Neostigmine evoked
bradycardia in vagotomized,
propranolol-treated cats. Heart rate decreased by 50% with 0.4 +/- 0.2 mg/kg (mean +/- S.D.) i.v. of
neostigmine. The
bradycardia was attenuated after
acetylcholine (ACh) depletion in the cardiac parasympathetic pathway suggesting ACh release within this pathway was involved. The
bradycardia was unchanged after preganglionic terminal degeneration suggesting ACh release was from cardiac
ganglion cells.
Edrophonium produced a much weaker
bradycardia suggesting the
anticholinesterase effect of
neostigmine may not produce the
bradycardia. The
neostigmine-induced
bradycardia was blocked by systemic
atropine (ED50, 0.005 +/- 0.001 mg/kg),
pancuronium bromide (ED50, 0.033 +/- 0.021 mg/kg),
pirenzepine (ED50, 74.7 +/- 7.9 micrograms/kg),
hexamethonium (ED50, 8.3 +/- 1.6 mg/kg) and
d-tubocurarine (ED50, 8.6 +/- 3.0 micrograms/kg). The doses of
hexamethonium and
d-tubocurarine that blocked the
neostigmine-induced
bradycardia were significantly higher than required for blocking the
bradycardia produced by
vagus nerve stimulation.
Hexamethonium (60 mg/kg i.v.) had no effect on the
bradycardia produced by the
muscarinic agonist methacholine (100-300 micrograms/kg/min i.v.). The dose of
pirenzepine that blocked the
neostigmine-induced
bradycardia was lower than required for blocking the
bradycardia produced by
vagus nerve stimulation.
McN-A-343 ([4-hydroxy-2-butynyl]-1-trimethyl
ammonium m-chlorocarbanilate
chloride) (1 mg/kg i.v.) did not produce
bradycardia. These observations suggest
neostigmine evokes
bradycardia by activation of
ACh receptors on cardiac
ganglion cells producing ACh release and activation of cardiac M2 receptors. The low sensitivity of the
neostigmine-induced
bradycardia to
pirenzepine, and the failure of
McN-A-343 to evoke
bradycardia, suggest the receptor on cardiac
ganglion cells is not an M1-type.(ABSTRACT TRUNCATED AT 250 WORDS)