DIFFERENCES IN THE CHRONOTROPIC AND INOTROPIC RESPONSE OF THE RAT ATRIUM TO CHOLINE ESTERS, CHOLINESTERASE INHIBITORS AND CERTAIN BLOCKING AGENTS

¹ Department of Pharmacology, University of Southern California, School of Medicine, Los Angeles, California

Pacemaker cells were more highly selective in cholinergic agonist requirements than contractile cells since rate was essentially unaffected by choline, butyrylcholine and long-chain choline esters that definitely depressed amplitude. Acetylcholine depressed rate and amplitude to about the same extent and was the most potent choline ester of the series. Choline esters of the same chain length as acetylcholine were about 10 times less potent. Cholinergic receptors of pacemaker cells appeared to be surrounded by denser cholinesterase activity than cholinergic receptors of contractile cells, since inhibition of cholinesterase produced profound potentiation of acetylcholine depression of rate and only moderate potentiation of acetylcholine depression of amplitude. Cholinesterase inhibition markedly potentiated the action of acetyl--methylcholine and propionylcholine but did not potentiate butyryl choline action. Hence, pseudocholinesterase which hydrolyzes butyryicholine may not be able to modify agonist action at atrial cholinergic receptors, although true acetylcholinesterase and pseudocholinesterase which hydrolyzes propionylcholine can modify agonist action. Thus, subdivision of pseudocholinesterase of rat atrium on the basis of cellular localization and function was suggested. Cholinesterase inhibitors, except di-isopropyl fluorophosphate, at low concentration potentiated agonist action but at high concentration blocked agonist action, the block on cholinergic receptors of pacemaker cells being more intense than on receptors of contractile cells. Pacemaker cell cholinergic receptors were more readily blocked by atropine than contractile cell receptors. Pacemaker cell cholinergic receptors were rapidly and intensely blocked by N-ethylmaleimide, suggesting functional —SH groups at the receptor active sites. N-ethylmaleimide produced a slowly developing, weaker block of contractile cell cholinergic receptors.

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