MECHANISM OF THE NEGATIVE INOTROPIC EFFECT OF ADENOSINE IN GUINEA-PIG ATRIAL MYOCYTES

The ionic basis of the negative inotropic effect of adenosine on guinea pig atrial myocytes was studied. Membrane potentials and currents were measured using a whole cell patch-clamp technique. The contractility was assessed by video quantitation of cell twitch amplitude. Adenosine shortened action potential duration [measured at 90% repolarization (APD(90))] and decreased twitch amplitude in a concentration-dependent manner. The maximal effects of adenosine (100 mu M) were to reduce APD(90) from 102 +/- 14 to 34 +/- 8 ms (n = 11) and twitch amplitude from 4.3 +/- 0.9 to 1.5 +/- 0.4 mu m (n = 8) The concentration of adenosine that caused one-half of the maximal reductions of twitch amplitude and of APD(90) was 0.6 mu M. Reductions in APD(90) and in twitch amplitude were parallel and highly correlated (r = 0.98). Decreases in twitch amplitude by adenosine could be mimicked by application of voltage-clamp pulses with durations similar to the durations of action potentials in the presence of adenosine. Clamp pulse could reverse adenosine-induced but not cadmium chloride-induced decreases in twitch amplitude. Adenosine activated the inwardly rectifying K+ current (I-K,I-Ado), but did not significantly decrease the L-type Ca2+ current (I-Ca,I-L). Adenosine reduced the effects of BAY K 8644 on APD(90) and twitch amplitude but did not attenuate the BAY K-induced increase in I-Ca,I-L. The effects of adenosine on APDSO and twitch amplitude could be reversed after activation of I-K,I-Ado was inhibited by intracellular application of cesium and tetraethylammonium chloride. Thus the negative inotropic effect of adenosine is mediated by shortening of APD(90) due to activation of I-K,I-Ado and not by direct decrease of I-Ca,I-L.