Cardiotonic drugs inhibit purified mammalian acetylcholinesterase

Abstract

Oxime- and non-oxime-related drugs, as well as cardiotonic drugs (CDs), have been used to treat the effects of organophosphorus (OP) poisoning. We conducted our experiments to determine what effects CDs may have on acetylcholinesterase (AChE), and how CDs interact with other treatment drugs as well as with OP-inhibited AChE. True AChE (EC 3.1.1.7) was purified from fetal bovine serum, and enzyme activity was measured according to Ellman et al. The CDs coumingine, cassaine, proscillaridin and convallatoxin were incubated with AChE at 550 microM at pH 7.6 and 25 degrees C. The CD ouabain was incubated with AChE at 500 microM. The CDs inhibited AChE by 97%, 89%, 10%, 7% and 6%, respectively. The mean AChE activities for these experiments, except for ouabain, were significantly different (P = 0.05) from their controls, as determined by the two-tailed Student's t-test. In a separate experiment, the oxime TMB-4.2Br (100 microM), which did not inhibit AChE, increased the inhibitory effect of proscillaridin from 4% to 11% (a 3.7-fold increase). When AChE was inhibited 39% with 37 nM VX, the addition of proscillaridin increased the inhibition to 51% (a 1.3-fold increase). When TMB-4 was added to the proscillaridin- and VX-inhibited AChE mixture, the inhibition decreased from 50% to 32% (a 0.37-fold decrease), whereas TMB-4 alone added to VX-inhibited AChE decreased the inhibition from 39% to 24% (a 0.38-fold decrease). The results show that TMB-4 increases the inhibition of AChE by proscillaridin. However, TMB-4 decreases the inhibition of AChE by VX and proscillaridin combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Progress on Cassaine-Type Diterpenoid Ester Amines and Amides (Erythrophleum Alkaloids)

“…Cassaine (1) and coumingine (3) produced 89 % and 97 % inhibition of AChE, respectively, after incubation at 25 ºC with AChE at a concentration of 550 μM at pH 7.6 [55]. In previous paper, we reported the cytotoxicities against a panel of human cancer cell lines [26].…”

Assessment of DNA-binding affinity of cholinesterase reactivators and electrophoretic determination of their effect on topoisomerase I and II activity

“…14 Furthermore, oximes are generally characterized by other significant biological activities. They have a positive effect on the cardiovascular system: pyridinium oximes act against ischemic heart disease and also as inhibitors of blood cell agglomeration, 15,16 and pyridinium ketoximes have been studied as antidepressants and tranquilizers. 17 Pyridinium aldoximes and O-substituted tetrahydropyridinium oximes showed good activity as analgesics, 18,19 and esters of arylpyridinium oximes have anti-inflammatory and antiasthmatic effects.…”