FUNCTIONAL CLASSIFICATION OF P-1-PURINOCEPTORS IN GUINEA-PIG LEFT ANDRIGHT ATRIA - ANOMALOUS CHARACTERISTICS OF ANTAGONISM BY CYCLOPENTYLTHEOPHYLINE

The P-1 purinoceptor subtype mediating the negative inotropic response s of guinea-pig left atria and the negative chronotropic responses of beating right atria were characterized. Guinea-pig isolated paced left atria (2Hz, 5ms, threshold voltage+50%) and spontaneously beating rig ht atria were set up in Krebs-bicarbonate solution and isometric tensi on and rate of contraction, respectively, were recorded. Concentration -response curves for the reduction of tension and rate, respectively, by adenosine receptor agonists, N-6-cyclopentyladenosine (CPA), the R- and S- stereoisomers of N-6-(2-phenylisopropyl)adenosine (R-PIA and S -PIA), 5'-(N-carboxamido)adenosine (NECA) and ((carboxyethyl)-phenethy lamino)-5'-(N-carboxamido) adenosine (CGS21680) were obtained. The ord ers of potency on the left atria (CPA=NECA>R-PIA>S-PIA>CGS21680) and r ight atria (CPA=R-PIA>S-PIA>CGS21680) were consistent with the respons es being mediated via A(1) receptors. Antagonism of the responses to C PA or R-PIA by 8-cyclo-1,3-dimethylxanthine (CPT) was examined by a fu ll Schild analysis. Concentration-response curves for CPA or R-PIA wer e obtained in the absence or presence of five or six concentrations (1 0(-7) -10(-5) or 3x10(-5)M) of CPT. The shift in the concentration-res ponse by CPT was expressed as the concentration-ratio (CR) and plotted as -log(CR-1) against log molar concentration of CPT (Schild plot). p A(2) values were calculated from the intercept on the concentration ax is and by application of the equation; pA(2)=log(antagonist concentrat ion) -log (CR-1). The Schild plots had unity slopes indicating competi tive antagonism and the pA(2) values derived therefrom indicated that the responses were mediated via A(1)-receptor. Closer inspection of th e Schild plots, however, showed that at the higher concentrations of C PT there was a limit to the displacement of the concentration-response curves of the left and right atria to CPA and of the left atria to R- PIA. There were also significant differences in the apparent pA(2) val ues calculated from the equation, when different concentrations of ant agonist were examined. These results indicated that at higher concentr ations of agonist there may be a component of the response that is res istant to antagonism by CPT. Whether this is related to the proposal t hat cardiac responses are mediated via A(3) receptors is discussed.