piperidines and pimagedine

An investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine.. Piperine (5, 10 and 20mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6h. Antianxiety activity was evaluated by employing elevated plus maze, light-dark box and social interaction test. Diazepam was employed as standard anxiolytic drug.. Piperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice.. These data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Anxiety; Benzodioxoles; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Guanidines; Indazoles; Male; Maze Learning; Mice; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Piperidines; Polyunsaturated Alkamides; Stress, Psychological

Responding of rats was maintained under a 120-response fixed ratio (FR) schedule of food delivery, and animals received individual and combined injections of N-methyl-D-aspartic acid (NMDA), phencyclidine hydrochloride, (+)-MK-801 hydrogen maleate (MK-801), (+/-)-2-amino-5-phosphonopentanoic acid (AP5), 7-chlorokynurenic acid (7CK), ifenprodil tartrate, N(G)-nitro-L-arginine methyl ester hydorchloride (L-NAME), 7-nitroindazole, aminoguanidine hemisulfate, L-arginine, molsidomine, sodium nitroprusside, and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8). Behavioral suppression after NMDA was completely and dose-dependently reversed by MK-801, phencyclidine, AP5, and aminoguanidine; partially and dose-dependently attenuated by molsidomine, ifenprodil, and 7CK; and not attenuated at all by L-NAME, 7-nitroindazole, or TMB-8. These findings suggested that behavioral suppression after NMDA was associated with nitric oxide from the inducible synthase. In a second series of experiments, comparable behavioral suppression by 0.1 mg/kg MK-801, but not 3 mg/kg phencyclidine, was attenuated by nitroprusside, molsidomine, and L-arginine, suggesting that suppressions from MK-801 and phencyclidine were mediated by different final common pathways, and that behavioral suppression from MK-801, but not phencyclidine, may be associated with Ca(2+)-dependent nitric oxide.

Topics: 2-Amino-5-phosphonovalerate; Animals; Arginine; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Gallic Acid; Guanidines; Indazoles; Injections, Intraperitoneal; Kynurenic Acid; Molsidomine; N-Methylaspartate; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroprusside; Phencyclidine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

It has been reported that several bronchoconstrictors generate nitric oxide (NO), counteracting bronchoconstriction, and removal of bronchial epithelia reduces NO production. However, it has not been elucidated whether neurokinin A (NKA), a potent bronchoconstrictor liberated from nerve terminals, generates NO. Specific questions in this study were (1) does NKA also generate NO, (2) does NO counteract NKA-induced bronchoconstriction, and (3) does the NO generation require bronchial epithelial cells? In an in vivo study exogenous as well as endogenous (capsaicin-induced) NKA increased airway opening pressure (P(ao)) and the exhaled NO level, and both were inhibited by an antagonist selective for NK(2) receptor (a receptor for NKA), SR48968. The exhaled NO level became negligible with an inhibitor of NO synthase (NOS) type 1-3 (N(G)-nitro-L-arginine methyl ester, L-NAME) with increased P(ao), but not with a NOS type 2 inhibitor. In an in vitro study, NKA increased the nitrite/nitrate level in superfused fluid of tracheal segments. Removing smooth muscle reduced nitrite/nitrate in the fluid to negligible levels, while the level was unchanged with removal of the epithelia. Pretreatment with l-NAME enhanced the tension of epithelia-removed tracheal segments. These findings indicate that (1) NKA generates NO, (2) NO counteracts NKA-induced bronchoconstriction, and (3) NKA activates NOS in the muscle layer, independently of bronchial epithelia.

Topics: Airway Resistance; Animals; Benzamides; Bronchoconstriction; Capsaicin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epithelial Cells; Guanidines; Guinea Pigs; In Vitro Techniques; Male; Muscle, Smooth; Neurokinin A; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Piperidines; Receptors, Neurokinin-2; Trachea

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

Topics: Animals; Cerebral Ventricles; Dizocilpine Maleate; Guanidines; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Motor Activity; Neurotoxins; Oxidoreductases Acting on CH-NH Group Donors; Piperidines; Putrescine; Receptors, N-Methyl-D-Aspartate; Spermidine; Stereotyped Behavior