Investigation of the antimuscarinic and other actions of proadifen in-vitro.
The possibility that proadifen (SKF 525A) antagonizes endothelium-dependent relaxations to acetylcholine (ACh) in isolated blood vessel preparations via a muscarinic receptor blocking action has been investigated. In phenylephrine-contracted rat isolated aortic ring preparations (with endothelium), proadifen (10-100 microM) shifts ACh relaxant curves to the right without affecting the maximal response, yet endothelium-dependent relaxations to ATP are unaffected. At lower concentrations, proadifen (1-10 microM) antagonizes negative inotropic responses to ACh and ATP in guinea-pig left atria, antagonizes contractile responses to ACh and elevated [K+] in guinea-pig ileal preparations, displaces (-)-[3H]quinuclidinyl benzilate from muscarinic binding sites in membrane homogenates of guinea-pig ileal longitudinal muscle and reduces contractile responses to elevated [K+] in rat aortic ring preparations. It is concluded that proadifen may possess complex interactions with muscarinic receptors and Ca2+ entry blocking properties in concentrations 10-100 times lower than those reported to inhibit cytochrome P450-catalysed reactions.
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010276:Parasympatholytics; D011189:Potassium Chloride / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate
D010276:Parasympatholytics; D011813:Quinuclidinyl Benzilate; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D011335:Proadifen; D000109:Acetylcholine