Effect of calcium antagonists (omega-conotoxin GVIA, verapamil, gallopamil, diltiazem) on bronchial smooth muscle contractions induced by soman.
The effect of the calcium antagonists omega-conotoxin GVIA, verapamil, gallopamil and diltiazem was investigated on in vitro bronchial smooth muscle contraction in the rat induced by the nerve agent soman. Soman inhibits the acetylcholinesterase activity irreversibly. The effect of the calcium channel antagonists on contractions induced by electrical field stimulation and carbachol was also investigated, in order to elucidate the mechanism by which calcium antagonists inhibit the soman induced contraction. omega-Conotoxin GVIA reduced the bronchial smooth muscle contraction induced by electrical field stimulation with an almost complete inhibition at approximately 1.0 x 10(-6) M. The soman induced contraction was only inhibited by 15% at a concentration of 3.0 x 10(-6) M omega-conotoxin GVIA. The organic calcium antagonists verapamil, gallopamil and diltiazem reduced both electrically and soman induced smooth muscle contraction. Complete inhibition of the contractions induced by soman was achieved at 1.4 x 10(-4) M for verapamil and gallopamil, while diltiazem inhibited the contraction to 7% of control at 1.4 x 10(-4) M. Verapamil, gallopamil and diltiazem increased the EC50 for carbachol significantly, while omega-conotoxin GVIA had no effect. None of the calcium antagonists had any effect on the maximal contraction induced by carbachol. Verapamil, gallopamil and diltiazem blocked, however, sub-maximal contractions induced by carbachol (10(-7)-10(-5) M) resulting in a right-shift of the dose response curve. The results show that omega-conotoxin GVIA inhibits the calcium-dependent release of acetylcholine which causes contraction of airway smooth muscle, while it has no effect on smooth muscle contraction induced by soman.(ABSTRACT TRUNCATED AT 250 WORDS)
Walday
P
P
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller.
Fyllingen
E
E
Aas
P
P
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects
D002121:Calcium Channel Blockers; D002217:Carbachol; D012999:Soman; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase