title: Reduction of beta-adrenoceptor function by oxidative stress in the heart.
abstract: The effect of oxidative stress on beta-adrenoceptor function in the heart was determined. To this end ventricle membranes, field-stimulated rat left atria and field-stimulated rat right ventricle strips were exposed to 0.1 mM cumene hydroperoxide for 20 min. It was found that oxidative stress increased beta-adrenoceptor number and reduced c-AMP formation in the ventricle membranes. In the rat left atria and rat right ventricle strips the efficacy of beta-adrenoceptor agonists was reduced to approximately 30% of the control value, whereas maximal beta-adrenoceptor-mediated response was reduced to 50%. Using membranes from control atria and from atria exposed to oxidative stress, it was found that oxidative stress had no effect on beta-adrenoceptor density, nor on the affinity of (-)isoproterenol for the receptor. c-AMP production in membranes prepared from atria exposed to oxidative stress was reduced to approximately 30% of the c-AMP production in membranes prepared of control atria. In addition, it was found that the shape of the function that transduces the stimulus which is generated by receptor activation into an effect, is not altered by oxidative stress. It was concluded that the reduction of the efficacy of beta-adrenoceptor agonists by oxidative stress is probably caused by the reduction of c-AMP formation. Because the efficacy of forskolin and of dibutyryl c-AMP was not affected by oxidative stress, the reduced c-AMP formation is probably caused by an impaired coupling between the receptor and adenylate cyclase. The reduction of maximal beta-adrenoceptor-mediated response might be the result of cytotoxic aldehydes that are produced during oxidative stress. In ischemia, catecholamine release and subsequent beta-adrenoceptor hyperstimulation lead to cardiotoxicity. As shown in the present study, oxidative stress reduces beta-adrenoceptor function. This might represent a protective physiological feedback mechanism that protects the heart against excessive beta-adrenoceptor stimulation.
authors.affiliation: Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: G R
authors.initials: GR
authors.lastname: Haenen
authors.forename: M
authors.initials: M
authors.lastname: Veerman
authors.forename: A
authors.initials: A
authors.lastname: Bast
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D003994:Bucladesine / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003327:Coronary Disease / Q000188:drug therapy; D005609:Free Radicals; D006325:Heart Atria / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013726:Terbutaline / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D001555:Benzene Derivatives; D002395:Catecholamines; D005609:Free Radicals; D005576:Colforsin; D003994:Bucladesine; D007545:Isoproterenol; D013726:Terbutaline; C007164:cumene hydroperoxide