+)-calmodulin (CaM) regulates both NO synthesis by NO synthase and cGMP hydrolysis by phosphodiesterase-1. We report that, unexpectedly, the CaM antagonists, calmidazolium, phenoxybenzamine and trifluoperazine, also inhibited cGMP accumulation in cerebellar cells evoked by an exogenous NO donor, with IC(50) values of 11, 80 and 180 microM respectively. Here we sought to elucidate the underlying mechanism(s).
EXPERIMENTAL APPROACH
We used cerebellar cell suspensions to determine the influence of CaM antagonists on all steps of the NO-cGMP pathway. Homogenized tissue and purified enzyme were used to test effects of calmidazolium on sGC activity.
KEY RESULTS
Inhibition of cGMP accumulation in the cells did not depend on changes in intracellular Ca(2+) concentration. Degradation of cGMP and inactivation of NO were both inhibited by the CaM antagonists, ruling out increased loss of cGMP or NO as explanations. Instead, calmidazolium directly inhibited purified sGC (IC(50)= 10 microM). The inhibition was not in competition with NO, nor did it arise from displacement of the haem moiety from sGC. Calmidazolium decreased enzyme V(max) and K(m), indicating that it acts in an uncompetitive manner.
CONCLUSIONS AND IMPLICATIONS
The disruption of every stage of NO signal transduction by common CaM antagonists, unrelated to CaM antagonism, cautions against their utility as pharmacological tools. More positively, the compounds exemplify a novel class of sGC inhibitors that, with improved selectivity, may be therapeutically valuable.
Topics: Animals; Calcium; Calmodulin; Cerebellum; Cyclic GMP; Guanylate Cyclase; Imidazoles; Inhibitory Concentration 50; Nitric Oxide; Nitric Oxide Donors; Phenoxybenzamine; Rats; Rats, Wistar; Signal Transduction; Trifluoperazine
PubMed: 19845679
DOI: 10.1111/j.1476-5381.2009.00416.x -
Proceedings of the National Academy of... Sep 1971Dopamine-beta-hydroxylase (EC 1.14.2.1), an enzyme localized in sympathetic synaptic vesicles, was released together with norepinephrine during in vitro stimulation of...
Dopamine-beta-hydroxylase (EC 1.14.2.1), an enzyme localized in sympathetic synaptic vesicles, was released together with norepinephrine during in vitro stimulation of the hypogastric nerve that innervates the vas deferens of the guinea pig. Stimulation of the nerve in the presence of high concentrations of calcium (7.5 mM) or phenoxybenzamine caused a marked increase in the amounts of the enzyme and norepinephrine released into the bath. The augmentation of release of dopamine-beta-hydroxylase by 7.5 mM calcium or phenoxybenzamine was reversed by prostaglandin E(2). These findings suggest that the release of the sympathetic neurotransmitter, norepinephrine, occurs by a process of exocytosis in which the vesicular content of soluble dopamine-beta-hydroxylase is also released. The depolarization-induced exocytosis, which is stimulated by calcium, may be affected by prostaglandin E(2) or phenoxybenzamine through inhibition or enhancement of the actions of calcium in the release process.
Topics: Animals; Calcium; Dopamine beta-Hydroxylase; Electric Stimulation; Enzyme Induction; Guinea Pigs; In Vitro Techniques; Male; Mixed Function Oxygenases; Norepinephrine; Phenoxybenzamine; Prostaglandins; Stimulation, Chemical; Sympathetic Nervous System; Synaptic Vesicles; Vas Deferens
PubMed: 5289380
DOI: 10.1073/pnas.68.9.2227 -
British Journal of Sports Medicine Dec 1978Two investigations have been carried out. The first studied the effects of autonomic blockade on the cardiovascular response to a step test, a 50% maximum isometric grip...
Two investigations have been carried out. The first studied the effects of autonomic blockade on the cardiovascular response to a step test, a 50% maximum isometric grip test and a Valsalva manoeuvre: the step test was of 5 minutes duration and the other two for as long as possible. beta adrenergic blockade by propanolol diminished the blood pressure and pulse rate response to both the step test and isometric grip. The pulse rate response to the step test was also affected by cholinergic blockade with atropine. The response to the Valsalva test showed a cholinergic blockade effect of pulse rate alone and a blood pressure response alone on alpha adrenergic blockade by phenoxybenzamine. The second studied psychological stressing on physical and mental ability. A potential 'punishment' situation increased the blood pressure and pulse rate response to isometric grip while decreasing the time for which it could be maintained. A potential 'reward' situation increased both the maximum grip and the time for which 50% grip could be maintained. It is concluded that psychological factors can affect performance dependant on whether the situation is perceived as one of 'reward' or 'punishment'. A factor in the mediation of the adverse response is an inappropriate response of the autonomic nervous system.
Topics: Adult; Atropine; Autonomic Nervous System; Blood Pressure; Female; Heart; Humans; Male; Motivation; Muscles; Oxygen Consumption; Phenoxybenzamine; Physical Endurance; Physical Fitness; Propranolol; Psychology; Pulse; Punishment; Respiratory Physiological Phenomena; Reward; Stress, Physiological; Stress, Psychological
PubMed: 444804
DOI: 10.1136/bjsm.12.4.179 -
BMC Veterinary Research Feb 2020Ectopic Cushing's syndrome (ECS) associated with malignant tumors, such as small cell lung carcinoma, bronchial carcinoids, and pheochromocytoma, has been reported in...
BACKGROUND
Ectopic Cushing's syndrome (ECS) associated with malignant tumors, such as small cell lung carcinoma, bronchial carcinoids, and pheochromocytoma, has been reported in human medicine. However, ECS related to pheochromocytoma has not been reported in dogs.
CASE PRESENTATION
An 11-year-old castrated, male Scottish terrier was diagnosed with a left adrenal mass. Cushing's syndrome was suspected based on clinical signs, including pot belly, polyuria, polydipsia, bilateral alopecia, recurrent pyoderma, and calcinosis cutis. Cushing's syndrome was diagnosed on the basis of consistent clinical signs and repeated adrenocorticotropic hormone (ACTH) stimulation tests. In addition, tests for fractionated plasma metanephrine/normetanephrine suggested a pheochromocytoma. Unilateral adrenalectomy was performed after medical management with trilostane and phenoxybenzamine. Histopathology confirmed a diagnosis of pheochromocytoma without cortical lesions. After surgery, fractionated metanephrine/normetanephrine and the findings of low-dose dexamethasone suppression and ACTH stimulation tests were within the normal ranges without any medication. There were no clinical signs or evidence of recurrence and metastasis on thoracic and abdominal X-rays and ultrasonography up to 8 months after surgery.
CONCLUSIONS
Pheochromocytoma should be considered a differential diagnosis for dogs with Cushing's syndrome with an adrenal tumor. A good prognosis can be expected with prompt diagnosis and surgical intervention.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Animals; Cushing Syndrome; Dihydrotestosterone; Dog Diseases; Dogs; Male; Phenoxybenzamine; Pheochromocytoma
PubMed: 32014021
DOI: 10.1186/s12917-020-2244-7 -
British Journal of Pharmacology Feb 2015The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation...
BACKGROUND AND PURPOSE
The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity.
EXPERIMENTAL APPROACH
LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein-protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology.
KEY RESULTS
LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation.
CONCLUSIONS AND IMPLICATIONS
Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery.
Topics: Cell Line, Tumor; Dimerization; HEK293 Cells; Humans; Membrane Proteins; Molecular Structure; Molecular Weight; Nerve Tissue Proteins; Phenoxybenzamine; Signal Transduction; Stereoisomerism; Structure-Activity Relationship
PubMed: 25257685
DOI: 10.1111/bph.12945 -
The Journal of Biological Chemistry Sep 1976Epinephrine and the alpha-adrenergic agonist phenylephrine activated phosphorylase, glycogenolysis, and gluconeogenesis from lactate in a dose-dependent manner in...
Studies on the alpha-adrenergic activation of hepatic glucose output. I. Studies on the alpha-adrenergic activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase in isolated rat liver parenchymal cells.
Epinephrine and the alpha-adrenergic agonist phenylephrine activated phosphorylase, glycogenolysis, and gluconeogenesis from lactate in a dose-dependent manner in isolated rat liver parenchymal cells. The half-maximally active dose of epinephrine was 10-7 M and of phenylephrine was 10(-6) M. These effects were blocked by alpha-adrenergic antagonists including phenoxybenzamine, but were largely unaffected by beta-adrenergic antagonists including propranolol. Epinephrine caused a transient 2-fold elevation of adenosine 3':5'-monophosphate (cAMP) which was abolished by propranolol and other beta blockers, but was unaffected by phenoxybenzamine and other alpha blockers. Phenoxybenzamine and propranolol were shown to be specific for their respective adrenergic receptors and to not affect the actions of glucagon or exogenous cAMP. Neither epinephrine (10-7 M), phenylephrine (10-5 M), nor glucagon (10-7 M) inactivated glycogen synthase in liver cells from fed rats. When the glycogen synthase activity ratio (-glucose 6-phosphate/+ glucose 6-phosphate) was increased from 0.09 to 0.66 by preincubation of such cells with 40 mM glucose, these agents substantially inactivated the enzyme. Incubation of hepatocytes from fed rats resulted in glycogen depletion which was correlated with an increase in the glycogen synthase activity ratio and a decrease in phosphorylase alpha activity. In hepatocytes from fasted animals, the glycogen synthase activity ratio was 0.32 +/- 0.03, and epinephrine, glucagon, and phenylephrine were able to lower this significantly. The effects of epinephrine and phenylephrine on the enzyme were blocked by phenoxybenzamine, but were largely unaffected by propranolol. Maximal phosphorylase activation in hepatocytes from fasted rats incubated with 10(-5) M phenylephrine preceded the maximal inactivation of glycogen synthase. Addition of glucose rapidly reduced, in a dose-dependent manner, both basal and phenylephrine-elevated phosphorylase alpha activity in hepatocytes prepared from fasted rats. Glucose also increased the glycogen synthase activity ratio, but this effect lagged behind the change in phosphorylase. Phenylephrine (10-5 M) and glucagon (5 x 10(-10) M) decreased by one-half the fall in phosphoryalse alpha activity seen with 10 mM glucose and markedly suppressed the elevation of glycogen synthase activity. The following conclusions are drawn from these findings. (a) The effects of epinephrine and phenylephrine on carbohydrate metabolism in rat liver parenchymal cells are mediated predominantly by alpha-adrenergic receptors. (b) Stimulation of these receptors by epinephrine or phenylephrine results in activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase by mechanisms not involving an increase in cellular cAMP. (c) Activation of beta-adrenergic receptors by epinephrine leads to the accumulation of cAMP, but this is associated with minimal activation of phosphorylase or inactivation of glycogen synthase...
Topics: Adrenergic alpha-Agonists; Animals; Cyclic AMP; Epinephrine; Glucagon; Gluconeogenesis; Glycogen Synthase; Kinetics; Liver; Phenoxybenzamine; Phenylephrine; Phosphorylases; Propranolol; Rats
PubMed: 8456
DOI: No ID Found -
The Journal of Clinical Investigation Sep 1966
Topics: Animals; Hydrocortisone; Penicillins; Phenoxybenzamine; Pneumococcal Infections; Rabbits; Staphylococcal Infections
PubMed: 5919345
DOI: 10.1172/JCI105450 -
Annals of Surgery Aug 1974The mechanism of protamine-induced hypotension and bradycardia was investigated in anesthetized, heparinized dogs. Several groups of animals with intact circulation were...
The mechanism of protamine-induced hypotension and bradycardia was investigated in anesthetized, heparinized dogs. Several groups of animals with intact circulation were studied for their responses to protamine under control conditions and following the administration of various pharmacological agents. The parameters observed include femoral arterial pressure (FAP), central venous pressure (CVP), left ventricular pressure (LVP) and its rate of rise (dp/dt), left ventricular contractile element velocity of shortening (Vce), maximal Vce (V max) and cardiac output (CO). Various groups were studied under the following pharmacological conditions: autonomic cholinergic blockade by atropine; alpha and beta adrenergic receptor blockade using phenoxybenzamine and propranolol respectively; ganglionic and adrenal medullary block using hexamethonium, and depletion of endogenous histamine by means of compound 48/80. Another group was placed on total cardiopulmonary bypass thus isolating the heart from the peripheral circulation. The effect of protamine on the vascular tree alone was then observed by monitoring FAP before and after protamine administration. The findings indicate that the cardiovascular effects of protamine are produced by a direct effect on the myocardium and vascular tree.
Topics: Animals; Atropine; Blood Pressure; Bradycardia; Cardiac Output; Central Venous Pressure; Dogs; Extracorporeal Circulation; Heart; Heart Ventricles; Heparin; Hexamethonium Compounds; Hypotension; Phenoxybenzamine; Propranolol; Protamines; Ventricular Function; p-Methoxy-N-methylphenethylamine
PubMed: 4842984
DOI: 10.1097/00000658-197408000-00018