Effect of benzylamine and its metabolites on the responses of the isolated perfused mesenteric arterial bed of the rat.
1. Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme activity which can be found in the plasma membrane of rat vascular smooth muscle cells. We have investigated the possibility that the products of deamination by this enzyme, namely ammonia, hydrogen peroxide and the aldehyde, may be important in the modulation of the responses of vascular smooth muscle to extracellular stimuli. 2. The isolated perfused mesenteric arterial bed of the rat was used and dose-pressure response curves (DRC) to bolus injections of adrenaline (Ad) or ATP were plotted by non-linear curve fitting. The relaxant effects of carbachol (CCh), which releases endothelium dependent relaxing factor (ERDF), were studied by co-administering CCh with Ad. The effects of including the preferred SSAO substrate, benzylamine (BZ; 25 microM), in the perfusion fluid throughout the experiment and of inhibition of SSAO by treatment of rats with (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145; 1 mg kg-1) 1 h before dissection, have been studied. 3. Neither BZ nor SSAO inhibition affected the DRC to ATP. BZ shifted Ad responses to the left, inhibition of SSAO increased this shift indicating that the amine, but not its metabolites, were responsible for the potentiation of the responses to Ad. DRC to CCh showed a shift to the left and a significant decrease in the Hill slope with BZ, indicative of a potentiation of low doses of CCh more than high doses. Inhibition of SSAO prevented this change and so the metabolites of BZ deamination appeared to be involved in the potentiation. 4. Ammonia generated by SSAO may contribute to the production of EDRF or hydrogen peroxide may sensitize guanylate cyclase to stimulation by EDRF and so explain these findings.
Elliott
J
J
Department of Pharmacology, University of Cambridge, UK.
Callingham
B A
BA
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000499:Allylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000641:Ammonia / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000378:metabolism / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012044:Regression Analysis; D012663:Semicarbazides / Q000494:pharmacology
D001596:Benzylamines; D012663:Semicarbazides; C010059:carbamylhydrazine; D000499:Allylamine; D000641:Ammonia; C040051:2-(3,4-dimethoxyphenyl)-3-fluoroallylamine; D000255:Adenosine Triphosphate; D002217:Carbachol; C030796:benzylamine; D006861:Hydrogen Peroxide; D006631:Amine Oxidase (Copper-Containing); D004837:Epinephrine