Selective attenuation of isoproterenol-stimulated arrhythmic activity by a partial agonist of adenosine A1 receptor

Background-The goal of this study was to examine the hypothesis that a partial agonist of the adenosine A(1) receptor (A(1)AdoR) may cause a greater attenuation of catecholamine-induced ventricular arrhythmic activity than of contractility. Methods and Results-The effects of CVT-2759 and adenosine, a partial and a full agonist of the A(1)AdoR, on isoproterenol-stimulated arrhythmic activity and contractility of guinea pig isolated ventricular myocytes were determined. CVT-2759 (10 mumol/L) and adenosine (10 mumol/L) significantly inhibited isoproterenol-induced arrhythmic activity (aftercontraction and transient inward current) but did not reduce the amplitudes of twitch shortening and L-type Ca2+ current. Increasing the concentration of the full agonist adenosine from 10 to 100 mumol/L, however, caused significant attenuation of twitch shortening as well as aftercontractions, whereas increasing the concentration of the partial agonist CVT-2759 from 10 to 100 mumol/L did not. CVT-2759 also significantly inhibited isoproterenol-induced spontaneous ventricular beats in isolated hearts, In contrast to adenosine, CVT-2759 neither activated adenosine-sensitive K+ current nor shortened the duration of the atrial APD. Conclusions-The present results support the hypothesis and suggest a potential role for a partial agonist of the A,AdoR in the treatment of cardiac arrhythmias.