Investigation of the antimuscarinic and other actions of proadifen in-vitro

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Abstract
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 μm) 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 μm) (i) antagonizes negative inotropic responses to ACh and ATP in guinea-pig left atria, (ii) antagonizes contractile responses to ACh and elevated [K+] in guinea-pig ileal preparations, (iii) displaces (−)-[3H]quinuclidinyl benzilate from muscarinic binding sites in membrane homogenates of guinea-pig ileal longitudinal muscle and (iv) reduces contractile responses to elevated K+] in rat aortic ring preparations. It is concluded that proadifen may possess (i) complex interactions with muscarinic receptors and (ii) Ca2+ entry blocking properties in concentrations 10–100 times lower than those reported to inhibit cytochrome P450-catalysed reactions.