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1 The effects of seven agonist and three antagonist adenosine receptor ligands were compared on the guinea-pig sinoatrial (SA) node (isolated right atrium) and atrioventricular (AV) node (perfused whole heart). Single agonist concentration-effect curves were obtained to 5'-N-ethylcarboxamidoadenosine (NECA), R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), N6-cycJohexyladenosine (CHA), 2-chloroadenosine (CADO),),S( + )-W-(2-phenylisopropyl)adenosine (L-PIA), 2-phenylaminoadenosine (CV 1808) and N6-aminoadenosine (MeAdo). Adenosine and/or NECA curves were obtained in the absence and presence of the antagonists 8-cyclopentyl-l,3-dipropylxanthine (DPCPX), 9-chloro-2-(2-furany1)-5,6- dihydro-l ,2,4-triazolo[1,5-c]quinazolin-5-imine (CGS 15943) and N6-(endonorbornan-2-yl)-9-methyladenine (N-0861). 2 A formal comparison of the agonist and antagonist potency data was made by fitting the data to a straight line using a least squares procedure based on principal components analysis to account for the variance on both axes. The antagonist affinity estimates made on the two assays did not deviate significantly from the line of identity. 3 The agonist p[A]50 data obtained on the two assays did not deviate from the line of identity, indicating that there were no significant differences in potencies between the two assays. The p[A]50 ratio of R-PIA and S-PIA was 1.24±0.09 in the SA node and 1.36±0.11 in the AV node, indicating no difference in the stereoselectivity of the PIA isomers between the two tissues. 4 The agonist potency and antagonist affinity data obtained are consistent with previous findings showing that the AV and SA node data are pharmacologically indistinguishable and belong to the adenosine A1-receptor class. No evidence for the reported A3-receptor was found.

1 In the isolated, lumen-perfused, stomach preparation of the mouse, metiamide was found by kinetic analysis to behave like a simple competitive antagonist of histamine-stimulated acid secretion. However, the pK(B) estimate of 5.08 was significantly lower than that found in guinea-pig atrium (6.0) or rat uterus (6.1) suggesting that H(2)-receptors might not be homogeneous.2 A similar analysis showed that atropine also behaved like a simple competitive antagonist of bethanechol-stimulated acid secretion and the estimated pK(B) (7.65) was significantly lower than the standard estimate of this parameter in guinea-pig ileum (9.0). Either the muscarinic cholinoceptors in mouse stomach were also anomalous or the preparation was introducing a systematic error. Lumen perfusion might distort this type of kinetic analysis by allowing steady-state conditions but not true equilibrium to develop at the receptor compartment due to loss of antagonist into the gastric secretion. Drug interactions at receptors in the muscle layers of the stomach would be expected to be much less sensitive to this error.3 When the atropine-bethanechol interaction was measured on the contraction of the isolated, lumen-perfused, stomach of the mouse the necessary conditions for simple competition were not met even though the sensitivity to atropine was obviously increased. The criteria for the expected simple competition were being obscured by events at low antagonist concentrations. Alterations in agonist or antagonist concentrations could be more or less eliminated so that physiological antagonism, perhaps by release of 5-hydroxytryptamine, was considered. This was supported, to some extent, by finding that, when stomachs from animals pretreated with reserpine were used, the kinetic analysis was normalized and gave a pK(B) of 8.99. Apparently, the muscarinic receptors in mouse stomach are homogeneous with those in other tissues.4 Therefore, we conclude that our results no more point to heterogeneity among histamine receptors than they point to differences in muscarinic cholinoceptors because this type of kinetic analysis can be readily distorted by special features of the measuring system.