ADENOSINE MEDIATES SUSTAINED ADRENERGIC DESENSITIZATION IN THE RAT-HEART VIA ACTIVATION OF PROTEIN-KINASE-C

Adenosine attenuates the myocardial metabolic and contractile response s induced by beta-adrenergic stimulation. Our study was conducted to i nvestigate the longevity of this antiadrenergic action after adenosine exposure. Adenosine (33 mu mol/L) was infused into isolated perfused rat hearts for I, 5, 30, or 60 minutes, and the adrenergic responsiven ess (AR) to isoproterenol (10(-8) mol/L) was determined at the end of each infusion period and during a 45-minute adenosine washout period, Interstitial levels of adenosine, as determined from epicardial surfac e transudates, returned to preinfusion levels within 10 minutes of was hout. The duration of adenosine infusion had no effect on the extent o f attenuation of AR at the end of the infusion. Whereas AR returned to preadenosine levels with washout of shorter adenosine infusions (1 an d 5 minutes), there was a slow and incomplete recovery of AR after the longer exposures (30 and 60 minutes) to adenosine. The magnitude of t his persistent antiadrenergic effect (PAE) of adenosine at 15 minutes of washout was proportional to the epicardial concentration of adenosi ne during infusion of the nucleoside. Infusion of adenosine either wit h the nonselective adenosine receptor antagonist 8-p-sulfophenyl theop hylline or with the selective A(1)-receptor antagonist 1,3-dipropyl. 8 -cyclopentylxanthine, abolished the PAE during the washout period. In addition, the PAE could be demonstrated only with the selective A(1)-r eceptor agonist 2-chloro-N-6-cyclopentyladenosine and not with the sel ective A(3)-receptor agonist 4-aminobenzyl-5'-N methylcarboxamido-aden osine. When the protein kinase C (PKC) inhibitor chelerythrine was coa dministered with adenosine, the PAE of adenosine was not apparent duri ng adenosine washout. A 30-minute infusion of phenylephrine, an alpha- adrenergic agonist that enhances PKC activity, produced a PAE that las ted for up to 30 minutes of washout. This effect was prevented by the coinfusion of chelerythrine. Thus, it is concluded that the PAE of ade nosine is determined by the myocardial concentration of this nucleosid e and is manifested when myocardial concentrations of adenosine return ed to baseline levels. Moreover, a 5-minute duration of adenosine expo sure is required for the expression of the PAE. This latter effect see ms to be dependent on adenosine-induced PKC activation via A(1)-recept ors.