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Biomedical subjects

J L Conklin

Publications and source records attributed to J L Conklin.

At least 19 recordsLinked to original sources
PubMed2004

Regional differences in oesophageal motor function.

We tested the hypotheses that oesophageal bolus transit and motor function vary regionally, with bolus viscosity and with body position. In healthy volunteers, we measured the bolus head advance time, bolus presence time and bolus transit time in the proximal and distal oesophagus using water and viscous materials. We compared concurrent manometric responses. Bolus head advance time, bolus presence time and bolus transit time were longer in the distal oesophagus during water and viscous swallows in the upright and supine positions. The total bolus head advance time and transit time, measured across the entire oesophageal body, were shorter for water than viscous swallows. The amplitudes of peristaltic pressure waves were lower for viscous swallows, and varied as a function of region. These studies demonstrated true functional differences between the proximal and distal oesophagus using multichannel intraluminal impedance and that the viscosity of the bolus is a determinant of oesophageal function.

Adolescent↗
PubMed2003

Effects of phosphodiesterase inhibitors on oesophageal neuromuscular functions.

The cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) mediate the inhibitory effects of vasoactive intestinal polypeptide and nitric oxide on oesophageal smooth muscle. Phosphodiesterases (PDE) terminate their actions. We hypothesized that PDE inhibitors alter nerve-induced responses of oesophageal and lower oesophageal sphincter (LES) smooth muscle. An electrical field known to activate intrinsic oesophageal nerves was used to stimulate transverse muscle strips from the opossum oesophagus. This produced a contractile off-response from circular oesophageal muscle and a biphasic relaxation of the LES - an initial rapid relaxation (R1) and a slower sustained relaxation (R2). The effects on LES and oesophageal muscle of zaprinast (type V), zardaverine (type III/IV) and theophylline (non-specific) PDE inhibitors were explored. All three PDE inhibitors decreased LES tone and attenuated the off-response. Zaprinast and theophylline increased the latency of the off-response. Zaprinast prolonged R1, and slowed its recovery. It also increased the percentage relaxation of the second R2. Zardaverine increased the percentage relaxation of R2. Theophylline slowed the recovery of R2. PDEs play a role in maintaining LES tone and its recovery after LES relaxation. They may also modulate oesophageal motor activity.

Animals↗
PubMed2003

The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus.

Type 5 phosphodiesterase terminates the action of nitric oxide (NO) induced 3',5'-cyclic monophosphate (cGMP). Sildenafil inhibits this phosphodiesterase, increases cellular cGMP concentrations and enhances NO-induced smooth muscle relaxation. We investigated the effect of sildenafil on the oesophageal motor function of healthy subjects and patients with nutcracker oesophagus. Eight healthy volunteers and nine patients with nutcracker oesophagus participated in this study. The participants underwent oesophageal manometries on two separate days after either 20 mL of distilled water or 0.8 mg kg-1 sildenafil dissolved in 20 mL of water was infused into the stomach. Lower oesophageal sphincter (LOS) resting pressure, the duration of LOS relaxation and the amplitudes of oesophageal pressure waves were examined before, and 7.5, 15, 30 and 60 min after either placebo or sildenafil. In both healthy subjects and patients with nutcracker oesophagus, sildenafil decreased resting LOS pressure and the amplitude of peristaltic pressure waves at 3, 8 and 13 cm above LOS. Sildenafil also prolonged the duration of LOS relaxation. It had no effect on the velocity of peristalsis or the amplitude of peristaltic pressure waves 18 cm above LOS. Sildenafil may be considered as an alternative treatment in nutcracker oesophagus although there are several limitations to be overcome.

Adult↗
PubMed2001

Lipopolysaccharide temporarily impairs sphincter of Oddi motility.

The aim of our study was to determine the effect of lipopolysaccharide (LPS) on sphincter of Oddi (SO) motility. Opossums received saline, Escherichia coli LPS (1.0 mg/kg), or E. coli LPS (1.0 mg/kg) and aminoguanidine (50 mg/kg), and the SO was removed 6-24 h later. At 12 h LPS decreased electrical field stimulation (EFS)-induced relaxation and increased baseline tone. These changes were reversed when the animals were pretreated with aminoguanidine. The dose-dependent decrease in EFS-induced relaxation by N(omega)-nitro-l-arginine was impaired after LPS, but not in animals that received LPS and aminoguanidine. The impaired EFS-induced relaxation after LPS was reversed when l-arginine was added to the tissue bath. Serum levels of NO(-)(2)/NO(-)(3) were increased with LPS as compared to saline or both LPS and aminoguanidine. Inducible nitric oxide synthase mRNA was readily seen in SO segments after LPS. LPS impairs EFS-induced relaxation and increases baseline tone of the SO. The effects of LPS on SO motility appear to be mediated by nitric oxide.

Animals↗
PubMed2001

Practical approaches to dysphagia caused by esophageal motor disorders.

Dysphagia is a common symptom with which patients present. This review focuses primarily on the esophageal motor disorders that result in dysphagia. Following a brief description of the normal swallowing mechanisms and the messengers involved, more specific motor abnormalities are discussed. The importance of achalasia, as the only pathophysiologically defined esophageal motor disorder, is discussed in some detail, including recent developments in pathogenesis and treatment options. Other esophageal spastic disorders are described, with relevant manometric tracings included. In recent years, the importance of gastroesophageal reflux as a primary cause of esophageal dysmotility has been recognized, and this is also discussed. In addition, the motility disturbances that develop after surgical fundoplication are reviewed.

Deglutition Disorders↗
PubMed2001

Effect of peroxynitrite on motor function of the opossum esophagus.

Nitric oxide (NO*) is a mediator of esophageal motility. Esophageal dysmotility accompanies esophagitis. During inflammation, superoxide and NO* form peroxynitrite (ONOO-), a reactive molecule that alters cellular function. We tested the hypotheses that ONOO- affects esophageal motility and is produced in association with esophagitis. Transverse muscle strips from the opossum esophagus were stimulated by an electrical field, and nitrotyrosine immunoblots were performed. Peroxynitrite, its decomposed form, or NaNO2 relaxed the lower esophageal sphincter (LES) and attenuated the off response. These effects were inhibited by oxyhemoglobin (Hgb). An antagonist of guanylate cyclase, 1H[1,2,4]oxadiazole[4,3]quinoxalin-1-one (ODQ), inhibited the LES relaxation produced by ONOO-. Nitrotyrosine, a footprint for ONOO- production, was detected in inflamed esophagus. These studies support the hypotheses that ONOO alters esophageal motor function and is formed in association with esophagitis. It is possible that some of the esophageal motor dysfunction seen with esophagitis may be related to the formation of ONOO-.

Animals↗
PubMed2000

Characterization of the off response to electrical field stimulation in gallbladder smooth muscle.

BACKGROUND: Low-frequency electrical stimulation of intramural nerves of gut smooth muscle produces an "off response," that is, a contraction that occurs after electrical field stimulation (EFS) of the intramural nerves is stopped. The off response coincides with a depolarization of the muscle following an EFS-induced hyperpolarization of that muscle. The aims of our study were to determine if the off response is present in gallbladder smooth muscle and to determine the mechanisms involved in this nerve-mediated response. MATERIALS AND METHODS: Gallbladder strips from opossums were placed in Krebs solution and passed through bipolar ring electrodes for EFS of intramural nerves, and isometric force measurements were recorded. Dose-response curves were determined with N(G)-nitro-L-arginine (L-NNA) a competitive inhibitor of nitric oxide (NO) synthase; 1H-¿1,2,4ŏxadiazolol¿4, 3aquinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase; and oxyhemoglobin, a scavenger of nitric oxide. RESULTS: A contraction termed the off response occurred shortly after EFS ended. The off response was abolished with tetrodotoxin and atropine. The amplitude of the off response increased with increasing voltage. The amplitude of the off response decreased by 41% with L-NNA 1.5 mM. Preincubation of the tissue with L-arginine (1 mM) prevented the inhibition of amplitude seen with L-NNA. The amplitude of the off response decreased by 43% with oxyhemoglobin (40 microM) and by 56% with ODQ (250 microM). CONCLUSION: We conclude that the off response is present in gallbladder smooth muscle after low-frequency EFS. NO may be a mediator of this off response and of nonadrenergic noncholinergic responses in gallbladder smooth muscle.

Animals↗
PubMed2000

Effect of endotoxin on opossum oesophageal motor function.

Endotoxin induces nitric oxide (NO*) synthase and alters gastrointestinal functions. We explored the effect of lipopolysaccharide (LPS) on oesophageal motor function at 6, 12, 24, and 48 h. The effects of inhibiting inducible NO* synthase (iNOS) were studied 12 h after administration of LPS with/without aminoguanidine (AG). Oesophageal manometry was performed and tissue bath studies were performed with muscle strips from the oesophagus and lower oesophageal sphincter (LOS). Plasma nitrite/nitrate concentrations were determined. The amplitudes of peristaltic pressure waves, resting LOS pressure and the percentage LOS relaxations were diminished by LPS. AG attenuated the decrease in amplitude of oesophageal pressure waves, LOS pressure, and percentage relaxation of LOS brought about by LPS. LPS decreased electrical field stimulation (EFS)-induced relaxation of LOS muscle. AG attenuated this decrease in LOS relaxation. The off-response of transverse oesophageal muscle strips was decreased, and AG antagonized this effect. Plasma concentrations of nitrite/nitrate were increased. The increase in plasma nitrite/nitrate was attenuated by AG. These studies support the hypothesis that endotoxin modulates oesophageal motor function by increasing NO production and suggest that this results from the induction of iNOS.

Animals↗
PubMed2000

Effect of endotoxin on opossum gallbladder motility: a model of acalculous cholecystitis.

OBJECTIVE: To determine whether endotoxin causes histologic changes in the gallbladder consistent with acalculous cholecystitis, and to determine the effects of endotoxin on gallbladder motility. SUMMARY BACKGROUND DATA: Acute acalculous cholecystitis is frequently seen in critically ill, septic patients, after prolonged fasting and gallbladder stasis. The pathogenesis of acalculous cholecystitis is unknown; however, previous studies have suggested that ischemia may play a role. METHODS: Adult opossums received Escherichia coli lipopolysaccharide. The gallbladder was removed for histologic examination or for physiologic studies 4 hours to 2 weeks later. For histologic examination, gallbladder strips underwent standard hematoxylin-and-eosin processing. For physiologic studies, they were mounted in a tissue bath to determine responses to cholecystokinin octapeptide or electrical field stimulation. RESULTS: Intravenous endotoxin at a dose of 0.005 mg/kg resulted in disrupted mucosal surfaces and areas of hemorrhage; higher doses of endotoxin resulted in coagulation necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult. Endotoxin abolished the contractile response to cholecystokinin octapeptide in gallbladder strips 4 hours after endotoxin administration. The 0.005-mg/kg dose of endotoxin decreased the contractile response to cholecystokinin octapeptide for up to 96 hours after endotoxin administration and decreased the contractile response to electrical field stimulation for 48 hours after administration. Inhibition of nitric oxide synthase reversed the decreased contractile response to cholecystokinin octapeptide. CONCLUSIONS: Endotoxin causes an ischemic insult to the gallbladder similar to that seen in acalculous cholecystitis. Also, endotoxin may lead to gallbladder stasis by decreasing gallbladder contractile responses to hormonal and neural stimuli.

Animals↗
PubMed2000

Role of cGMP as a mediator of nerve-induced motor functions of the opossum esophagus.

Stimulation of esophageal nerves produces biphasic relaxation of the lower esophageal sphincter (LES) and an off response of circular esophageal muscle. Previously, we proposed that cGMP mediates nerve-induced hyperpolarization of circular LES muscle but not LES relaxation. These experiments explore whether cGMP mediates LES relaxation or the off response. Strips of muscle from the opossum esophagus and LES were connected to force-displacement transducers, placed in tissue baths containing oxygenated Krebs solution at 37 degrees C, and stimulated by an electrical field. 1H-[1,2, 4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of guanylyl cyclase, antagonized the off response, shortened its latency, and blocked the first phase of LES relaxation. ODQ also antagonized LES relaxation by exogenous nitric oxide (NO) but not relaxations by vasoactive intestinal polypeptide (VIP). Part of the nerve-induced LES relaxation and the off response appear to be mediated by the second messenger cGMP. These studies indicate that VIP-induced LES relaxation is not mediated by cGMP and therefore do not support the hypothesis that VIP produces LES relaxation by causing the generation of NO.

Animals↗
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↗
PubMed1999

The role of antioxidant enzymes in the control of opossum gallbladder motility.

BACKGROUND: 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 gallbladder and to localize the antioxidant enzymes in the gallbladder. MATERIALS AND METHODS: Immunostaining and immunoblots were performed and enzyme activities were measured in the gallbladder. In physiologic experiments, force-displacement transducers recorded tension in gallbladder muscle strips. Superoxide was generated by the addition of xanthine with xanthine oxidase, while superoxide radicals were scavenged by the addition of superoxide dismutase (SOD) and catalase. SOD was inhibited by deithyldithiocarbamate. RESULTS: Immunostaining demonstrated superoxide dismutase and catalase immunoreactivity in ganglia situated throughout the smooth muscle. Total superoxide dismutase activity was 115 +/- 12 U/mg. Western blots detected expression of proteins of 19.4 kDa for copper/zinc SOD and 25.0 kDa for manganese SOD. Generation of superoxide increased isometric tension, while pretreatment with SOD prevented the increase in isometric tension induced by superoxide. Inhibition of SOD diminished the EFS-induced off response. CONCLUSIONS: We conclude that superoxide alters gallbladder motor function, and the presence of superoxide scavenging enzymes in enteric plexuses suggests that they may regulate gallbladder neuromuscular function by clearing endogenous superoxide.

Animals↗
PubMed1999

Neuromuscular control of esophageal peristalsis.

The esophagus is a muscular conduit connecting the pharynx and the stomach. Its function is controlled by an intrinsic nervous system and by input from the central nervous system through the vagus nerve. Peristalsis in its striated muscle is directed by sequential vagal excitation arising in the brain stem, whereas peristalsis in its smooth muscle involves complex interactions among the central and peripheral neural systems and the smooth muscle elements of the esophagus. The peripheral neuronal elements responsible for producing esophageal off-response, relaxation of the lower esophageal sphincter, and hyperpolarization of the circular esophageal muscle cells reside in the myenteric plexus of the esophagus. For many years these nerves were considered nonadrenergic and noncholinergic because the inhibitory neurotransmitter released on their activation was unknown. We now know that nitric oxide or a related compound is that inhibitory neurotransmitter. The primary excitatory neurotransmitter controlling esophageal motor function is acetylcholine. Some disorders of esophageal motor function, including diffuse esophageal spasm and achalasia, may result from defects in or an imbalance between these excitatory and inhibitory neuromuscular systems.

Acetylcholine↗
PubMed1999

Manometric tests of anorectal function in healthy adults.

OBJECTIVE: Although tests of anorectal function are useful in the assessment of defecation disorders, there is inadequate and inconsistent information regarding normative data. Also, there are discrepancies in manometric techniques and data interpretation. Our aim was to perform a comprehensive evaluation of anorectal function in healthy adults. METHODS: We used a 6-mm diameter probe containing six radially arrayed microtransducers, and a 4-cm-long latex balloon for performing anorectal manometry in 45 healthy subjects who were controlled for gender and age. Sequentially, subjects were asked to squeeze, bear down, or blow up a party balloon. Subsequently, rectal sensation, rectal compliance, and rectoanal reflexes were assessed simultaneously by performing intermittent phasic balloon distentions. Additionally, balloon defecation, pudendal nerve latency, and saline continence tests were performed. RESULTS: In men, the anal sphincter was longer (p < 0.05) and squeeze sphincter pressure and squeeze duration were higher (p < 0.01), but resting sphincter pressure was similar to that in women. When bearing down, although not significant, the defecation index was higher in men. Distinct thresholds for rectal sensation were identified but there was no gender difference. Likewise, rectal compliance and balloon expulsion time were similar. However, during saline infusion, the onset of first leak and total volume retained were higher (p < 0.001) and pudendal nerve latency was shorter (p < 0.05) in men. Overall, parity or age did not influence anorectal function. CONCLUSIONS: This study represents the most comprehensive age- and gender-controlled assessment of anorectal function using solid state technology. Gender influences some parameters of anorectal function. Our results could serve as a valuable resource of normative data.

Action Potentials↗
PubMed1999

Biphasic relaxation of the opossum lower esophageal sphincter: roles of NO., VIP, and CGRP.

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO.) are thought to mediate lower esophageal sphincter (LES) relaxation. Transverse muscle strips from the opossum LES were used to test this hypothesis. Electrical field stimulation (EFS) produced a biphasic LES relaxation: a rapid component during the stimulus was more prominent at lower stimulus frequencies, and a sustained component was more prominent at higher frequencies. N(omega)-nitro-L-arginine and hemoglobin inhibited the rapid component but affected the sustained component less. Exogenous VIP decreased LES tone. A number of purported VIP antagonists blocked neither VIP-induced nor EFS-induced relaxation of the LES. The calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) did not alter EFS-induced LES relaxation. EFS-induced relaxation of opossum LES muscle is biphasic, and the initial, rapid component of the relaxation is mediated primarily by NO. The mediator of the sustained component was not identified.

Animals↗
PubMed1999

Effects of endotoxin on regulation of intestinal smooth muscle nitric oxide synthase and intestinal transit.

BACKGROUND: The disrupted intestinal transit during endotoxemia may be mediated by nitric oxide (NO). We hypothesized that the isoforms of nitric oxide synthase (NOS) are up-regulated in intestinal smooth muscle during endotoxemia and that the scavenging of NO will normalize transit. METHODS: Rats were given Escherichia coli lipopolysaccharide (LPS) 10 mg/kg intravenously and were killed 4 hours later. To determine the activity of NOS isoforms in the jejunum and ileum, the conversion of tritiated L-arginine to tritiated L-citrulline was measured. Western immunoblots were performed by incubating the extracted protein with specific polyclonal antibodies. To determine intestinal transit, rats were divided into 4 groups: 0.9% sodium chloride 1 mL/h intravenously for 5 hours, LPS 10 mg/kg intravenous bolus plus 1 mL/h 0.9% sodium chloride intravenously, LPS plus oxyhemoglobin 0.5 g/kg/h intravenously, and oxyhemoglobin 0.5 g/kg/h intravenously. RESULTS: LPS increased the constitutive and inducible NOS enzyme activities in the jejunum and ileum. Western blots demonstrated that LPS up-regulates both the NOS1 and NOS2 isoforms in jejunal and ileal smooth muscle. Oxyhemoglobin alone increased intestinal transit compared with controls, whereas endotoxemia increased intestinal transit, which was ameliorated with infusions of oxyhemoglobin. CONCLUSIONS: NO may play a major role in mediating the rapid intestinal transit induced by endotoxemia.

Animals↗