liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Bronchial hyperresponsiveness of ß-adrenoceptor agonists and antagonists in guinea pig airways
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Asthma is one of the most common diseases in the industrialised countries. The underlying mechanisms are complex and still not fully understood although inflammation of the airways plays an important role. There are to day several types of drugs used in the treatment of asthma such as anti-inflammatory drugs, specific antagonists for inflammatory mediators and bronchodilators. Beta-agonists are the main choice for relaxing airway constriction, however unwanted effects of beta-agonists on patients with asthma has been reported. The betaantagonists that are used for treatment of hypertension and various other conditions also is shown to be deleterious in asthmatics. In the present study we have used guinea pig airways to examine the proposed deleterious effects of beta-agonists and antagonists. We have shown that the (S)-enantiomeric forms of salbutamol and formoterol are able to potentiate cholinergic stimuli and we have shown that the potentiation was indomethacin sensitive in airway preparations of sensitised guinea pigs. We also showed and confirmed that the (R)-enantiomeric forms of salbutamol and formoterol were more potent in relaxing airway smooth muscle contracted with different stimuli compared to the (S)-enantiomers. The betaantagonists propranolol and pindolol were shown to be able to contract tracheal preparations if they had been pre-treated with a beta-agonist and the contraction was not simply a blockade of the beta-adrenoceptor induced relaxation. Propranolol contraction was stereo-selective and (S)-propranolol was more effective in inducing contraction than (R)-propranolol. Moreover, atenolol a betacselective antagonist induced significantly smaller contractions compared to general beta-antagonists. This indicates that the beta2-adrenocepor probably is involved in the beta-antagonist induced contraction. The cyclooxygenase inhibitor indomethacin, the 5-lipoxygenase inhibitor MK886 and a thromboxane A2 antagonist as well as capsaicin reduced the beta-antagonist induced contraction. This indicates that several arachidonic acid products as well as neuropeptides may be involved in the beta-antagonistinduced contraction.

The worsening of asthma by beta-antagonists is well known and the risks associated with beta-agonists are discussed, but the mechanisms behind these effects need further clarification. In this thesis some of the possible mechanism have been discussed, further studies are needed in order to get more safe and effective asthma treatment regime.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 780
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27499Local ID: 12153ISBN: 91-7373-541-8 (print)OAI: oai:DiVA.org:liu-27499DiVA: diva2:248051
Public defence
2003-04-10, Viktoriasalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-15Bibliographically approved
List of papers
1. Effects of albuterol enantiomers on in vitro bronchial reactivity
Open this publication in new window or tab >>Effects of albuterol enantiomers on in vitro bronchial reactivity
1996 (English)In: Clinical reviews in allergy and immunology, ISSN 1080-0549, E-ISSN 1559-0267, Vol. 14, no 1, 57-64 p.Article in journal (Refereed) Published
Abstract [en]

No abstract available

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84602 (URN)10.1007/BF02772203 (DOI)
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
2. Biological actions of formoterol isomers
Open this publication in new window or tab >>Biological actions of formoterol isomers
Show others...
2002 (English)In: Pulmonary Pharmacology & Therapeutics, ISSN 1094-5539, E-ISSN 1522-9629, Vol. 15, no 2, 135-145 p.Article in journal (Refereed) Published
Abstract [en]

Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.

Keyword
ß2 adrenoceptor, Asthma, Formoterol, Isomers, Tracheal tissue
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26775 (URN)10.1006/pupt.2001.0327 (DOI)11379 (Local ID)11379 (Archive number)11379 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-15Bibliographically approved
3. An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways
Open this publication in new window or tab >>An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways
2004 (English)In: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 82, no 6, 393-401 p.Article in journal (Refereed) Published
Abstract [en]

β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.

Keyword
beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-23707 (URN)10.1139/y04-039 (DOI)3208 (Local ID)3208 (Archive number)3208 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-15Bibliographically approved
4. Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitro
Open this publication in new window or tab >>Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitro
(English)Manuscript (preprint) (Other academic)
Abstract [en]

In the present study we establish that the ß-AA antagonist propranolol can, besides its ß-AR blocking effect, either amplify or direct induce a contraction in guinea pig airway preparations, in vitro.

Propranolol significantly enhanced the contractile response to ovalbumin (OA). The enhancement was reduced by capsaicin but insensitive to indomethacin pretreatment. These results suggest that propranolol produce airway hyperreactivity to OA by activating a pathway involving tachykinins and that COX-products are of minor significance.

We also confirm that propranolol can induce a tracheal smooth muscle contraction directly, although pre-treatment with carbachol/formoterol is a prerequisite. Direct contractile responses were completely diminished by indomethacin and reduced by capsaicin and L-659,877 (a NK2-receptor antagonist) pre-treatment. The present study shows that propranolol also enhances NANC (excitatory non-adrenergic noncholinergic) contractions but this enhancement requires pre-treatment with a 13-agonist. When the pre-treatment was excluded propranolol failed to exert either a direct or an amplifying effect on EFS (electrical field stimulation). These results contrast to the recorded enhancement of the OA-induced response, which did not request any pre-treatment.

In addition, propranolol induced an elevation of [Ca2+], in ASMC (airway smooth muscle cells), this effect was not dependent on any pre-treatment and inhibited by indomethacin treatment.

The mechanism behind these adverse effects of propranolol is not known, but our results demonstrate that contractile mediators do not originate from the airway epithelium. Since, epithelium removal did not reduce the contractile response. Furthermore, pertussis toxin (PTX) treatment did not effect the propranolol-induced contraction, indicating that a PTX sensitive G-protein coupling pathway not is involved.

In conclusion our results show that both indomethacin and capsaicin sensitive pathways are involved in the contractile response to propranolol. The relative significance of these systems differs; the direct contractile effect is strongly dependent on an indomethacin sensitive pathway, while the amplifying effect is sensitive to capsaicin and insensitive to indomethacin pre-treatment.

Further studies are required to elucidate the clinical relevance of these results.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84603 (URN)
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2012-10-15Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Johansson, Fredrik

Search in DiVA

By author/editor
Johansson, Fredrik
By organisation
PharmacologyFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 67 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf