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Biomedical subjects

A Ledlow

Publications and source records attributed to A Ledlow.

15 recordsLinked to original sources
PubMed1999

The effect of peroxynitrite on sphincter of Oddi motility.

BACKGROUND: Nitric oxide (NO*) is an inhibitory neurotransmitter that induces sphincter of Oddi relaxation. Superoxide (O*-2)-scavenging enzymes are present in enteric plexuses of the sphincter of Oddi and O*-2 alters sphincter of Oddi motor function. O*-2 rapidly oxidizes nitric oxide (NO*) to form peroxynitrite (ONOO-), thus terminating the biological activity of NO*. The aim of our study was to determine the effects of ONOO- on sphincter of Oddi motility in vitro. MATERIALS AND METHODS: Adult opossums were sacrificed and the sphincter of Oddi was removed and placed in a tissue bath containing oxygenated Krebs solution at 37 degreesC. In the first series of experiments, force transducers recorded tension in a transverse orientation at two sites along the spontaneously contracting sphincter of Oddi. In a second series of experiments, circular muscle strips were precontracted with carbachol and stimulated by an electrical field. RESULTS: ONOO-, superoxide dismutase (SOD), Nomega-nitro-l-arginine (l-NNA), or oxyhemoglobin were added to the tissue baths. ONOO- decreased the frequency of contractions in the spontaneously contracting sphincter of Oddi. Adding hemoglobin increased the frequency of contractions. ONOO- also increased the stimulation-induced relaxation compared to controls. The increase in relaxation induced by ONOO- was inhibited by oxyhemoglobin and l-NNA but not SOD. Pretreatment with oxyhemoglobin prevented the increase in the stimulation-induced relaxation caused by ONOO-. CONCLUSION: These results suggest that hemoglobin binds ONOO- or that ONOO- generates NO.

Animals↗
PubMed1997

The effect of ethanol on sphincter of Oddi motility in vitro.

Antioxidant enzymes are present in nerves supplying the sphincter of Oddi and regulate its motor function. Oxygen free radicals (O2.-) produce hydrogen peroxide (H2O2) by the action of superoxide dismutase (SOD). Hydroxyl radical (OH.), an important mediator of H2O2 toxicity, oxidizes ETOH. Thus, the aim of our study was determine the effects of ETOH on sphincter of Oddi motility. The sphincter of Oddi was removed from opossums and force transducers recorded tension in its transverse axis. Alcohol (ETOH) was added to the tissue bath in concentrations from 0.1 to 0.4%. OH. was generated by the addition of 0.01% H2O2. Nitric oxide production was inhibited by the addition of 0.3 mM N omega-nitro-L-arginine (L-NNA). H2O2 increased the frequency of sphincter of Oddi contractions. Concentrations of ETOH > 0.3% decreased contractile frequency; however, 0.2% ETOH alone had no affect on the basal frequency of contraction but inhibited the increase in contractile frequency caused by H2O2. L-NNA also increased the contractile frequency; however, this effect was not inhibited by ETOH. We conclude that ETOH attenuates the effect of H2O2 on sphincter of Oddi motility.

Animals↗
PubMed1997

The role of antioxidant enzymes in the control of opossum sphincter of Oddi motility.

Superoxide rapidly oxidizes nitric oxide (NO) to form peroxynitrite, thus terminating the biological activity of NO. The aims of our study were to determine if superoxide alters the motor function of the sphincter of Oddi and to localize the antioxidant enzymes in the sphincter of Oddi. Immunostaining was performed and enzyme activities were measured in the sphincter of Oddi. In physiological experiments, force-displacement transducers recorded tension in the spontaneously contracting sphincter of Oddi and after electrical field stimulation (EFS) of precontracted sphincter of Oddi. Superoxide was generated by the addition of xanthine with xanthine oxidase, superoxide radicals were scavenged by the addition of superoxide dismutase (SOD), and catalase or SOD was inhibited by diethyldithiocarbamic acid. Immunostaining demonstrated SOD and catalase immunoreactivity in ganglia situated at the serosal surface of the circular muscle. Total SOD activity was 202 +/- 12 U/mg. Generation of superoxide or inhibition of SOD increased the contractile frequency and decreased relaxation after EFS. We conclude that superoxide alters sphincter of Oddi motor function, and the presence of superoxide scavenging enzymes in enteric plexuses suggests that they may regulate sphincter of Oddi neuromuscular function by clearing endogenous superoxide.

Animals↗
PubMed1997

Effect of hydroxyl radical (OH.) on sphincter of Oddi motility.

Antioxidant enzymes are present in sphincter of Oddi nerves and regulate sphincter of Oddi motor function mediated by NO-releasing nerves. Oxygen free radicals (O2-.) produce hydrogen peroxide (H2O2) by the action of superoxide dismutase (SOD). Hydroxyl radical (OH.) has been shown to play an important role as a mediator of H2O2 toxicity. The aims of our study were to determine the effects of H2O2 on sphincter of Oddi motility and if these effects are mediated by OH.. Adult opossums were sacrificed and the sphincter of Oddi removed and placed in a tissue bath containing oxygenated Krebs solution. Force transducers recorded tension in a transverse orientation at two sites along the sphincter of Oddi specimen. H2O2 was added into the tissue bath at concentrations from 0.01 to 0.5%. O2-. radicals were inhibited by the addition of SOD, while OH. was scavenged by the addition of alcohol (ETOH) or dimethyl sulfoxide (DMSO). H2O2 produced a dose-dependent increase in baseline amplitude, frequency, and peak amplitude of contractions. The effect of 0.01% H2O2 on sphincter of Oddi contractile frequency was inhibited by 0.2% ETOH and DMSO, but not by SOD. We conclude that H2O2 has profound effects on sphincter of Oddi motility and that the actions of H2O2 are probably mediated through OH..

Animals↗
PubMed1996

Effects of recombinant human hemoglobin on opossum sphincter of Oddi motor function in vivo and in vitro.

Nitric oxide (NO) acts as a nonadrenergic, noncholinergic inhibitor neurotransmitter that regulates sphincter of Oddi (SO) motor function. Hemoglobin blocks NO activity by binding it after it is synthesized. We hypothesized that recombinant human hemoglobin (rHb1.1) affects SO motor function by scavenging NO. Under anesthesia, 12 opossums underwent biliary tract manometry. Following a stabilization period, six animals were given rHb1.1 (0.28 g/kg over 30 min), while six received bovine albumin (0.28 g/kg over 30 min). Recordings were made during the infusion and for 3 hr after the infusion. In an in vitro preparation, force transducers were used to record spontaneous contractions at two sites along the sphincter segment. After a control period, rHb1.1 (0.1 mM) or cyanomethemoglobin (0.1 mM) was added to the tissue bath and recordings continued for another 2 hr. Recombinant human hemoglobin decreased the frequency of contractions, increased resting tone, and blocked the relaxation phase of contraction in vivo. It increased the baseline amplitude, the frequency, and the peak amplitudes of contractions in vitro. Albumin or cyanomethoglobin, which are unable to bind NO, had little effect on SO motor activity. We conclude that rHb1.1 may alter SO motor function by binding endogenous NO.

Analysis of Variance↗
PubMed1996

Antioxidant enzymes in intramural nerves of the opossum esophagus.

Superoxide radical (O2-.) combines with nitric oxide (NO) to form peroxynitrite, thereby nullifying the biological activity of NO. Superoxide dismutase (SOD) prevents this reaction by converting O2-. to H2O2. We tested the hypotheses that the antioxidant enzymes catalase (CAT), Mn SOD, and Cu/Zn SOD are present in enteric neurons of the opossum esophagus, and that O2-. alters esophageal motor function. Immunostaining demonstrated CAT, Mn SOD, and Cu/Zn SOD immunoreactivity in interganglionic nerve bundles and ganglia of the myenteric and submucosal plexuses. Western blot analysis confirmed the presence of these enzymes in homogenates of esophageal muscularis propria, and enzyme assays demonstrated Cu/Zn SOD and Mn SOD activities of 262 and 73 U/mg protein, respectively. Both diethyldithiocarbamic acid, an inhibitor of Cu/Zn SOD, and xanthine (X) with xanthine oxidase (XO), which generate O2-., shortened the latency of the nerve-mediated contraction of circular esophageal muscle, the off response, by 20.2 and 23.4%, respectively. SOD alone did not affect the latency, but it inhibited the effect of X with XO on the latency. Antioxidant enzymes found in intramural esophageal nerves may play a role in regulating NO-mediated neuromuscular communication in the esophagus.

Animals↗
PubMed1995

The effects of recombinant human hemoglobin on esophageal motor functions in humans.

BACKGROUND & AIMS: Nitric oxide controls lower esophageal sphincter (LES) relaxation and esophageal peristalsis in opossums, but its role in the control of esophageal motility in humans is not defined. Hemoglobin inactivates NO by binding it. Recombinant human hemoglobin (rHb1.1) was used to test the hypothesis that NO mediates esophageal motor functions in humans. METHODS: rHb1.1 or human serum albumin was administered intravenously to fasting male volunteers. Esophageal manometric studies were performed before, during, and up to 6 hours after the infusion. RESULTS: rHb1.1 increased the velocities of peristaltic contractions to produce simultaneous contractions in 6 of 9 subjects. It increased the amplitude and duration of contractile waves in the esophagus. There was no consistent effect on the resting tone of the LES, but LES relaxation was inhibited. Spontaneous, simultaneous high-pressure contractions occurred in 8 of 9 subjects. Lower retrosternal chest pain during swallowing was observed in 4 subjects. CONCLUSIONS: rHb1.1 interfered with esophageal peristalsis and LES relaxation. It precipitated esophageal spasm in some subjects. These data support the hypothesis that the timing of smooth muscle esophageal peristalsis and LES relaxation are mediated by NO. They suggest that some disorders of esophageal motor function may result from defects in NO neuromuscular communication.

Adult↗
PubMed1995

Effects of recombinant human hemoglobin on motor functions of the opossum esophagus.

Chemically altered hemoglobins are being investigated as blood substitutes. They may affect numerous biological processes since free hemoglobin binds nitric oxide (NO). Nitric oxide is a neural mediator of relaxation of the lower esophageal sphincter (LES) and esophageal peristalsis. We hypothesize that recombinant human hemoglobin (rHb1.1) alters esophageal motor function by scavenging NO. Contraction of transverse muscle strips from the opossum esophagus and LES was monitored. Transmembrane potential differences of circular smooth muscle from the esophagus were recorded using glass microelectrodes. Intrinsic esophageal nerves were stimulated electrically. Esophageal manometries were performed with a low-compliance perfused-catheter system. The activity of the enzyme NO synthase was determined with the citrulline assay. Recombinant hemoglobin diminished nerve-induced relaxation of LES muscle but did not alter LES tone. Circular esophageal muscle responded to nerve stimulation with an inhibitory junction potential and a mechanical off response. Recombinant hemoglobin diminished the inhibitory junction potential and shortened the latency of the off response. It increased the velocity of esophageal peristalsis, decreased the amplitudes of these contractions and diminished LES relaxation. Cyanomethemoglobin had little effect on nerve- or swallow-induced responses. Hemoglobin did not inhibit the activity of NO synthase. Recombinant human hemoglobin appears to alter esophageal motor function by scavenging NO.

Amino Acid Oxidoreductases↗
PubMed1994

Vasoactive intestinal contractor: localization in the opossum esophagus and effects on motor functions.

BACKGROUND/AIMS: Vasoactive intestinal contractor (VIC), an endothelinlike peptide and a putative gastrointestinal hormone, contracts gastrointestinal smooth muscle. The aim was to study VIC in relation to esophageal function. METHODS: Intramural nerves in opossum esophageal smooth muscle strips were stimulated in the presence of various concentrations of VIC and were stained for VIC immunoreactivity. RESULTS: VIC caused an atropine-resistant increase in the amplitude of nerve-induced contractions of the circular muscle. VIC alone contracted longitudinal muscle, and this effect was nearly eliminated by 1 mmol/L atropine. VIC caused an atropine-resistant increase in the resting tone of the lower esophageal sphincter muscle, but it did not affect nerve-induced relaxation of that muscle. VIC-immunoreactive nerve fibers occurred in the longitudinal muscle layer, in the muscularis mucosae, and around the ducts of esophageal glands. A few such fibers were found in the circular muscle layer. Nerve fibers and cell bodies of the myenteric plexus showed VIC immunoreactivity. In the stomach, immunoreactive nerve fibers occurred in muscularis mucosae and circular muscle but not in longitudinal muscle. CONCLUSIONS: VIC is localized in neuronal elements of the opossum esophagus and excites contractions in esophageal smooth muscle.

Animals↗
PubMed1992

Guanylate cyclase inhibitors: effect on tone, relaxation, and cGMP content of lower esophageal sphincter.

Relaxation of the lower esophageal sphincter (LES) results from activation of its intrinsic innervation. This relaxation is associated temporally with an increase in the guanosine 3',5'-cyclic monophosphate (cGMP) content of the muscle. This study tests the hypothesis that variations in the production of cGMP mediate resting LES tone and nerve-induced relaxation. We examined the effects of guanylate cyclase inhibitors, such as cystamine and methylene blue (MB), on the resting tone, resting membrane potential, electrical field stimulation (EFS)-induced relaxation, and cGMP content of circular smooth muscle from the LES of the opossum. Strips of sphincter muscle were placed in a tissue bath and stretched to 125% resting length. Both cystamine and MB increased the resting tone of LES muscle in a concentration-dependent manner (EC50 = 1.1 +/- 0.2, n = 12, and 1.6 +/- 0.4 mM, n = 10, respectively). The increase in tone by cystamine was not blocked by tetrodotoxin, atropine, or propranolol. Cystamine (1 mM) did not alter the resting membrane potential of circular muscle cells of the LES. The removal of extracellular Ca2+ by the addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA, 4 mM) and nifedipine (1 microM) shortened the duration but not the amplitude of the response to cystamine. Pretreatment with caffeine (5 mM) in the presence of EGTA and nifedipine to deplete intracellular Ca2+ stores blocked the increase in tone by cystamine. Cystamine (1 mM) failed to inhibit LES relaxation induced by EFS. Carbachol, at a concentration that induced a similar increase in base-line tone, attenuated the nerve-mediated relaxation. Cystamine did not alter basal cGMP levels, but inhibited the rise in cGMP induced by EFS. The data indicate that cystamine increases LES tone but does not inhibit EFS-induced relaxation, even though it inhibits EFS-induced increases in cGMP content. The increase in tone is dependent on the presence of intracellular Ca2+ stores.

Animals↗
PubMed1991

Nitric oxide: mediator of nonadrenergic noncholinergic responses of opossum esophageal muscle.

Nonadrenergic noncholinergic (NANC) nerves of the opossum esophagus mediate relaxation of circular muscle from the lower esophageal sphincter (LES) and the off contraction of circular esophageal muscle. The latencies between the end of the stimulus and the off contraction describe a gradient so that the latency is longest in muscle from the caudad esophagus. NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide (NO) synthase, and NO were used to test the hypothesis whether NO is a mediator of these nerve-induced responses. Both electrical field stimulation (EFS) of intrinsic esophageal nerves and exogenous NO relaxed LES muscle. Only EFS-induced relaxation was inhibited by L-NNA [half-maximal response (EC50) = 60.0 +/- 20.0 microM]. L-Arginine, the substrate for NO synthase, reversed the inhibitory effect of L-NNA. Exogenous NO did not contact circular esophageal muscle. Both the amplitude (EC50 = 14.7 +/- 4.0 microM) and the latency of the off contraction (EC50 = 41.1 +/- 5.6 microM) were diminished by L-NNA. L-Arginine prevented the action of L-NNA. NG-nitro-L-arginine also attenuated the gradient in the latency of the off response by shortening latencies in muscle from the caudad esophagus. It had no effect on cholinergic nerve-induced contraction of longitudinal esophageal muscle. These data support the hypothesis that NO or an NO-containing compound may be a mediator of NANC nerve-induced responses of the esophagus and LES.

Animals↗
PubMed1982

Methylphenidate increases selectivity of visual scanning in children referred for hyperactivity.

Visual scanning patterns were investigated in 32 children referred for symptoms of hyperactivity in a double-blind crossover comparison of methylphenidate and placebo treatments. Total errors, response latency, and visual fixations were recorded as the child scanned computer-generated visual matching-to-sample problems. Results indicated that the number of fixations on the standard stimulus in the matching task was significantly larger in the methylphenidate state. Drug treatment also resulted in a significant increase in the number of systematic comparisons between the standard and the variants in the task. However, the increased selectivity of attention to the standard stimulus was not accompanied by a reduction of total errors. It was suggested that the stimulant drug may increase attentional selectivity even when such a shift fails to produce improvement in task performance.

Association Learning↗
PubMed1978

Differences in reaction times and average evoked potentials as a function of direct and indirect neural pathways.

Average evoked potentials and manula response latencies were collected during a simple detection task in which brief visual stimuli were presented to the left and right visual fields. Latencies generated by the ipsilateral stimulus-hand combinations were shorter than contralateral combinations only under certain conditions, impugning the hypothesis that the reaction time difference reflects interhemispheric transfer time. Certain evoked potential components recorded contralateral to the stimulus occurred earlier than their ipsilateral counterparts, but whether this difference can be interpreted as representing interhemispheric transfer time is also questioned.

Adult↗
PubMed1978

Reaction times and evoked potentials as indicators of hemispheric differences for laterally presented name and physical matches.

Letter pairs, which could be name matches, physical matches, or mismatches, were presented at fixation or 2.5 degrees left or right of fixation. During different experimental sessions, the locations and the types of matches were fixed (and therefore known in advance by the subject) or were randomized. Right visual field superiority in reaction time occurred for name matches only when location was randomized, and then the extent of the superiority depended on whether the types of match called for were predictable. Evoked potentials to the letter pairs during this task revealed hemispheric and neural pathway differences that were independent of expectancy condition. Right hemisphere responses were larger than left. For some components, amplitudes were smaller and latencies were shorter for direct than for indirect projection of stimuli to each cerebral hemisphere. Indirect-direct differences in P300 amplitude varied for each cerebral hemisphere according to whether a physical or name match occurred. The P130 and N170 components manifested hemispheric differences that depended on whether the two letters of a pair were in the same or different cases.

Adult↗