Organophosphate inhibition of human heart muscle cholinesterase isoenzymes

  • Chemnitius J
  • Sadowski R
  • Winkel H
 et al. 
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Abstract

The rate of acetylcholine hydrolysis of mammalian heart muscle influences cardiac responses to vagal innervation. We characterized cholinesterases of human left ventricular heart muscle with respect to both substrate specificity and irreversible inhibition kinetics with the organophosphorus inhibitor N,N'-di-isopropylphosphorodiamidic fluoride (mipafox). Specimens were obtained postmortem from three men and four women (61±5 years) with no history of cardiovascular disease. Myocardial choline ester hydrolyzing activity was determined with acetylthiocholine (ASCh; 1.25 mM), acetyl-β-methylthiocholine (AβMSCh; 2.0 mM), and butyrylthiocholine (BSCh; 30 mM). After irreversible and covalent inhibition (60 min; 25°C) with a wide range of mipafox concentrations (50 nM-5 mM), residual choline ester hydrolyzing activities were fitted to a sum of up to five exponentials using weighted least-squares non-linear curve fitting. In each ease, quality of curve fitting reached its optimum on the basis of a four component model. Final classification of heart muscle cholinesterases was achieved according to substrate hydrolysis patterns (nmol/min per g wet weight) and to second-order organophosphate inhibition rate constants k2(l/mol per min); one choline ester hydrolyzing enzyme was identified as acetylcholinesterase (AChE; k2/mipafox=6.1 (±0.8)x102), and one as butyrylcholinesterase (BChE; k2/mipafox=5.3 (±1.1)x103). An enzyme exhibiting both ChE-like substrate specificity and relative resistance to mipafox inhibition (k2/mipafox=5.2 (±1.0)x10-1) was classified as atypical cholinesterase. Copyright (C) 1999 Elsevier Science Ireland Ltd.

Author-supplied keywords

  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Cholinesterase isoenzymes
  • Human heart muscle
  • Inhibition kinetics
  • Organophosphorus compounds

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Authors

  • Jörg Michael Chemnitius

  • Rita Sadowski

  • Holger Winkel

  • Ronald Zech

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