piperidines and 1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole

Although the new histamine H2 receptor antagonist, lafutidine (FRG-8813), N-[4-[4-(piperidinylmethyl)pyridyl-2-oxy]-(Z)-2-butenyl]-2-(fur furylsulfinyl)acetamide accelerates mucin metabolism of rat gastric mucosa, the physiological mechanisms by which this drug stimulates the biosynthesis remain unclear. In this paper, we report the effect of lafutidine on mucin biosynthesis in distinct sites and layers of rat gastric mucosa, including the possible participation of nitric oxide (NO). Lafutidine enhanced [3H]glucosamine incorporation into the mucin in the full thickness corpus mucosa, but not in the antrum. This stimulation on mucin biosynthesis disappeared by the removal treatment of surface mucosal cells. The lafutidine-induced increase of [3H]-labeled mucin in the corpus was completely blocked by either NG-nitro-L-arginine (10[-5] M) or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazolne-1-oxyl-3-oxide (10[-5] M). The inhibitory action of NG-nitro-L-arginine was totally reversed by L-arginine (5 x 10[-3] M). These results suggest that the lafutidine-induced stimulation of mucin biosynthesis mediated by NO is limited to the surface mucous cells of rat gastric oxyntic mucosa.

Topics: Acetamides; Animals; Benzoates; Enzyme Inhibitors; Free Radical Scavengers; Gastric Mucosa; Glucosamine; Histamine H2 Antagonists; Imidazoles; Male; Mucins; Nitric Acid; Nitric Oxide Synthase; Piperidines; Pyridines; Rats; Rats, Wistar; Stimulation, Chemical

1. The structural requirements of the histamine H2-receptor antagonist, roxatidine (2-acetoxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide hydrochloride), for the stimulant effect on mucin biosynthesis and their relation to histamine H2-receptor antagonism were identified by considering the structural analogues of this drug using an organ culture system of the rat stomach and competition studies with [125I]iodoaminopotentidine ([125I]-APT) binding to membranes of the guinea pig striatum. 2. [3H]Glucosamine incorporation into mucin during 5 h incubation period was stimulated by roxatidine and its structural analogues A (2-hydroxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide) and B (N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide). This effect was seen in mucosal cultures of the corpus, but not antrum, region. 3. Structural analogues, in which the length of the flexible chain between the benzene ring and the amide structure differs from that of roxatidine, failed to activate mucin synthesis. No significant change in mucus synthesis occurred with the addition of analogues in which the piperidine ring attached to the benzene ring via a methylene bridge was changed. 4. Specific [125I]-APT binding to the histamine H2 receptor of guinea pig brain membranes was inhibited by roxatidine and all structural analogues used in this study, except F (N-(3-[m-(N, N-dimethyl-aminomethyl)phenoxy]-propyl)acetamide). 5. Ranitidine at 10(-4) M did not suppress the roxatidine-induced increase in [3H]glucosamine incorporation into mucin. 6. Roxatidine-induced stimulation of [3H]glucosamine incorporation into mucin was completely blocked by the addition of either NG-nitro-L-arginine (10(-5) M) or 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide sodium salt (10(-5) M). The inhibitory action of NG-nitro-L-arginine was totally reversed by L-arginine (5 x 10(-3) M). 7. These results suggest that the cardinal chemical features of roxatidine for the activation of mucin biosynthesis in the corpus region of the rat stomach are the appropriate length of the flexible chain between the amide structure and the aromatic ring system bearing the methylpiperidinyl group at the meta position. The activity of roxatidine and its analogues to stimulate mucin synthesis is not related to their histamine H2 receptor antagonistic activity. Roxatidine-induced activation of mucin biosynthesis in the corpus tissue is mediated by nitric oxide.

Topics: Animals; Benzoates; Enzyme Inhibitors; Free Radical Scavengers; Gastric Mucosa; Histamine H2 Antagonists; Imidazoles; Male; Mucins; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Piperidines; Ranitidine; Rats; Rats, Wistar; Receptors, Histamine H2