nitroarginine and 7-7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one

Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)(-/-) mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS(-/-) mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 +/- 0.6 mV; nNOS(-/-): 11.2 +/- 1.5 mV). Both atropine (1 microM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 microM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 microM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS(-/-) mouse colon (wild-type: 47.9 +/- 2.4 mm; nNOS(-/-): 57.8 +/- 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.

Topics: Action Potentials; Analgesics; Animals; Atropine; Colon; Enzyme Inhibitors; Intestinal Mucosa; Isoindoles; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscarinic Antagonists; Muscle, Smooth; Myoelectric Complex, Migrating; Nitric Oxide; Nitric Oxide Synthase Type I; Nitroarginine

Tachykinins are important mediators in neuromuscular signalling but have not been thoroughly characterised in the mouse gut. We investigated the participation of tachykinin receptors in contractility of circular muscle strips of the mouse ileum.. Electrical field stimulation (EFS) of excitatory nonadrenergic noncholinergic (NANC) nerves induced frequency-dependent contractions which were mimicked by substance P (SP). Desensitisation of SP and NK(1), NK(2) or NK(3) receptors significantly reduced contractions to EFS. The NK(1) receptor blocker RP67580 significantly inhibited NANC contractions to EFS. The NK(2) and NK(3) receptor blockers nepadutant and SR142801 did not affect NANC contractions per se but increased the RP67580-induced inhibition of NANC contractions to EFS. Contractions to SP were significantly reduced by RP67580 but not affected by nepadutant or SR142801. The NK(1) and NK(2) receptor agonists, septide and [beta-ala(8)]-NKA 4-10 (beta-A-NKA), respectively, but not the NK(3) receptor agonist senktide-induced dose-dependent contractions. Atropine inhibited and l-NNA augmented contractions to septide. Contractions to beta-A-NKA were insensitive to atropine but augmented by l-NNA.. Tachykinins mediate NANC contractions to EFS in the mouse small intestine. Endogenously released tachykinins activate mainly NK(1) receptors, located on cholinergic nerves and smooth muscle cells and, to a lesser degree, NK(2) and NK(3) receptors, most likely located presynaptically.

Topics: Action Potentials; Analgesics; Animals; Antipsychotic Agents; Atropine; Electric Stimulation; Ileum; Indoles; Isoindoles; Mice; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Neurons; Nitroarginine; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P

1. We have assessed the effect of L-nitroarginine (L-NOARG), a nitric oxide (NO) synthase inhibitor, on hypotension and plasma protein extravasation produced by i.v. administration of substance P (SP) in urethane-anaesthetized rats. 2. I.v. administered SP (1 nmol kg-1) produced maximal blood pressure lowering effect which was not modified by previous administration of L-NOARG (45.6 mumol kg-1 i.v.). The hypotensive response to SP was greatly reduced by the nonpeptide SP antagonist, RP 67,580 (0.68 mumol kg-1) indicating the involvement of tachykinin NK-1 receptor. L-NOARG caused by itself a sustained increase in both systolic and diastolic blood pressure, while RP 67,580 was without effect. 3. I.v. administration of SP produced plasma protein extravasation in the trachea, ureter and urinary bladder (determined by the Evans blue leakage technique). A dose of 10 nmol kg-1 SP was necessary to produce a maximal effect, while the tachykinin NK-1 receptor selective agonist [Sar9]SP sulphone produced a similar maximal response at 3 nmol kg-1 in the various organs tested. 4. L-NOARG failed to affect plasma protein extravasation produced by either SP or [Sar9]SP sulphone while RP 67,580 inhibited the response to both agents. 5. The present findings fail to reveal a significant contribution of NO production in the hypotensive and inflammatory response to NK-1 receptor stimulation in urethane-anaesthetized rats.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Blood Proteins; Indoles; Injections, Intravenous; Isoindoles; Male; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Receptors, Neurokinin-2; Receptors, Neurotransmitter; Substance P