@article {Srinivas683, author = {Miduturu Srinivas and John C. Shryock and Donn M. Dennis and Stephen P. Baker and Luiz Belardinelli}, title = {Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes}, volume = {52}, number = {4}, pages = {683--691}, year = {1997}, doi = {10.1124/mol.52.4.683}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 {\textpm} 0.2 to 3.2 {\textpm} 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 {\textpm} 4\% to 58.7 {\textpm} 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 {\textpm} 3.5\% but activated IKAdo by only 18.1 {\textpm} 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/52/4/683}, eprint = {https://molpharm.aspetjournals.org/content/52/4/683.full.pdf}, journal = {Molecular Pharmacology} }