Phosphodiesterase 4 and tolerance to β2-adrenoceptor agonists in asthma

doi:10.1016/0165-6147(96)10039-0

Trends in Pharmacological Sciences

Volume 17, Issue 9, September 1996, Pages 331-336

https://doi.org/10.1016/0165-6147(96)10039-0 Get rights and content

Abstract

β₂-Adrenoceptor agonists provide a mainstay in the treatment of asthma worldwide. However, despite their ability to provide symptomatic relief, chronic or repeated exposure to β₂-adrenoceptor agonists does not resolve asthmatic inflammation, because of the rapid development of tolerance by pro-inflammatory and immune cells of the lung. The prevailing belief is that tolerance to the so-called non-bronchodilator actions of β₂-adrenoceptor agonists is largely attributable to direct receptor desensitization mediated by G protein receptor-coupled kinases and/or cAMP-dependent protein kinase. Here, Mark Giembycz suggests another, largely ignored, explanation for β₂-adrenoceptor desensitization that is based on the accelerated degradation of cAMP by Phosphodiesterase.

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Depending on their mode of regulation, kinetics and pharmacological properties, PDEs is sub classified into 11 families (PDE1–PDE11) (Table 1). Out of 11 PDE families, 3 families (PDEs 4, 7, and 8) preferably hydrolyze cAMP, 3 families (PDEs 5, 6, and 9) selectively hydrolyze cGMP, and 5 families (PDEs 1, 2, 3, 10, and 11) hydrolyze both cyclic nucleotides with different competency [39–116]. The enzymatic activity and properties of PDEs in the kidney as well as in different organs and tissues have been validated [117].
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An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out. To understand the functioning of Phosphodiesterases (PDEs) and its pharmacological modulation in Renal Ischemia-Reperfusion Injury.
Current therapeutic options may not be enough to treat renal I/R injury in group of patients and therefore, the current review has discussed the general characteristics and physiology of PDEs and preclinical-studies defining the relationship between PDEs expression in renal injury due to I/R and its outcome on renal function.
The role of PDE inhibitors in renal I/R injury and the clinical status of drugs for various renal diseases have been summarized in this review.
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Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically β-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.
Recent developments in the chemistry of pyrazolo[4,3-c]quinolines
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As a result of these observations, highly selective A3 adenosine receptor antagonists are being sought as potential antiasthmatic,119 antiinflammatory,120 and cerebroprotective agents.121 In the past few years, Colotta and co-workers directed much effort toward the study of adenosine receptor antagonists122 and they focused their attention on 2-aryl-pyrazolo[3,4-c]quinoline derivatives. A new synthetic route for the synthesis of 2-aryl-pyrazolo[4,3-c]quinolines 156, to be used as potent and selective A3 adenosine receptor antagonists, has been reported.80
Improving the relaxing effect of terbutaline with phosphodiesterase inhibitors: Studies on pregnant rat uteri in vitro
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Citation Excerpt :
Our observations are in concordance with previous finding that restraining the breakdown of cAMP with PDE4 inhibitors might act to potentiate the effects of β2-AR agonists in asthma or COPD, which may in turn result in synergy for inflammatory outcome measures such as exacerbations (Lipworth, 2005). Unfortunately, long-term administration of β2-AR agonists often leads to reduced therapeutic response due to drug-induced desensitization of β2-ARs, and their effectiveness is also corrupted by physiological changes in late pregnancy (Gáspár et al., 2005; Giembycz, 1996). It is desirable to test the efficacy of the above drug combination on a long run, before drawing a conclusion related to clinical application.
Previous results by our group showed that the in vitro uterus-relaxing potency of β₂-adrenergic receptor (β₂-AR) agonists and uterine cAMP accumulation are enhanced in case of visceral inflammation. Our aim was to study the effects of the non-selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on the uteri of intact late-pregnant female rats (on days 20 and 22 of pregnancy) and of pregnant rats treated with lipopolysaccharide (LPS) to evoke preterm labor (on day 20).
The effects of theophylline and rolipram alone and of rolipram with terbutaline were investigated in isolated organ system. Contractions were evoked with KCl. The forskolin- and terbutaline-stimulated cAMP accumulations were determined by enzyme immunoassay, with or without rolipram.
The maximum uterus-relaxing effects of theophylline and rolipram decreased significantly (p < 0.05) with the progression of pregnancy in intact rats. The most pronounced effect of rolipram was detected in rats challenged with LPS on day 20. Rolipram increased the in vitro effect of terbutaline both in intact and in LPS-treated rats. In the presence of rolipram, the forskolin- and terbutaline-stimulated cAMP accumulations were higher in LPS-treated than in intact rats.
The previous findings led us to conclude that the combined administration of PDE4 inhibitors with β₂-agonists is of therapeutic value for the inhibition for uterine contractions, especially in the case of genital inflammation, which often triggers preterm birth. Combination therapy in general is associated with lesser side-effects, as a consequence of lower effective doses of each drug.
Theophylline
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Theophylline remains one of the most widely prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) worldwide, since it is inexpensive and widely available. The frequency of side-effects at the previously recommended doses and the relatively low efficacy of theophylline have recently led to reduced usage, since inhaled β₂-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Despite the fact that theophylline has been used in asthma therapy for over 70 years, there is still considerable uncertainty about its molecular mode of action in asthma and its logical place in therapy. Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Many salts of theophylline have also been marketed, the most common being aminophylline, the ethylene diamine salt used to increase solubility at neutral pH, so that intravenous administration is possible. Theophylline has several cellular effects that may contribute to its clinical efficacy in the treatment of asthma. The primary effect of theophylline is assumed to be the relaxation of airway smooth muscle. It is suggested that theophylline may exert its effects in asthma via some action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved. The molecular mechanism of anti-inflammatory effects of theophylline is now becoming clearer, and it seems likely that there is a synergistic interaction with the anti-inflammatory mechanism of corticosteroids through restoration of HDAC activity. This interaction may underlie the beneficial effects of theophylline when added to inhaled corticosteroids. This may be particularly appropriate in patients with more severe asthma in whom corticosteroids are less effective as there may be a reduction in HDAC activity in these patients as well as in smoking asthmatics patients and patients with COPD.

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Trends in Pharmacological Sciences

ReviewPhosphodiesterase 4 and tolerance to β2-adrenoceptor agonists in asthma

Abstract

Trends Pharmacol. Sci.

Lancet

J. Biol. Chem.

Biochem. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Contmun.

J. Invest. Dermatol.

Mol. Cell Endocrinol.

J. Allergy Clin. Immunol.

J. Allergy Clin. Immunol.

J. Invest. Dermatol.

J. Allergy Clin. Immunol.

J. Allergy Clin. Immunol.

Clin. Exp. Allergy

Annu. Rev. Med.

Physiol. Rev.

Am. J. Respir. Crit. Care Med.

New Engl. J. Med.

Am. J. Respir. Crit. Care Med.

FASEB J.

Science

Review
Phosphodiesterase 4 and tolerance to β₂-adrenoceptor agonists in asthma