Inhibition of Acetylcholinesterase by Histamine Agonists and Antagonists

Abstract

The histamine H1 and/or H2-receptor agonists showed weak acetylcholinesterase inhibitory activity. Their dissociation constants (Kis and/or Kii) were 2-methyl histamine (Kis = 1751 mumol/l, s.e. = 163) less than 4-methyl histamine (Kis = 3551 mumol/l, s.e. = 414) less than dimaprit (Kis = 2931 mumol/l, s.e. = 605; Kii = 3668 mumol/l, s.e. = 901) less than histamine (Kis = 6480 mumol/l, s.e. = 1360). Both histamine H1 and H2-receptor antagonists showed stronger acetylcholinesterase inhibitory activity. Their dissociation constants were ranitidine (Kii = 1.56 mumol/l, s.e. = 0.14) less than oxmetidine (Kis = 14.7 mumol/l, s.e. = 1) less than mepyramine (Kis = 178 mumol/l, s.e. = 23; Kii = 440 mumol/l, s.e. = 98) less than cimetidine (Kis = 199 mumol/l, s.e. = 12; Kii = 827 mumol/l, s.e. = 126). Using the ROSFIT programs for fitting data to common enzyme kinetic models, the inhibition caused by histamine, 4-methyl histamine, 2-methyl histamine, oxmetidine and neostigmine was of the competitive type. Mepyramine, cimetidine and dimaprit appeared to exhibit the modern non-competitive type of inhibition with their primary action on the enzyme rather than on the enzyme-substrate complex. Ranitidine seemed to act on the enzyme-substrate complex rather than the enzyme, conforming to the uncompetitive inhibition model. The clinical implications of acetylcholinesterase inhibition by cimetidine and ranitidine are discussed.

Cimetidine and Ranitidine: A Study of Competitive and Ion‐channel Blockade in the Toad Isolated Rectus Abdominis Muscle

“…(1985) have reported that cimetidine and ranitidine can potentiate and, with increasing concentration, block the responses of the toad isolated rectus abdominis muscle to cumulative doses of acetylcholine (ACh). Potentiation by cimetidine and ranitidine has been attributed to the inhibition of cholinesterase (Hansen & Bert1 1983a,b;Lee et al 1985) whereas the characteristic features of the blockade suggest involvement of ion-channel block (Dreyer 1982;Cheah et al 1985).…”