Resistance of β2-adrenoceptor-mediated responses of lung strips to desensitization by long-term agonist exposure - comparison with atrial β1-adrenoceptor-mediated responses

Herepath, Michael L.; Broadley, Kenneth J.

doi:10.1016/0014-2999(92)90030-8

Cited by 12 publications

(3 citation statements)

References 44 publications

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“…That the concentrations of isoprenaline and dopexamine used here did not produce significant desensitization in the tissues examined may therefore be due to genuine resistance of the P2-receptors therein to undergo that process. This is confirmed by the results of our previous in vitro studies in which incubation of lung parenchymal strips or rat pulmonary artery or aorta with isoprenaline failed to induce desensitization of the 132-receptor-mediated relaxation responses (Martin & Broadley, 1990;Herepath & Broadley, 1992).…”

Section: P2-adrenoceptor-mediated Vascular Responsessupporting

confidence: 86%

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Martin

Broadley

1994

British J Pharmacology

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1 Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1-dopamine receptors and P2-adrenoceptors (240 ,g kg-' h-1), isoprenaline, a P,-and P2-adrenoceptor agonist (40 fig kg- and paced left atrium (increase in tension) showed significant reductions in sensitivity to isoprenaline following isoprenaline infusion. The EC5 values were significantly increased from 5.6 to 17.7 nM in right atria and from 7.4 to 27.1 nM in left atria. The maximum rate increase of right atria was also significantly less after isoprenaline infusion compared with controls (164.0 and 251.9 beats min-', respectively) but the maximum tension responses of left atria were not significantly different. After infusion with dopexamine, however, there was no change in sensitivity of the left or right atria to PI-adrenoceptor stimulation by isoprenaline.3 P2-Adrenoceptor-mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 x 108 M), showed no significant difference in maximum response or ECm in tissue from isoprenaline-or dopexamine-infused rats compared with vehicle-infused controls. P2-Adrenoceptormediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 x 10-8 M) to raise perfusion pressure. As with the pulmonary artery, there was no significant difference in ED50 or maximum response to isoprenaline in kidneys from isoprenalineinfused animals compared with vehicle controls.4 The DI-receptor-mediated vasodilator responses to dopamine of the kidney perfused with U46619 were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure (16.0 mmHg) and ED50 value (5.2 rig) were significantly different from those after vehicle infusion (31.5 mmHg; 1.5 pg). 5 These results show that functional responses mediated via P1-adrenoceptors and DI-receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the P2-adrenoceptor-mediated vasodilator responses of the pulmonary artery and kidney are not reduced by these agonists. Thus, under identical conditions, there appears to be selective down-regulation of peripheral P,-and D,-receptors, but not of P2-adrenoceptors.

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Section: P2-adrenoceptor-mediated Vascular Responsessupporting

confidence: 86%

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Martin

Broadley

1994

British J Pharmacology

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“…As has been suggested from animal models (Fernandes et al , 1988), at moderate to high concentrations both the selective and non‐selective β‐agonist elicited a statistically similar reduction of about 20% in maximal bronchodilatation and in EC 50 . Similar results have been obtained in guinea‐pig and in pig lung, in which isoprenaline administered at concentrations of 1–5 μmol 1 −1 over 1–3 h evoked a significant reduction in responsiveness to subsequent relaxant stimuli (Goldie et al , 1986; Fernandes et al , 1988; Herepath & Broadley, 1992).…”

Section: Discussionsupporting

confidence: 81%

Effects of β₂‐agonist‐ and dexamethasone‐treatment on relaxation and regulation of β‐adrenoceptors in human bronchi and lung tissue

Hauck

Harth

Schulz

et al. 1997

British J Pharmacology

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1 Long-term treatment with b 2 -adrenoceptor agonists can lead to a decreased therapeutic e cacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to b-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with b 2 -adrenoceptor agonists. Additionally, the in¯uence of pretreatment with dexamethasone on desensitization was studied.2 The e ect of b 2 -agonist incubation alone and after coincubation with dexamethasone on density and a nity of b-adrenoceptors was investigated by radioligand binding experiments. 3 In human isolated bronchi, isoprenaline induces a time-and concentration-dependent b-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73+4% in e cacy of isoprenaline to relax human bronchial smooth muscle. 4 After an incubation period of 60 min with 100 mmol l 71 terbutaline, a signi®cant decline in its relaxing e cacy (81+8%) and potency (by a factor 5.5) occurred. 5 Incubation with 30 mmol l 71 isoprenaline for 60 min did not impair the maximal e ect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6 Coincubation of dexamethasone with isoprenaline (120 min; 30 mmol l 71 ) preserved the e ect of isoprenaline on relaxation (129+15%). In conclusion, pretreatment of human bronchi with b-adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down-regulation of b-adrenoceptors. This e ect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identi®cation of mechanisms of b-adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable e ects of long-term b-adrenoceptor stimulation.

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“…Некоторые исследователи все же не исключают, что развитие гиперреактивности дыхательных путей и снижение бронхопротекторного действия сальбутамола на молекулярном уровне может объясняться функциональной десентиситизацией (down-регуляция) β 2 -адренорецепторов, экспрессируемых в гладкомышечных клетках дыхательных путей с сопутствующим повышением активности ассоциированной с ними аденилатциклазы (Herepath and Broadley, 1992;Hauck et al, 1997;Boskabady and Aslani, 2007). Cooper and Panettieri (2008) в эксперименте с применением тонких срезов легкого человека, содержащих фрагменты дыхательных путей, установили, что сальбутамол стимулирует время-и дозозависимое снижение изопротеренол-индуцированой релаксации, достигающей 45,0% (Р = 0,011).…”

Section: гиперреактивность дыхательных путейобратная сторона бронхолиunclassified

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

Miroshnichenko

Bulgakova

Perfiliev

et al. 2017

Regul. Mech. Biosyst.

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The aim of the work is to conduct an analytical review of the results of preclinical studies of levosalbutamol. The review discusses the pharmacodynamic features of the R-stereoisomer of salbutamol in vitro. The chemical bases of interaction of levosalbutamol with β 2 -adrenoreceptors, intracellular signaling cascades associated with β 2 -adrenoreceptors, and structural features of clinically significant ligands of β 2 -adrenoreceptors are presented. Broncholytic activity, influence on the contractility of the diaphragmatic muscles, mucociliary clearance of R-salbutamol in comparison with racemic salbutamol are described. The data presented indicate that all known β 2 -adrenergic receptor-dependent effects of racemic salbutamol, including bronchodilation, are realized by its R-enantiomer. There is evidence that the regular inhalation administration of racemic salbutamol is accompanied by a partial decrease in the bronchoprotective effect and an increase in airway hyperreactivity in response to the action of provocative factors. It was found that the development of hyperreactivity of the respiratory tract is excluded in the case of regular inhalation of levosalbutamol. Possible mechanisms of the paradoxical bronchoconstrictor effect of the salbutamol dystomer are described. This article shows the beneficial effect of levosalbutamol on mucociliary clearance, its anti-inflammatory activity and antiallergic effect. The image data are compared between the enantiomers and the racemate of salbutamol. Special attention is paid to the pharmacokinetics of enantiomers of salbutamol. The data presented from the preclinical studies provide evidence of chiral inversion of stereoisomers of salbutamol.Левосальбутамол как альтернатива лекарственным препаратам на основе рацемического сальбутамола: обзор результатов доклинических исследований А. Г. Мирошниченко, Я. С. Булгакова, В. Ю. Перфильев, Н. Г. Базарнова Алтайский государственный университет, Барнаул, РоссияПроанализированы результаты доклинических исследований лекарственного средства левосальбутамол. Обсуждаются фармакодинамические особенности R-стереоизомера сальбутамола in vitro. Представлены химические основы взаимодействия левосальбутамола с β 2 -адренорецепторами, внутриклеточные сигнальные каскады, ассоциированные с β 2 -адренорецепторами, а также структурные особенности клинически значимых лигандов β 2 -адренорецепторов. Описана бронхолитическая активность, влияние на контрактильность диафрагмальных мышц, мукоцилиарный клиренс R-сальбутамола по сравнению с рацемическим сальбутамолом. Приведены данные, которые указывают на то, что все известные β 2 -адренорецепторзависимые эффекты рацемического сальбутамола, включая бронходилатацию, реализуются за счет его R-энантиомера. Имеются свидетельства того, что регулярное ингаляционное введение рацемического сальбутамола сопровождается парциальным снижением бронхопротективного эффекта и увеличением гиперреактивности дыхательных путей в ответ на действие провокационных факторов. При этом развитие гиперреактивности дыхательных п...

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Resistance of β2-adrenoceptor-mediated responses of lung strips to desensitization by long-term agonist exposure - comparison with atrial β1-adrenoceptor-mediated responses

Cited by 12 publications

References 44 publications

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of β₂‐agonist‐ and dexamethasone‐treatment on relaxation and regulation of β‐adrenoceptors in human bronchi and lung tissue

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

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Resistance of β2-adrenoceptor-mediated responses of lung strips to desensitization by long-term agonist exposure - comparison with atrial β1-adrenoceptor-mediated responses

Cited by 12 publications

References 44 publications

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

Effects of β2‐agonist‐ and dexamethasone‐treatment on relaxation and regulation of β‐adrenoceptors in human bronchi and lung tissue

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

Contact Info

Product

Resources

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Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of β₂‐agonist‐ and dexamethasone‐treatment on relaxation and regulation of β‐adrenoceptors in human bronchi and lung tissue