title: Characterization of guinea-pig cardiac muscarinic receptors by radioligand dissociation kinetics.
abstract: The question of cardiac muscarinic receptor heterogeneity was studied in guinea-pig auricles and ventricle. Radioligand dissociation kinetics were analyzed in the absence and presence of alinidine and AQ-A 39, two muscarinic agents and allosteric modulators of radiotracer dissociation. The dissociation kinetics were monophasic with all 3 radiotracers used and in both auricles and ventricle. [125I]3-Quinuclidinyl 4-iodobenzilate ([125I]QNB) dissociated with an identical half-life (t1/2 off) in ventricle and in left and right auricle, respectively. Alinidine (1 mM) decreased t1/2 off by 50% in ventricle but had no significant influence in auricles. AQ-A 39 (= falipamil) uniformly increased t1/2 off 4-fold in all 3 tissues. The binding of tritium-labelled quinuclidinyl benzilate ([3H]QNB) dissociated equally rapidly from both ventricular and auricular receptors under control conditions but was not affected by alinidine. AQ-A 39 (1 mM) slowed [3H]QNB dissociation 6.5-fold in ventricle but only 3-fold in both auricles. [3H]N-Methyl scopolamine ([3H]NMS) dissociation was uniform in both auricles but was somewhat slower in the ventricle, both in the absence and presence of alinidine. AQ-A 39 was without effect. These results demonstrate differences in ventricular versus auricular receptors detected by [125I]QNB in the presence of alinidine and by [3H]QNB in the presence of AQ-A 39. The quaternary ligand [3H]NMS was unable to detect receptor heterogeneity. No differences were found between right and left auricular receptors. The results presented provide no evidence for the existence of different subtypes of muscarinic receptors for the negative chronotropic and inotropic actions of muscarinic agonists.
authors.affiliation: Institut für Pharmakodynamik und Toxikologie, Graz, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Brunner
authors.forename: W R
authors.initials: WR
authors.lastname: Kukovetz
mesh_terms: D000495:Allosteric Site; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D066298:In Vitro Techniques; D054833:Isoindoles; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010797:Phthalimides / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D054833:Isoindoles; D010797:Phthalimides; D011976:Receptors, Muscarinic; C022192:alinidine; D003000:Clonidine; C030532:falipamil