CHOLINESTERASES IN CARDIAC GANGLIA AND MODULATION OF CANINE INTRINSICCARDIAC NEURONAL-ACTIVITY

Cholinergic neurotransmission plays a significant role in intrinsic ca rdiac ganglia with the action of acetylcholine being terminated by ace tylcholinesterase (AChE, EC 3.1.1.7). Anatomical studies were performe d to characterize neurons associated with AChE and a closely related e nzyme, butyrylcholinesterase (BuChE, EC 3.1.1.8), in canine intrinsic cardiac ganglia. Histochemical staining for AChE and BuChE in canine r ight atrial neurons showed that there were four neuronal populations, namely, those that contained AChE only, BuChE only, both AChE and BuCh E, and those that did not contain either enzymes. The neuronal activit y of intrinsic cardiac neurons in response to substrates and inhibitor s of cholinesterases were studied in anesthetized dogs. The activity o f intrinsic cardiac neurons, as measured by changes in the number of a ction potentials, increased by local application of acetylcholine. How ever, local application of butyrylcholine led to a considerably greate r increase in the activity of intrinsic cardiac neurons. In keeping wi th the neurochemical heterogeneity in intrinsic cardiac ganglia with r espect to cholinesterases, the activity generated by most butyrylcholi ne-sensitive neurons was not influenced by acetylcholine and the activ ity generated by, the most acetylcholine-sensitive neurons was not inf luenced by butyrylcholine. This suggests that these two agents prefere ntially influence different populations of intrinsic cardiac neurons. Enzyme kinetic studies demonstrated that canine AChE preferentially ca talyzed the hydrolysis of acetylcholine while canine BuChE preferentia lly catalyzed the hydrolysis of butyrylcholine. Cholinesterase inhibit ors Ro 2-1250 and Ro 2-0638 inhibited both canine cholinesterases, whi le huperzine A preferentially inhibited canine AChE and ethopropazine inhibited canine BuChE. The activity of neurons in the intrinsic cardi ac ganglia significantly increased when Ro 2-1250 or Ro 2-0638 was adm inistered locally. The activity of neurons was not affected when huper zine A or ethopropazine was administered, indicating that both choline sterases must be inhibited to increase neuronal activity. In summary, these data show that in addition to AChE, intrinsic cardiac ganglia al so contain distinct populations of neurons that are associated with Bu ChE, and the activity generated by these neurons is differentially inf luenced by their substrates. Because simultaneous inhibition of AChE a nd BuChE leads to increased neuronal activity, it is concluded that AC hE- and BuChE-positive intrinsic cardiac neurons may act synergistical ly to influence the overall tonic activity of intrinsic cardiac gangli a. (C) 1998 Elsevier Science B.V. All rights reserved.