DIFFERENTIAL A(1) ADENOSINE RECEPTOR RESERVE FOR 2 ACTIONS OF ADENOSINE ON GUINEA-PIG ATRIAL MYOCYTES

Adenosine activates adenosine-induced inwardly rectifying K+ current ( I-KAdo) and inhibits isoproterenol (100 nM)-stimulated L-type Ca2+ cur rent (beta-I-Ca,I-L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 mu M, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greate r A(1) adenosine receptor reserve for the inhibition of beta-I-Ca,I-L than for the activation of I-KAdo. Atrial myocytes were pretreated wit h vehicle (control) or the irreversible A(1) adenosine receptor antago nist luorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (FSCPX) (10 an d 50 nM) for 30 min, and after a 60-min washout period, concentration- response curves were determined for the adenosine-induced activation o f I-KAdo and inhibition of beta-I-Ca,I-L. Pretreatment of atrial myocy tes with 10 nM FSCPX reduced the maximal activation of I-KAdo by 60% ( 7.9 +/- 0.2 to 3.2 +/- 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nM) was required to reduce the maximal inhibition of bet a-I-Ca,I-L by 39% (95 +/- 4% to 58.7 +/- 5.6%) and caused a 15-fold in crease in the EC50 value of adenosine. Values of the equilibrium disso ciation constant (K-A) for adenosine to activate I-KAdo and inhibit be ta-I-Ca,I-L, estimated according to the method of Furchgott, were 2.7 and 5.6 mu M, respectively. These values were used to determine the re lationship between adenosine receptor occupancy and response. Half-max imal and maximal activations of I-KAdo required occupancies of 40% and 98% of A(1) adenosine receptors, respectively. In contrast, occupanci es of only 4% and 70%, respectively, of A(1) adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of beta-I-Ca, I-L. Consistent with this result, a partial agonist of the A(1) adenos ine receptor SHA040 inhibited beta-I-Ca,I-L, by 60 +/- 3.5% but activa ted I-KAdo by only 18.1 +/- 2.5%. The results indicate that the A(1) a denosine receptor is coupled more efficiently to an inhibition of beta -I-Ca,I-L than to an activation of I-KAdo.