Inhibition of acetylcholinesterase by histamine agonists and antagonists.

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.