AF-DX 116: a selective antagonist of the slow inhibitory postsynaptic potential and methacholine-induced hyperpolarization in superior cervical ganglion of the rabbit.
AF-DX 116 [11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiaze pine-6-one], a muscarinic receptor antagonist that divides the M2-type muscarinic receptor into additional functional classes, modified muscarinic responses recorded from the superior cervical ganglion of the rabbit with sucrose or air gap techniques. Incubation of ganglia with AF-DX 116 suppressed the amplitude of the slow-inhibitory postsynaptic potential (s-IPSP) in a concentration-dependent and highly specific manner. At concentrations which reduced the amplitude of the s-IPSP by 80 to 90%, there was no significant reduction of the amplitudes of the muscarinic slow-excitatory postsynaptic potential or the nicotinic fast-excitatory postsynaptic potential. In addition, superfusion of ganglia with AF-DX 116 resulted in the concentration-dependent suppression of ganglionic hyperpolarization induced by methacholine without suppression of methacholine-induced depolarization. Ganglionic hyperpolarization that was produced by norepinephrine was unaffected by AF-DX 116. Increasing the level of acetylcholine available for interaction with muscarinic receptors by increasing the number of stimulus volleys that were applied to the preganglionic nerve resulted in a parallel shift, to the right, of the concentration-response curve for suppression of the s-IPSP by AF-DX 116. Similarly, incubation of ganglia with the specific antiacetylcholinesterase, BW 284 (1-5-bis[4-allyl dimethylammonium phenyl]pentan-3 one dibromide), increased the concentration of AF-DX 116 that was required to produce a comparable suppression of the s-IPSP. These results indicate that the s-IPSP in mammalian superior cervical ganglion involves an action of acetylcholine at the M2 type receptor that is preferentially blocked by AF-DX 116.
Yarosh
C A
CA
Department of Psychology, University of California, Riverside.
Olito
A C
AC
Ashe
J H
JH
D000818:Animals; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D008688:Methacholine Compounds; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride; D010890:Pirenzepine; C048593:otenzepad