REDUCTION OF BETA-ADRENOCEPTOR FUNCTION BY OXIDATIVE STRESS IN THE HEART

The effect of oxidative stress on β-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 β-adrenoceptor number and reduced c-AMP formation in the ventricle membranes. In the rat left atria and rat right ventricle strips the efficacy of β-adrenoceptor agonists was reduced to approximately 30% of the control value, whereas maximal β-adrenoceptor-mediated response was reduced to 50%. Using membranes from control atria and from atria exposed stress, it was found that oxidative stress had no effect on β-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 β-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 β-adrenoceptor-mediated response might be the result of cytotoxic aldehydes that are produced during oxidative stress. In ischemia, catecholamine release and subsequent β-adrenoceptor hyperstimulation lead to cardiotoxicity. As shown in the present study, oxidative stress reduces β-adrenoceptor function. This might represent a protective physiological feedback mechanism that protects the heart against excessive β-adrenoceptor stimulation. © 1990.