Contractile responses of tracheal smooth muscle in organophosphate-treated swine: 2. Effects of antagonists.
1. Swine tracheal smooth muscles (TSM) developed spontaneous contractions following the acute administration of DFP in vivo and/or in vitro which could be blocked pharmacologically using atropine (2 x 10(-7) M), pirenzepine (3 x 10(-7) M), or hemicholinium 3 (HC3, 5 x 10(-6) M). 2. Treatment of TSM in vitro with DFP caused them to become responsive to ACh concentrations as low as 10(-10) M. 3. Atropine and pirenzepine (at 2 and 3 x 10(-7) M respectively) increased the EC50 concentrations for ACh approximately 300- and 8-fold respectively. The shifts caused by atropine and pirenzepine in the dose-response curves for ACh were not parallel after in vitro treatment of the muscle with DFP. By contrast, the shifts in the dose-response curves were parallel when muscles from swine injected for 7 days with DFP were used. 4. HC3 had no effect on the control dose-response curve for ACh, but steepened the dose-response curve after in vitro treatment of the muscle with DFP. The ACh dose-response curve obtained in the presence of HC3 and DFP was identical to that obtained using muscles from swine treated for 7 days with DFP. 5. McN-A-343, a partial agonist at muscarinic receptors, also induced contraction although the maximal tension induced was 56% of the maximal tension obtained using ACh. In vitro treatment of the muscle with DFP caused a leftward shift in the dose-response curve for McN-A-343. The muscles from animals treated for 7 days with DFP did not respond to McN-A-343 at doses up to 10(-3) M. 6. McN-A-343 competition for [3H]QNB binding suggested that the loss of the contractile response can be correlated with the loss of a high affinity site for McN-A-343 from the muscle. 7. We conclude that tolerance to DFP with subacute treatment results in part from the reduction in sensitivity of neural elements associated with swine tracheal smooth muscle to ACh. In addition the response to the partial agonist McN-A-343 is lost after subacute DFP treatment.
Murali Mohan
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P
Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson 39216.
Yang
C M
CM
Dwyer
T M
TM
Farley
J M
JM
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000633:toxicity*; D008464:Mecamylamine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D010890:Pirenzepine / Q000494:pharmacology; D013552:Swine; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D010276:Parasympatholytics; D007531:Isoflurophate; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D008464:Mecamylamine; D001285:Atropine; D000109:Acetylcholine