Adenosine Mediates Sustained Adrenergic Desensitization in the Rat Heart via Activation of Protein Kinase C

From the Departments of Medicine (E.P.K., G.R.N., E.S.C., T.E.M.) and Physiology (R.A.F., J.G.D.), University of Massachusetts, University of Massachusetts Medical Center, Worcester, and Centro Fisiologia Clinica e Ipertensione e Divisione di Cardiologia, IRCCS Ospedale "Maggiore," Milano, Italy (S.P.).

Correspondence to Theo E. Meyer, MD, D Phil, Division of Cardiology, Department of Medicine, University of Massachusetts Medical Center, 55 Lake Ave N, Worcester, MA 01655. E-mail theo.meyer{at}banyan.ummed.edu

Abstract—Adenosine attenuates the myocardial metabolic and contractile responses induced by ß-adrenergic stimulation. Our study was conducted to investigate the longevity of this antiadrenergic action after adenosine exposure. Adenosine (33 µmol/L) was infused into isolated perfused rat hearts for 1, 5, 30, or 60 minutes, and the adrenergic responsiveness (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 surface transudates, returned to preinfusion levels within 10 minutes of washout. The duration of adenosine infusion had no effect on the extent of attenuation of AR at the end of the infusion. Whereas AR returned to preadenosine levels with washout of shorter adenosine infusions (1 and 5 minutes), there was a slow and incomplete recovery of AR after the longer exposures (30 and 60 minutes) to adenosine. The magnitude of this persistent antiadrenergic effect (PAE) of adenosine at 15 minutes of washout was proportional to the epicardial concentration of adenosine during infusion of the nucleoside. Infusion of adenosine either with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or with the selective A₁-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 A₁-receptor agonist 2-chloro-N⁶-cyclopentyladenosine and not with the selective A₃-receptor agonist 4-aminobenzyl-5'-N methylcarboxamido-adenosine. When the protein kinase C (PKC) inhibitor chelerythrine was coadministered with adenosine, the PAE of adenosine was not apparent during adenosine washout. A 30-minute infusion of phenylephrine, an -adrenergic agonist that enhances PKC activity, produced a PAE that lasted for up to 30 minutes of washout. This effect was prevented by the coinfusion of chelerythrine. Thus, it is concluded that the PAE of adenosine is determined by the myocardial concentration of this nucleoside and is manifested when myocardial concentrations of adenosine returned to baseline levels. Moreover, a 5-minute duration of adenosine exposure is required for the expression of the PAE. This latter effect seems to be dependent on adenosine-induced PKC activation via A₁-receptors.

Key Words: adenosine • protein kinase C • adrenergic responsiveness • antiadrenergic effect

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