Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants.
There have been reports of hypotension and flushing following vecuronium administration. The etiology of these symptoms, which are similar to those of histamine release, is not clear. The steroidal neuromuscular relaxants (NMRs), unlike muscle relaxants structurally similar to curare, have been shown not to cause histamine release after the administration of typical clinical doses. Histamine levels in plasma reflect a balance between release and catabolism. In humans, histamine N-methyl-transferase (HNMT) is the enzyme primarily degrading for histamine. Therefore, we performed in vitro kinetic studies of purified HNMT to determine the effects of the steroidal and curare-like NMRs and also of gallamine on histamine catabolism. We demonstrated that all NMRs tested were inhibitors of HNMT in vitro. The inhibition was competitive with respect to the cosubstrate S-adenosyl-L-[3H-methyl] methionine, and noncompetitive with respect to histamine. The rank order of inhibition was vecuronium greater than pancuronium greater than gallamine greater than d-tubocurarine greater than metocurine greater than atracurium greater than pipecuronium, with Ki values ranging from 1.2 to 44.8 microM. Our data suggest that HNMT-based radioenzymatic assays for histamine should be susceptible to inhibition by concurrent use of NMRs, particularly vecuronium.
Futo
J
J
Department of Anesthesia and Critical Care, University of Chicago, IL 60637.
Kupferberg
J P
JP
Moss
J
J
D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001279:Atracurium / Q000494:pharmacology; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000201:enzymology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D010197:Pancuronium / Q000494:pharmacology; D017300:Pipecuronium; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D014403:Tubocurarine / Q000031:analogs & derivatives / Q000494:pharmacology; D014673:Vecuronium Bromide / Q000494:pharmacology
D009466:Neuromuscular Blocking Agents; D003473:Neuromuscular Nondepolarizing Agents; D010879:Piperazines; D017300:Pipecuronium; D015113:Androstane-3,17-diol; D001279:Atracurium; D014673:Vecuronium Bromide; D008780:Methyltransferases; D006637:Histamine N-Methyltransferase; D010197:Pancuronium; D005703:Gallamine Triethiodide; C032943:metocurine; D014403:Tubocurarine