Cardiotoxic Effects in Rats and Rabbits Treated with Terbutaline Alone and in Combination with Aminophylline

1983 ◽  
Vol 2 (2) ◽  
pp. 147-153 ◽  
Author(s):  
Virgil E. Whitehurst ◽  
Xavier Joseph ◽  
John R. Hohmann ◽  
Gordon Pledger ◽  
Tibor Balazs
Keyword(s):  
Plasma Levels ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Plasma Theophylline ◽  
Cardiac Lesions ◽  
Dose Dependent ◽  
Myocardial Lesions

Studies were conducted to determine the myocardial effects of a selective beta-adrenoceptor agonist, terbutaline, administered alone and in combination with aminophylline in the 4-to 5-month-old, 500-600 g (heavy) rat and the rabbit, using electrocardiographic and histopathological methods. Terbutaline given at high (5.0 mg/kg) and low (0.1 mg/kg) doses was not arrhythmogenic in the heavy rat; however, dose-dependent myocardial lesions were observed. Terbutaline given at the same doses to heavy rats pretreated with aminophylline was arrhythmogenic and produced severe cardiac lesions. Rats administered aminophylline at a dose of 18.75 mg/kg had plasma theophylline levels of 15-22 μg/ml; these concentrations are similar to the recommended human therapeutic levels, i.e., 10-20 μg/ml. The administration of terbutaline in conjunction with aminophylline did not seem to affect the plasma levels of theophylline. No arrythmias were detected in rabbits given terbutaline alone or in combination with aminophylline and no deaths occurred.

The effect of d,l-4-hydroxypropranolol on the thyroxine to 3,5,3'-triiodothyronine conversion in rat renal and liver microsomes

1984 ◽  
Vol 105 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Preben Holme Jørgensen ◽  
lb Bo Lumholtz ◽  
Jens Faber ◽  
Carsten Kirkegaard ◽  
Kaj Siersbæk-Nielsen ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Liver Microsomes ◽  
Parent Drug ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Vitro Effect ◽  
Dose Dependent

Abstract. The in vitro effect of d,l-4-hydroxypropranolol, a major pharmacological active metabolite of the beta adrenoceptor blocking drug d,l-propranolol, on the thyroxine (T4) to 3,5,3'-triiodothyronine (T3) conversion has been studied using rat renal and liver microsomal fractions. The results showed, that primarily the metabolite, but also the parent drug inhibits the T3-production in a dose dependent manner. The potency, expressed as the 50% inhibition of the T3-production, was reached using 65 ± 12 (sd) μm d,l-4-OH-propranolol and 1000 ± 22 (sd) μm d,l-propranolol, respectively in both tissues. The efficacy of 4-OH-propranolol corresponded to a maximal inhibition of 86 ± 7% while it for d,l-propranolol corresponded to 58 ± 6% (P < 0.001). The beta adrenoceptor agonist isoprenaline itself did not effect the T4 to T3 conversion but considerably opposed the inhibitory effect of d,l-4-OH-propranolol but not of d,l-propranolol. The D-isomer form of propranolol, which is without beta receptor blocking activity inhibited the T3-production in the same degree as d,l-propranolol. Evaluation of the enzyme kinetic data suggested that 4-OH-propranolol caused a competitive inhibition of both T4 and DTT. It is concluded, that the metabolite d,l-4-OH-propranolol is a much more potent and efficacious inhibitor of the T4-5'-deiodination than d,l-propranolol.

Actions of norepinephrine on rat hypoglossal motoneurons

1995 ◽  
Vol 74 (5) ◽  
pp. 1911-1919 ◽  
Author(s):  
M. A. Parkis ◽  
D. A. Bayliss ◽  
A. J. Berger
Keyword(s):  
Choline Chloride ◽  
Reversal Potential ◽  
Repetitive Firing ◽  
Inward Current ◽  
Hypoglossal Motoneurons ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Antagonist ◽  
Perfusion Solution ◽  
Adrenoceptor Agonist ◽  
Firing Properties

1. We used conventional intracellular recording techniques in 400-microns-thick slices from the brain stems of juvenile rats to investigate the action of norepinephrine (NE) on subthreshold and firing properties of hypoglossal motoneurons (HMs). 2. In recordings in current-clamp mode, 50 or 100 microM NE elicited a reversible depolarization accompanied by an increase in input resistance (RN) in all HMs tested (n = 74). In recordings in single-electrode voltage-clamp mode, NE induced a reversible inward current (INE) accompanied by a reduction in input conductance. The average reversal potential for INE was -104 mV. The NE responses could be elicited in a Ca(2+)-free solution containing tetrodotoxin, indicating that they were postsynaptic. 3. The NE response could be blocked by the alpha-adrenoceptor antagonist prazosin, but not by the beta-adrenoceptor antagonist propranolol, and could be mimicked by the alpha 1-adrenoceptor agonist phenylephrine but not by the alpha 2-adrenoceptor agonist UK 14,304 or by the beta-adrenoceptor agonist isoproterenol when alpha-adrenoceptors were blocked. 4. Substitution of barium for calcium in the perfusion solution blocked the increase in RN in response to NE without completely blocking the depolarization. Replacement of sodium chloride with choline chloride in the barium-substituted perfusion solution blocked the remaining depolarization. 5. The neuropeptide thyrotropin-releasing hormone (TRH), which also depolarizes and increases the RN of HMs, occluded the response of HMs to NE. 6. NE altered HM firing properties in three ways: it always lowered the minimum amount of injected current needed to elicit repetitive firing, it increased the slope of the firing frequency versus injected current relation in 8 of 14 cells tested, and it increased the delay from the onset of the depolarizing current pulse to the first evoked spike in all cells tested. 7. We conclude that NE acts directly on alpha 1-adrenoceptors to increase the excitability of HMs. It does this by reducing a barium-sensitive resting potassium current and activating a barium-insensitive inward current carried primarily by sodium ions. A portion of the intracellular pathway for these actions is shared by TRH. In addition, there is evidence that NE alters HM firing patterns by affecting currents that are activated following depolarization.

scholarly journals In Hemophilia Α Plasma Treated with Emicizumab, Factor IX Activation By Factor VIIa Drives Thrombin Generation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Dougald Monroe ◽  
Mirella Ezban ◽  
Maureane Hoffman
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Factor Ix ◽  
Factor X ◽  
Dose Dependent

Background.Recently a novel bifunctional antibody (emicizumab) that binds both factor IXa (FIXa) and factor X (FX) has been used to treat hemophilia A. Emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A; however there are patients that still experience bleeding. An approach to safely and effectively treating this bleeding in hemophilia A patients with inhibitors is recombinant factor VIIa (rFVIIa). When given at therapeutic levels, rFVIIa can enhance tissue factor (TF) dependent activation of FX as well as activating FX independently of TF. At therapeutic levels rFVIIa can also activate FIX. The goal of this study was to assess the role of the FIXa activated by rFVIIa when emicizumab is added to hemophilia A plasma. Methods. Thrombin generation assays were done in plasma using 100 µM lipid and 420 µM Z-Gly-Gly-Arg-AMC with or without emicizumab at 55 µg/mL which is the clinical steady state level. The reactions were initiated with low (1 pM) tissue factor (TF). rFVIIa was added at concentrations of 25-100 nM with 25 nM corresponding to the plasma levels achieved by a single clinical dose of 90 µg/mL. To study to the role of factor IX in the absence of factor VIII, it was necessary to create a double deficient plasma (factors VIII and IX deficient). This was done by taking antigen negative hemophilia B plasma and adding a neutralizing antibody to factor VIII (Haematologic Technologies, Essex Junction, VT, USA). Now varying concentrations of factor IX could be reconstituted into the plasma to give hemophilia A plasma. Results. As expected, in the double deficient plasma with low TF there was essentially no thrombin generation. Also as expected from previous studies, addition of rFVIIa to double deficient plasma gave a dose dependent increase in thrombin generation through activation of FX. Interestingly addition of plasma levels of FIX to the rFVIIa did not increase thrombin generation. Starting from double deficient plasma, as expected emicizumab did not increase thrombin generation since no factor IX was present. Also, in double deficient plasma with rFVIIa, emicizumab did not increase thrombin generation. But in double deficient plasma with FIX and rFVIIa, emicizumab significantly increased thrombin generation. The levels of thrombin generation increased in a dose dependent fashion with higher concentrations of rFVIIa giving higher levels of thrombin generation. Conclusion. Since addition of FIX to the double deficient plasma with rFVIIa did not increase thrombin generation, it suggests that rFVIIa activation of FX is the only source of the FXa needed for thrombin generation. So in the absence of factor VIII (or emicizumab) FIX activation does not contribute to thrombin generation. However, in the presence of emicizumab, while rFVIIa can still activate FX, FIXa formed by rFVIIa can complex with emicizumab to provide an additional source of FX activation. Thus rFVIIa activation of FIX explains the synergistic effect in thrombin generation observed when combining rFVIIa with emicizumab. The generation of FIXa at a site of injury is consistent with the safety profile observed in clinical use. Disclosures Monroe: Novo Nordisk:Research Funding.Ezban:Novo Nordisk:Current Employment.Hoffman:Novo Nordisk:Research Funding.

Downregulation of beta-adrenergic receptors and signal transduction response in salivary glands of NOD mice

1994 ◽  
Vol 266 (3) ◽  
pp. G433-G443
Author(s):  
Y. Hu ◽  
K. R. Purushotham ◽  
P. Wang ◽  
R. Dawson ◽  
M. G. Humphreys-Beher
Keyword(s):  
Salivary Glands ◽  
Adrenergic Receptor ◽  
Radioligand Binding ◽  
Nod Mice ◽  
Exocrine Function ◽  
Beta Adrenergic ◽  
Beta Adrenoceptor ◽  
Stimulus Response ◽  
Adrenoceptor Agonist ◽  
Second Messenger Signaling

The nonobese diabetic (NOD) mouse is subject to autoimmune disease-associated lymphocytic attack on the salivary glands with a corresponding loss of exocrine function. Downregulation of stimulus response to the beta-adrenoceptor agonist, isoproterenol, appears to be related to a decline in beta-adrenergic receptor density, changes in the level of intracellular second messenger signaling component adenosine 3',5'-cyclic monophosphate, and protein kinase A activity. An autoantibody to the beta 1-adrenergic receptor present in the sera of diabetic NOD mice may be involved in the reduced agonist response by virtue of its ability to retard dihydroalprenolol radioligand binding to receptors in the membranes of salivary glands from control mice and recognition of purified beta 1-adrenergic receptor by immunoblotting techniques.

ATP-sensitive K+ channel opener pinacidil augments beta 1-adrenoceptor-induced coronary vasodilation in dogs

1996 ◽  
Vol 270 (6) ◽  
pp. H2210-H2215 ◽  
Author(s):  
Y. Katsuda ◽  
K. Egashira ◽  
H. Ueno ◽  
Y. Arai ◽  
Y. Akatsuka ◽  
...  
Keyword(s):  
Metabolic Stress ◽  
K Channel ◽  
Coronary Vasodilation ◽  
Beta Adrenoceptor ◽  
Intracoronary Infusion ◽  
Channel Opener ◽  
Adrenoceptor Agonist ◽  
Anesthetized Dogs ◽  
Beta 2 ◽  
K Channel Opener

The opening of ATP-sensitive K+ (K+ATP) channels contributes to the mechanism of metabolic coronary vasodilation. The aim of the present study was to determine whether K+ATP channel opener pinacidil augments coronary vasodilation induced by beta-adrenoceptor stimulation. In anesthetized dogs, coronary vasodilation in response to intracoronary infusion of a beta 1-adrenoceptor agonist denopamine, selective beta 2-adrenoceptor stimulation with isoproterenol after bisoprolol or nitroglycerin was studied before and during simultaneous intracoronary infusion of pinacidil at a dose of 1 microgram/min, which had no effect on basal hemodynamics. Pinacidil augmented the denopamine-induced increase in coronary blood flow (CBF) from 38 +/- 9 to 66 +/- 16% (P < 0.05) but did not affect the denopamine-induced by isoproterenol or nitroglycerin. Thus pinacidil selectively augmented beta 1-adrenoceptor-mediated coronary vasodilation. These observations suggest that the K+ATP channel opener pinacidil may increase myocardial perfusion during metabolic stress associated with beta 1-adrenoceptor stimulation.

scholarly journals Cyclic AMP-evoked oscillations of intracellular [Ca2+] in guinea-pig hepatocytes

1991 ◽  
Vol 275 (1) ◽  
pp. 277-280 ◽  
Author(s):  
T Capiod ◽  
J Noel ◽  
L Combettes ◽  
M Claret
Keyword(s):  
Angiotensin Ii ◽  
Cyclic Amp ◽  
Guinea Pig ◽  
Intracellular Perfusion ◽  
Beta Adrenoceptor ◽  
Adrenoceptor Agonist ◽  
Patch Pipette

The effects of the beta-adrenoceptor agonist isoprenaline and cyclic AMP (cAMP) on cytosolic free Ca2+ ([Ca2+]i) were studied in the single guinea-pig hepatocyte. In common with InsP3-dependent agonists such as noradrenaline or angiotensin II, isoprenaline (0.5-10 microM) and cAMP (50-100 mM, perfused into the cell via the patch-pipette), were able to generate fast and slow fluctuations of [Ca2+]i. Responses to isoprenaline and cAMP also were observed in the absence of external Ca2+. Isoprenaline-evoked [Ca2+]i rises were not blocked by the intracellular perfusion of heparin, suggesting that these fluctuations are independent of the binding of InsP3 to its receptor.

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