SUSTAINED INCREASE IN RAT MYOCARDIAL ALPHA(1A)-ADRENOCEPTORS INDUCED BY 6-HYDROXYDOPAMINE TREATMENT INVOLVES A DECELERATED RECEPTOR TURNOVER

The biochemical mechanisms involved in the alpha(1)-adrenoceptor up-re gulation and possible changes in subtypes of adrenoceptors in the rat heart after chemical denervation were investigated. The effects of acu te 6-hydroxydopamine treatment (two increasing doses 24 h apart) on th e pseudo-steady state densities and turnover rates of alpha(1)-adrenoc eptors were studied in ventricular myocardium of the rat. We have asse ssed the repopulation kinetics of [H-3]prazosin binding sites after ir reversible inactivation of alpha(1)-adrenoceptors induced by a single dose of phenoxybenzamine (1 mg/kg i.p.) in rats acutely treated either with 6-hydroxydopamine or with vehicle (control animals). Seven days after the last administration of 6-hydroxydopamine an enhanced density of [H-3]prazosin binding sites (B-max 58.7 +/- 3.6 fmol/mg protein ve hicle-treated rats versus 82.6 +/- 5.3 fmol/mg protein 6-hydroxydopami ne-treated rats) was observed. This was not accompanied by changes in the dissociation constant value. Furthermore, the proportion of high a ffinity sites for WB-4101 was altered (21 +/- 2% versus 72 +/- 3% for animals treated with vehicle and 6-hydroxydopamine, respectively). In rat myocardium, alpha(1)-adrenoceptor turnover, evaluated during the 6 -hydroxydopamine-induced upregulation (7-19 days after the completion of treatment with 6-hydroxydopamine) revealed an increase in the half- life of the alpha(1)-adrenoceptor (t(1/2) of 67.2 h versus 38.7 h in c ontrol animals). The present study confirms an increase in alpha(1)-ad renoceptors in rat myocardium after chemical denervation and reveals t hat the effect is almost completely confined to the alpha(1A)-adrenoce ptor subtype. Furthermore, the up-regulation of alpha(1A)-adrenoceptor s is the result of a decrease in the cellular processes that control t he rate of receptor degradation.