RT Journal Article SR Electronic T1 Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 683 OP 691 DO 10.1124/mol.52.4.683 VO 52 IS 4 A1 Miduturu Srinivas A1 John C. Shryock A1 Donn M. Dennis A1 Stephen P. Baker A1 Luiz Belardinelli YR 1997 UL http://molpharm.aspetjournals.org/content/52/4/683.abstract AB Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nm)-stimulated L-type Ca2+ current (β-ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 μm, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greater A1adenosine receptor reserve for the inhibition of β-ICa,Lthan for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1adenosine receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (FSCPX) (10 and 50 nm) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the adenosine-induced activation of IKAdo and inhibition of β-ICa,L. Pretreatment of atrial myocytes with 10 nm FSCPX reduced the maximal activation of IKAdo 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 β-ICa,L by 39% (95 ± 4% to 58.7 ± 5.6%) and caused a 15-fold increase in the EC50 value of adenosine. Values of the equilibrium dissociation constant (K A) for adenosine to activate IKAdo and inhibit β-ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 μm, respectively. These values were used to determine the relationship between adenosine receptor occupancy and response. Half-maximal and maximal activations of IKAdorequired occupancies of 40% and 98% of A1 adenosine receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of β-ICa,L. Consistent with this result, a partial agonist of the A1adenosine receptor SHA040 inhibited β-ICa,L by 60 ± 3.5% but activated IKAdo by only 18.1 ± 2.5%. The results indicate that the A1 adenosine receptor is coupled more efficiently to an inhibition of β-ICa,L than to an activation of IKAdo.