Presynaptic inhibition produced by histamine at nicotinic synapses in enteric ganglia.
Intracellular methods were used to record fast excitatory postsynaptic potentials in myenteric neurons of the guinea-pig small intestine in vitro. The excitatory postsynaptic potentials were suppressed by hexamethonium, mimicked by acetylcholine and assumed to be mediated by nicotinic cholinergic receptors. Application of histamine either by addition to the superfusion solution or by focal application from fine-tipped pipettes reversibly reduced the amplitude or abolished the excitatory postsynaptic potentials. Postsynaptic responses to focal application of acetylcholine by pressure ejection from micropipettes were either unaffected or were potentiated by histamine. Failure of histamine to affect antidromic action potentials excluded a local anesthetic action on the presynaptic fibers. Neither 2-methylhistamine nor dimaprit, which are selective H1 and H2 agonists respectively, suppressed the excitatory postsynaptic potentials when applied in concentrations nearly one hundred times greater than the ED50 for histamine. The selective H1 and H2 antagonists, pyrilamine and cimetidine did not suppress the inhibitory action of histamine when applied separately or in combination. Based on these results, the presynaptic receptors involved in this inhibitory mechanism appeared to be of a pharmacologically atypical histamine receptor subtype. The putative histamine agonist, N,alpha-methylhistamine, which has been reported to have high stereoselectivity and activity for a receptor subtype classified as H3, potently reduced or abolished the excitatory postsynaptic potentials. The ED50 for N,alpha-methylhistamine was 8.8 nM compared to an ED50 of 220 nM for histamine. Burimamide, a histamine antagonist with higher activity at putative H3 receptors than H2 receptors, effectively reversed the inhibitory action of histamine on the excitatory postsynaptic potentials.(ABSTRACT TRUNCATED AT 250 WORDS)
Tamura
K
K
Department of Physiology, College of Medicine, Ohio State University, Columbus 43210.
Palmer
J M
JM
Wood
J D
JD
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005724:Ganglia / Q000166:cytology*; D006168:Guinea Pigs; D006584:Hexamethonium Compounds / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D007422:Intestines / Q000294:innervation*; D011738:Pyrilamine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*
D006584:Hexamethonium Compounds; D002927:Cimetidine; D006632:Histamine; D011738:Pyrilamine; D000109:Acetylcholine