title: Effects of deuterium substitution on the chronotropic responses to some sympathomimetic amines in the isolated rat atria.
abstract: In spontaneously beating rat atria the potencies for the chronotropic effects of the following deuterated phenylethylamine derivatives were higher than the potencies of the corresponding non-substituted (protio-) amines: alpha,alpha,d2-beta-phenylethylamine; alpha,alpha,beta,beta-d4-p-tyramine; alpha,alpha,beta,beta-d4-m-tyramine; alpha,alpha,beta-d3-p-octopamine. In contrast, alpha,alpha,beta-d3-noradrenaline and alpha,alpha,beta-d3-m-octopamine were equipotent with the corresponding protio-amines. Experiments performed in atria depleted of endogenous noradrenaline by pretreatment with reserpine and in atria exposed to the monoamine oxidase (MAO) inhibitor pargyline indicated: a. p-octopamine had both direct and indirect effects, but the chronotropic responses to p-octopamine in tissues with normal MAO activity depended mostly on the direct action of the amine; deuterium substitution enhanced the indirect component of action of p-octopamine; b. m-octopamine possessed considerable indirect effects while d3-m-octopamine behaved as an amine of direct action. The substitution of deuterium for hydrogens in the alpha-carbon of the alkyl-side chain of phenylethylamines decreases the rate of deamination by MAO. Therefore, the results obtained with all the amines, except for m-octopamine and alpha, alpha,p-d3-m-octopamine, could be interpreted in terms of the direct, indirect or mixed action of those compounds and/or of the influence that MAO activity has on the chronotropic responses to these amines. The results obtained with protio- and deuterio-m-octopamine suggested that deuterium substitution, either at the alpha- or the beta-carbon, can alter some other mechanisms in addition to the enzymatic deamination.
mesh_terms: D000818:Animals; D003903:Deuterium; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009655:Octopamine / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology*
chemical_list: D010627:Phenethylamines; D013566:Sympathomimetics; D009655:Octopamine; D012110:Reserpine; D010293:Pargyline; D003903:Deuterium