A carbamate-type cholinesterase inhibitor 2-sec-butylphenyl N-methylcarbamate insecticide blocks L-type Ca2+ channel in guinea pig ventricular myocytes.
2-sec-Butylphenyl N-methylcarbamate (BPMC) is a carbamate-type cholinesterase (ChE) inhibitor with unique toxicological properties such as noncholinergic cardiovascular collapse. Effects of BPMC on L-type Ca2+ channel currents (ICa(L)) were studied in isolated guinea pig ventricular myocytes using the whole-cell patch-clamp technique, since the examination of cardiovascular responses indicated its Ca2+ antagonistic action. BPMC induced bradycardic and hypotensive responses in vivo and inhibited contraction of isolated papillary muscles (IC50 = 1.3 x 10(-4) M) in guinea pigs. BPMC produced reversible block of ICa(L) in the concentration range of 10(-4) - 10(-3) M. At test potentials between -30 mV and +20 mV, BPMC at 3 x 10(-4) M caused marked acceleration of decay rate of ICa(L) with moderate reduction of peak ICa(L) amplitude. BPMC (3 x 10(-4) M) shifted the steady-state inactivation curve to the hyperpolarizing direction by 12.7 mV. Decay rate of Ba2+ currents (IBa(L)) was also accelerated by BPMC. Fitting analysis of inactivation kinetics of IBa(L) with a two-exponential equation revealed that BPMC accelerates the slow inactivation component. At concentrations for blocking peak IBa(L) by ca. 30%, the inactivation kinetics of IBa(L) were significantly accelerated by BPMC, but merely slightly accelerated by Ca2+ channel antagonists such as diltiazem, nifedipine, or verapamil. These results indicate that BPMC, in addition to the inhibition of ChE, blocks L-type Ca2+ channels by accelerating voltage-dependent inactivation.
Futagawa
Haruko
H
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Takahashi
Hiroaki
H
Nagao
Taku
T
Adachi-Akahane
Satomi
S
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology
D020746:Calcium Channels, L-Type; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007306:Insecticides; C019276:BPMC; C116697:cholinesterase 2; D002802:Cholinesterases