Binding of two specific bradycardic agents, alinidine and AQ-A 39, to muscarinic receptors of guinea pig atria and ventricle.
The mechanism of action of the two "specific bradycardic agents" alinidine and AQ-A 39 (falipamil) is still a matter of controversy. Their binding properties to atrial and ventricular myocardium of the guinea pig and rat were, therefore, investigated by the radioligand binding technique. In competition studies against the nonselective antagonists [125I]3-quinuclidinyl 4-iodobenzilate [( 125I]QNB) and 1-N-methyl-[3H]scopolamine methylchloride [( 3H]NMS), both alinidine and AQ-A 39 competitively displaced the radioligands with I50 values (corrected for radioligand concentration) of 1-2 microM (alinidine/[125I]QNB) and 4 microM (alinidine/[3H]NMS), respectively. The I50 values for AQ-A 39 were lower by a factor of two. Slope factors (pseudo Hill coefficients) were 0.7-0.8 (AQ-A 39) and 0.8-0.9 (alinidine), and significantly lower than unity in both atria and ventricle. The guanosine triphosphate (GTP) (100 microM) and 5'-guanylimido-di-phosphate [Gpp(NH)p] (100 microM) slightly creased [3H]QNB binding and produced no or only a small (factor 2-3) rightward shift of alinidine and AQ-A 39 competition curves. At high concentration (1 mM), AQ-A 39 drastically decreased [125I]QNB dissociation rate from both atrial and ventricular receptors (t1/2 control, 19 min; plus AQ-A 39, 75 min) while alinidine (1 mM) decreased dissociation half-life in ventricle with no change in atria. It is concluded that both bradycardic agents possess some but not all characteristics of weak agonists in binding studies, and that they also bind to an allosteric site of the muscarinic receptors. Association with this site could possibly activate a mixed Na+/K+ inward pacemaker current (if) resulting in bradycardia.
D000818:Animals; D001667:Binding, Competitive; D002317:Cardiovascular Agents / Q000378:metabolism*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D054833:Isoindoles; D009206:Myocardium / Q000378:metabolism*; D010797:Phthalimides / Q000378:metabolism*; D011812:Quinuclidines / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives*; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D002317:Cardiovascular Agents; D054833:Isoindoles; D010797:Phthalimides; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; C040062:3-quinuclidinyl-4-iodobenzilate; D006160:Guanosine Triphosphate; C022192:alinidine; D003000:Clonidine; C030532:falipamil