A comparative study of structure and function of the longitudinal muscle of the anal canal and the internal anal sphincter in pigs.

PURPOSE: This study aims to compare the physiology of the longitudinal muscle of the anal canal with the internal anal sphincter in pigs. METHODS: Histology and in vitro studies were performed to compare the effect of neural responses induced by electric stimulation and through nicotinic, purinergic, and serotoninergic receptors. RESULTS: The longitudinal muscle and the internal anal sphincter are constituted exclusively by smooth muscle. Strips from the internal anal sphincter a) developed myogenic tone; b) responded to electric stimulation with an "on" relaxation antagonized by nitric oxide synthase inhibitors and purinergic P2Y1 antagonists, and with an "off" contraction antagonized by atropine and phentolamine; and c) responded to stimulation of nicotinic receptors with a relaxation antagonized by nitrergic and purinergic P2Y1 antagonists, responded to stimulation of serotoninergic 5-hydroxytryptamine 3 receptors with a contraction, and relaxed to carbachol and purinergic P2X agonists. Strips from the longitudinal muscle a) did not develop tone, b) responded to electric stimulation with an "on" contraction antagonized by atropine, and c) did not respond to stimulation of nicotinic or serotoninergic 5-hydroxytryptamine 3 receptors, and carbachol and purinergic P2X agonists induced a contraction. CONCLUSIONS: The motility of the internal anal sphincter includes myogenic tone, relaxation mediated by nitric oxide and purinergic P2Y1 receptors, and contraction mediated by cholinergic motor neurons and sympathetic fibers. The motility of the longitudinal muscle is limited to a contraction mediated by cholinergic neurons, suggesting that longitudinal muscle contracts during relaxation of the internal sphincter, shortening the anal canal. Nicotinic, muscarinic, and serotoninergic receptors might be therapeutic targets for anal motor disorders.

Competitive Mechanisms and Origins of Stereocontrol in the [2 + 2] Thermal Cycloaddition between Imines and Keteniminium Cations. A Complementary Entry to 2-Azetidinones (beta-Lactams) and Related Compounds.

The different reaction paths associated with the formal [2 + 2] thermal cycloaddition between several keteniminium cations and imines has been studied computationally. It is found that the reaction takes place via stepwise mechanisms that involve the sequential formation of the N1-C2 and the C3-C4 bonds. In some cases, the second step of the reaction is subjected to torquoelectronic effects and determines its stereochemical outcome. Under these conditions, preferential or exclusive formation of cis cycloadducts is predicted, in good agreement with part of the experimental evidence available. When chloroenamines are used as precursors of the keteniminium ions, the step in which the C3-C4 bond is formed can consist of an intramolecular S(N)2 reaction. Under these conditions, the stereocontrol of the reaction is significantly lower and the trans isomer is preferentially formed. According to our results, generation of keteniminium cations from enamines having good leaving groups is recommended to improve the stereocontrol of the reaction.

Origins of the Stereodivergent Outcome in the Staudinger Reaction between Acyl Chlorides and Imines.

Calculations using density functional theory (DFT, B3LYP/6-31G level) provide an explanation for the stereodivergent outcome observed in the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (beta-lactams). When the ketene is formed prior to the cycloaddition stages, preferential or exclusive formation of cis stereomers is predicted. When the imine reacts directly with the acyl chloride, the step that determines the stereochemical outcome of the reaction is an intramolecular S(N)2 displacement. Under these conditions, preferential or exclusive formation of trans stereomers is predicted, in good agreement with the experimental evidence available. It is found that both competitive processes are subjected to torquoelectronic effects. In addition, the reported calculations suggest that in both cases the polarity of the solvent enhances the diastereomeric excess of the reaction.

Solvent and Substituent Effects in the Periselectivity of the Staudinger Reaction between Ketenes and alpha,beta-Unsaturated Imines. A Theoretical and Experimental Study.

The outcome of the cycloaddition between activated ketenes and alpha,beta-unsaturated imines has been investigated both experimentally and theoretically. Our results indicate that activated monosubstituted ketenes yield exclusively [2 + 2] cycloadducts. Disubstituted activated ketenes yield [2 + 2] and/or [4 + 2] cycloadducts. In one case, an unexpected piperidin-2-one has been obtained, although its relative abundance with respect to the corresponding [2 + 2] or [4 + 2] cycloadducts can be minimized by the proper choice of experimental conditions. The ability of different ab initio and semiempirical methods to account for these results has been tested. The best agreement between theory and experiment is achieved at the MP2/6-31G level of theory, with solvent effects taken into account. The semiempirical hamiltonian AM1, at the RHF level, tends to overestimate the stability of the transition structures leading to six-membered cycloadducts, whereas 3 x 3CI-HE/AM1 and CASSCF(2,2)/6-31G methods tend to overestimate the stability and the biradical character of the transition structures leading to [2 + 2] cycloadducts.

On the Aromatic Character of Electrocyclic and Pseudopericyclic Reactions: Thermal Cyclization of (2Z)-Hexa-2,4-5-trienals and Their Schiff Bases.

Pericyclic or pseudopericyclic? Although both mechanisms lead to the same product, they are deeply different in nature. The ring-current model proves to be a useful tool to define different kinds of aromaticity and to distinguish between pericyclic and pseudopericyclic reactions.

Physiology of the upper segment, body, and lower segment of the esophagus.

The following discussion on the physiology of the esophagus includes commentaries on the function of the muscularis mucosa and submucosa as a mechanical antireflux barrier in the esophagus; the different mechanisms of neurological control in the esophageal striated and smooth muscle; new insights from animal models into the neurotransmitters mediating lower esophageal sphincter (LES) relaxation, peristalsis in the esophageal body (EB), and motility of esophageal smooth muscle; differentiation between in vitro properties of the lower esophageal circular muscle, clasp muscle, and sling fibers; alterations in the relationship between pharyngeal contraction and relaxation of the upper esophageal sphincter (UES) in patients with dysphagia; the mechanical relationships between anterior hyoid movement, the extent of upper esophageal opening, and aspiration; the application of fluoroscopy and manometry with biomechanics to define the stages of UES opening; and nonpharmacological approaches to alter the gastroesophageal junction (GEJ).

Theoretical study on the mechanism of the [2+1] thermal cycloaddition between alkenes and stable singlet (phosphino)(silyl)carbenes.

The mechanism and the origins of the stereocontrol observed in the reaction between differently substituted alkenes and stable (phosphino)(silyl)carbenes giving cyclopropanes have been studied computationally. These cyclopropanation reactions proceed via asynchronous concerted mechanisms involving early transition structures with a significant charge transfer from the carbene to the alkene moiety. The geometric features of these transition structures preclude a significant overlap between the orbitals required for secondary orbital interactions between the reactants. The stereoselectivity observed experimentally stems from favorable electrostatic and steric interactions between the reactants leading to the stereoisomers in which the phosphanyl and carbonyl or aryl groups are cis to each other.

Pharmacologic characterization of intrinsic mechanisms controlling tone and relaxation of porcine lower esophageal sphincter.

The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 microM), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 microM), ATP (10 microM-30 mM), and tricarbonyldichlororuthenum dimer (1 microM-1 mM) was unaffected by tetrodotoxin (1 microM) or l-N(G)-nitroarginine methyl ester (l-NAME; 100 microM). Calcitonin gene-related peptide (CGRP; 1 nM-1 microM) did not affect LES tone. ATP relaxation was blocked by 1 microM apamin and the P2Y(1) antagonist MRS 2179 (N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate; 10 microM). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml alpha-chymotrypsin. L-NAME (-62.52 +/- 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-alpha]quinoxalin-1-one (ODQ; 10 microM, -67.67 +/- 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 microM) was inhibited by L-NAME (-60.37 +/- 10.8%) and ODQ (-41.90 +/- 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by alpha-chymotrypsin and the P2X(1,2,3) receptor antagonist NF 279 (8,8 cent-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 microM), and unaffected by tin protoporphyrin IX (100 microM). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y1 receptors and a minor contribution of purinergic P2X1,2,3 receptors and PACAP. Nitrergic and purinergic co-transmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.

Reaction of N-vinylic phosphazenes with alpha,beta-unsaturated aldehydes. Azatriene-mediated synthesis of dihydropyridines and pyridines derived from beta-amino acids.

Aza-Wittig reaction of N-vinylic phosphazenes (1,2 addition), derived from diphenylmethylphosphine or derived from trimethylphosphine with alpha,beta-unsaturated aldehydes, leads to the formation of 3-azatrienes through a [2 + 2]-cycloaddition-cycloreversion sequence. The presence of an alkyl substituent in position 3 of N-vinylic phosphazenes increases the steric interactions, and [4 + 2] periselectivity (1,4 addition) is observed. Reaction of azatrienes with alpha,beta-unsaturated aldehydes yields pyridines.

Mechanism and stereoselectivity of the aza-Wittig reaction between phosphazenes and aldehydes.

The mechanism of the aza-Wittig reaction between phosphazenes and aldehydes has been studied computationally, using DFT methods (B3LYP/6-31G level), and experimentally. It has been found that the reaction consists of a tandem [2+2] cycloaddition-cycloreversion sequence in which pi and sigma orbitals as well as lone pairs are involved. Both [2+2] processes take place via thermally allowed supra-supra mechanisms. P-trimethyl-lambda(5)-phosphazenes are predicted to be more reactive than their P-triphenyl analogues. The stereochemical outcome of the whole reaction depends only on the second step, because conformational changes in the intermediate 1,3,2-lambda(5)-oxazaphosphazetidines have a much lower activation energy than the second [2+2] cycloreversion reaction. Preferential or exclusive formation of the corresponding (E)-imines is predicted.

Substituent effects in eight-electron electrocyclic reactions.

The main features of transition structures associated with eight-electron electrocyclic reactions have been studied with Density Functional Theory. It is found that conrotatory electrocyclization reaction of (3Z,5Z)-octa-1,3,5,7-tetraenes takes place via Möbius aromatic transition structures of helical conformation. The reaction is completely periselective. In general, transition structures having outward substituents are preferred with respect to the inward transition structures, irrespective of the pi-donor or pi-acceptor character of the substituent. In contrast with four-electron thermal conrotatory electrocyclic reactions, there is no satisfactory correlation between the difference in energy of activation between inward and outward substituents and the Taft resonance sigma(R) parameter.

[4+3] versus [4+2] mechanisms in the dimerization of 2-boryl-1,3-butadienes. A theoretical and experimental study.

The thermal dimerization of 2-boryl-1,3-butadienes and the scope of this reaction to prepare six-membered rings difficult to synthesize by other methodologies have been studied. In addition, the nature of this dimerization has been studied theoretically. It has been found that the reaction coordinate associated with the formation of the cycloadduct of lowest energy has significant [4+3] character. This behavior is caused by the favorable carbon-carbon overlap and the large values of the corresponding resonance integrals. However, beyond the transition structure, the [4+2] pathway becomes the preferred one thus leading to the exclusive formation of the [4+2] cycloadduct. Aside from this effect, donating groups at the boryl moiety favor the [4+2] mechanism.

Light-induced aminocarbene to imine dyotropic rearrangement in a chromium(0) center: an unprecedented reaction pathway.

1,2-Dyotropic rearrangement can be induced by irradiation of properly functionalized Fischer carbenes. This novel reaction takes place by a stepwise mechanism and with double inversion of configuration at the static scaffold. Good yields are obtained with both cyclic and acyclic structures, thus suggesting that this unprecedented transformation can be extended to other organometallic systems.