The effects of AF-DX 116, a cardioselective muscarinic antagonist, on the negative inotropic action of acetylcholine.
In superfused left atria from male guinea pigs, rats, and rabbits, myocardial contractility was measured before and after addition of acetylcholine (ACh) and AF-DX 116 ((11[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro- 6H-pyrido[2,3-b] [1,4]benzodiazepine-6-) one), a selective muscarinic antagonist. Characteristic dose-response curves for acetylcholine showing greater negative inotropic response with dose were seen. Increasing AF-DX 116 concentrations reversed the negative inotropy of acetylcholine and, in fact, increased the inotropic response approximately 100% and 50% above the baseline contractile force in a dose-dependent manner in the guinea pig and rabbit, respectively. This increase in contractility following AF-DX 116 addition was not observed in rat atria. The capacity of AF-DX 116 to produce the positive inotropic response only occurred at concentrations above 1 x 10(-5) M. The positive inotropic response of AF-DX 116 was antagonized by dl-propranolol, which suggests that the administration of AF-DX 116 at higher concentrations may unmask the effect of norepinephrine released from underlying viable adrenergic terminals which exist in the left atria.
Baskin
S I
SI
United States Army Medical Research Institute of Chemical Defense, SGRD-UV-PB, Aberdeen Proving Ground, MD 21010-5425.
Thomsen
R H
RH
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010890:Pirenzepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology
D011976:Receptors, Muscarinic; D010890:Pirenzepine; D011433:Propranolol; D000109:Acetylcholine; C048593:otenzepad