A dose-response study of anticholinesterase drugs on contractile and phosphatidylinositol responses of rat trachea.
We investigated whether anticholinesterase drugs in large doses inhibit muscarinic receptors of airway smooth muscle. In vitro measurements of isometric tension and [(3)H]inositol monophosphate (IP(1)) that formed were conducted by using rat tracheal rings or slices. Neostigmine and pyridostigmine caused muscular contraction and IP(1) accumulation in small doses (10 microM and < or = 100 microM, respectively), but they attenuated muscular contraction and IP(1) accumulation in larger doses (1000 microM). Edrophonium did not affect the smooth muscle tone and IP(1) levels. Neostigmine, pyridostigmine, and edrophonium attenuated the carbachol (5.5 microM)-induced smooth muscle contraction and IP(1) accumulation, when administered in large doses (1000 microM). The attenuation of contraction by neostigmine at large doses was not affected by methoctramine, an M(2) muscarinic receptor antagonist, but was reversed by washing with fresh Krebs-Henseleit solution. The results suggest that anticholinesterase drugs have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy.


CONCLUSIONS
Neostigmine and pyridostigmine, but not edrophonium, have dual effects on the tension and phosphatidylinositol responses of rat trachea. Large doses of anticholinesterase drugs cause airway smooth muscle relaxation, which may be seen in patients with myasthenia gravis who have received excessive anticholinesterase therapy.
Tsuda
A
A
Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan. d397049x@stcc.nagasaki-u.ac.jp
Shibata
O
O
Saito
M
M
Hashimoto
S
S
Iwanaga
S
S
Makita
T
T
Sumikawa
K
K
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004491:Edrophonium / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009388:Neostigmine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000096:biosynthesis*; D010880:Piperidines / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D007295:Inositol Phosphates; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D010880:Piperidines; D009388:Neostigmine; D004491:Edrophonium; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; D011729:Pyridostigmine Bromide