Inhibition of rat colonic motility and cardiovascular effects of new gut-specific beta-adrenergic phenylethanolaminotetralines.
We have investigated the ability of the new putative beta-adrenergic agonists phenylethanolaminotetralines (PEAT) to inhibit intestinal motility in relation to their cardiovascular effects, in ethylurethane-anesthetized rats. The representative PEAT SR 58375A, SR 58572A and SR 58539B and the reference beta-adrenergic agonists isoproterenol, salbutamol and ritodrine caused dose-related inhibition of proximal colon spontaneous motility: ED50 (microgram/kg, i.v.) 210, 92 and 19; 5.6, 176 and 201, as listed. This inhibition was prevented by the beta-adrenergic antagonist alprenolol, but not by desipramine (which prevented the inhibition of colonic motility by tyramine and enhanced that by norepinephrine). The minimal effective doses (MED) of isoproterenol, salbutamol and ritodrine raising heart rate and/or lowering blood pressure (by 10 to 20%), was substantially lower (about 1/10 to 1/150) than their ED50 for inhibition of colonic motility. The MED raising heart rate of the three PEAT, on the other hand, was about twice (SR 58375A and SR 58572A) to five (SR 58539B) times their ED50 for inhibition of colonic motility. None of the PEAT lowered blood pressure up to the top tested dose. Therefore the PEAT may prove preferable to the currently best tolerated beta-adrenoceptor agonists, because they appear less liable to induce cardiovascular side effects. This supports the prospective therapeutic interest of PEAT for intestinal hypermotility disorders.
Giudice
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A
Groupe SANOFI, Research Center MIDY S.p.A. Via Piranesi 38, Milan, Italy.
Croci
T
T
Bianchetti
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A
Manara
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L
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D003891:Desipramine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013329:Structure-Activity Relationship
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D003891:Desipramine