Phosphodiesterase 4 Inhibitor Roflumilast Improves the Bronchodilative Effect of Sevoflurane in Sensitized Airways

2014 ◽  
Vol 120 (5) ◽  
pp. 1152-1159 ◽  
Author(s):  
Jing Zhou ◽  
Sohshi Iwasaki ◽  
Michiaki Yamakage
Keyword(s):  
Smooth Muscle ◽  
Volatile Anesthetic ◽  
Cyclic Adenosine Monophosphate ◽  
Relaxation Effect ◽  
Adenosine Monophosphate ◽  
Bronchodilator Effect ◽  
Phosphodiesterase 4 ◽  
Phosphodiesterase 4 Inhibitors ◽  
Lung Resistance ◽  
Total Lung Resistance

Abstract Background: Although phosphodiesterase 4 inhibitors and the volatile anesthetic sevoflurane are known to have independent bronchodilator properties, the combined administration of these two agents may have the potential to exert an additive or synergistic bronchodilator effect. The authors tested this hypothesis and investigated the common site of this combined relaxation effect in a model of airway hyperresponsiveness with ovalbumin-sensitized guinea pigs. Methods: Ovalbumin-sensitized animals (n = 138) were randomized into six groups: sensitized, sevoflurane, rolipram1.0, roflumilast1.0, sevoflurane/rolipram1.0, and sevoflurane/roflumilast1.0. Total lung resistance in vivo, airway smooth muscle tension in vitro, and intracellular cyclic adenosine monophosphate levels were measured to evaluate the relaxation effect. Results: Among the six sensitized groups, total lung resistance was higher in the order of sensitized > sevoflurane > rolipram 1.0 > roflumilast1.0 > sevoflurane/rolipram1.0 > sevoflurane/roflumilast1.0, with an increase in acetylcholine concentration. Compared with the other five groups, the muscle tensions in the sevoflurane/roflumilast1.0 group were significantly lower at carbacholine doses of 10−7, 10−6, and 10−5 M; the cyclic adenosine monophosphate concentrations (means ± SD) in the sevoflurane/rolipram1.0 (1.61 ± 0.34) and sevoflurane/roflumilast1.0 (1.50 ± 0.20) groups were higher than that in the sensitized (0.52 ± 0.15) and sevoflurane (1.12 ± 0.32) groups. Conclusions: The combined use of phosphodiesterase 4 inhibitors with the volatile anesthetic sevoflurane had an additive bronchodilator effect in ovalbumin-sensitized guinea pigs. The concurrent increase in cyclic adenosine monophosphate levels in sensitized airway smooth muscle might be a mechanism of this combined relaxation effect.

scholarly journals Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

Blood ◽  
2016 ◽  
Vol 128 (25) ◽  
pp. 2886-2890 ◽  
Author(s):  
Jeffrey D. Cooney ◽  
Ricardo C. T. Aguiar
Keyword(s):  
B Cell ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cell Receptor ◽  
Immunomodulatory Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
B Cell Malignancies ◽  
Phosphodiesterase 4 ◽  
Phosphodiesterase 4 Inhibitors ◽  
Endothelial Growth Factor

Abstract Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3′,5′-cyclic adenosine monophosphate in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases spleen tyrosine kinase and phosphatidylinositol 3-kinase and inhibits vascular endothelial growth factor A secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets.

Activation of neurons in the rostral ventrolateral medulla increases bronchomotor tone in dogs

1991 ◽  
Vol 71 (1) ◽  
pp. 210-216 ◽  
Author(s):  
J. R. Haselton ◽  
P. A. Padrid ◽  
M. P. Kaufman
Keyword(s):  
Smooth Muscle ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Ventrolateral Medulla ◽  
Adrenergic Blockade ◽  
Homocysteic Acid ◽  
Lung Resistance ◽  
Anesthetized Dogs ◽  
Total Lung Resistance ◽  
Bronchomotor Tone

Previous work from this laboratory has demonstrated that the chemical activation of cell bodies in the caudal ventrolateral medulla of chloralose-anesthetized dogs decreased bronchomotor tone by withdrawing cholinergic input to airway smooth muscle. In the present study we determined the bronchomotor responses to microinjection of DL-homocysteic acid (100 mM; 25–50 nl) into the rostral ventrolateral (RVL) medulla of chloralose-anesthetized dogs. Total lung resistance was used as a functional index of bronchomotor tone. Microinjection of DL-homocysteic acid into the 20 sites located in the lateral aspect of the RVL medulla increased both total lung resistance [from 6.5 +/- 0.4 to 9.1 +/- 0.8 (SE) cmH2O.l-1.s; P less than 0.05] and mean arterial pressure (from 125 +/- 5 to 148 +/- 8 mmHg; P less than 0.05). Microinjection of this amino acid into nine sites located in the medial aspect of the RVL medulla increased mean arterial pressure (from 130 +/- 6 to 153 +/- 6 mmHg; P less than 0.05) but had no effect on total lung resistance. We confirmed in three sites that the increase in total lung resistance evoked by microinjection of DL-homocysteic acid was accompanied by an increase in tracheal smooth muscle tension. The increase in total lung resistance evoked by DL-homocysteic acid was not affected by beta-adrenergic blockade but was abolished by muscarinic blockade.

scholarly journals Identification and characterization of an atypical Gαs-biased β2AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis

2021 ◽  
Vol 118 (49) ◽  
pp. e2026668118
Author(s):  
Donghwa Kim ◽  
Alina Tokmakova ◽  
Lauren K. Lujan ◽  
Hannah R. Strzelinski ◽  
Nicholas Kim ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Chemical Space ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Airway Smooth Muscle Cell ◽  
Functional Studies ◽  
G Protein Coupled ◽  
Identification And Characterization

G protein–coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β2-adrenergic receptors (β2AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP] production/human airway smooth muscle [HASM] cell relaxation) and β-arrestin engagement, the latter acting to quench Gαs signaling, contributing to receptor desensitization/tachyphylaxis. We screened a 40-million-compound scaffold ranking library, revealing unanticipated agonists with dihydroimidazolyl-butyl-cyclic urea scaffolds. The S-stereoisomer of compound C1 shows no detectable β-arrestin engagement/signaling by four methods. However, C1-S retained Gαs signaling—a divergence of the outputs favorable for treating asthma. Functional studies with two models confirmed the biasing: β2AR-mediated cAMP signaling underwent desensitization to the unbiased agonist albuterol but not to C1-S, and desensitization of HASM cell relaxation was observed with albuterol but not with C1-S. These HASM results indicate biologically pertinent biasing of C1-S, in the context of the relevant physiologic response, in the human cell type of interest. Thus, C1-S was apparently strongly biased away from β-arrestin, in contrast to albuterol and C5-S. C1-S structural modeling and simulations revealed binding differences compared with unbiased epinephrine at transmembrane (TM) segments 3,5,6,7 and ECL2. C1-S (R2 = cyclohexane) was repositioned in the pocket such that it lost a TM6 interaction and gained a TM7 interaction compared with the analogous unbiased C5-S (R2 = benzene group), which appears to contribute to C1-S biasing away from β-arrestin. Thus, an agnostic large chemical-space library identified agonists with receptor interactions that resulted in relevant signal splitting of β2AR actions favorable for treating obstructive lung disease.

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