RESUMO
BACKGROUND: We have previously reported that chronic treatment with certain 'beta-blockers' reduces airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma. METHODS: Airway resistance was measured using the forced oscillation technique in ovalbulmin-sensitized and ovalbulmin-challenged mice treated with several beta-adrenoceptor (beta-AR) ligands. We used the selective beta 2-AR ligand ICI 118,551 and the preferential beta 1-AR ligand metoprolol to investigate the receptor subtype mediating the beneficial effect. Expression of beta-ARs was evaluated using immunofluorescence. We evaluated several signaling proteins by western blot using lung homogenates, and measured the relaxation of the isolated trachea produced by EP2 and IP receptor agonists. RESULTS: Four findings were associated with the decreased AHR after chronic beta-blocker treatment: (1) the highly selective beta 2-AR antagonist/inverse agonist, ICI 118,551 produced the bronchoprotective effect; (2) beta 2-AR up-regulation resulted from chronic 'beta-blocker' treatment; (3) reduced expression of certain proteins involved in regulating bronchial tone, namely, Gi, phosphodiesterase 4D and phospholipase C-beta 1; and (4) an enhanced bronchodilatory response to prostanoid agonists for the IP and EP2 receptors. CONCLUSIONS: These data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Asma/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metoprolol/farmacologia , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Antagonistas Adrenérgicos beta/administração & dosagem , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Western Blotting , Testes de Provocação Brônquica , Esquema de Medicação , Imunofluorescência , Masculino , Cloreto de Metacolina , Metoprolol/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Nadolol/farmacologia , Ovalbumina/imunologia , Propanolaminas/administração & dosagemRESUMO
Recent publications in the field of asthma therapeutics and studies performed over the last decade in the treatment of chronic heart failure suggest a phenomenon called 'temporal hormesis'. This phenomenon can be defined as the beneficial action of drug after chronic administration as opposed to its detrimental acute effects. Temporal hormesis may be related to the classification of the drug molecule as an agonist, antagonist or an inverse agonist. This phenomenon may be a more general principal applicable in the treatment of other diseases apart from asthma and chronic heart failure.
