title: Differential desensitization of A1 adenosine receptor-mediated inhibition of cardiac myocyte contractility and adenylate cyclase activity. Relation to the regulation of receptor affinity and density.
abstract: Effects of chronic exposure of cultured atrial myocytes to R-N6-(2-phenylisopropyl)-adenosine (R-PIA) on the A1 adenosine receptor-mediated inhibition of adenylate cyclase activity and myocyte contractility were examined. Chronic exposure of atrial myocytes cultured from 14-day-old chick embryos to R-PIA desensitized the myocyte to the inhibitory effects of R-PIA on contractility and adenylate cyclase activity in a time- and dose-dependent manner. Desensitization of the negative inotropic response was only partial, whereas the adenosine receptor-mediated inhibition of adenylate cyclase activity was almost completely absent after 24 hours of R-PIA (1 microM) exposure. Furthermore, the contractile response to R-PIA desensitized more slowly than the desensitization of A1 adenosine receptor-mediated inhibition of adenylate cyclase (t1/2 = 11.4 +/- 0.7 hours versus 7.5 +/- 1 hours, mean +/- SEM, n = 12 and 6, respectively). Thus, the two A1 adenosine receptor-linked functional responses desensitized differently in response to chronic exposure of the myocyte to R-PIA. Binding of the antagonist radioligand [3H]-8-cyclopentyl-1,3-dipropylxanthine [( 3H]CPX) in membranes from myocytes preexposed to R-PIA demonstrated a time-dependent decrease in receptor density without any change in the affinity for the antagonist radioligand. Computer analyses of agonist competition with [3H]CPX binding in membranes from control and R-PIA-treated myocytes revealed a conversion of the high-affinity A1 adenosine receptor to a low-affinity form such that after 24 hours of 1 microM R-PIA exposure, all of the receptors were in a low-affinity form.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Philadelphia, Pa.
authors.forename: B T
authors.initials: BT
authors.lastname: Liang
authors.forename: L A
authors.initials: LA
authors.lastname: Donovan
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D011869:Radioligand Assay; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology*
chemical_list: D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; D006160:Guanosine Triphosphate; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol