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J Rhodes

Publications and source records attributed to J Rhodes.

At least 19 recordsLinked to original sources
PubMed2005

Plasma fibrinogen in ulcerative colitis: the effect of disease activity and nicotine therapy in a randomised controlled trial.

BACKGROUND: Smoking increases plasma fibrinogen and cardiovascular risk whereas transdermal nicotine may not. Fibrinogen is an acute phase protein and may reflect disease activity in ulcerative colitis. AIMS: To examine the effect of topical nicotine on plasma fibrinogen and any relationship between fibrinogen and ulcerative colitis disease activity. PATIENTS: Forty-eight non-smokers with moderately active ulcerative colitis. METHODS: Patients were randomised to 6 mg nicotine enema or placebo for 6 weeks, followed by open nicotine therapy for 4 weeks. Plasma fibrinogen was measured at baseline and after 6 and 10 weeks; at each assessment sigmoidoscopy with a rectal biopsy was performed. RESULTS.: At 6 weeks median plasma fibrinogen was 3.30 g/l on nicotine compared to 3.05 g/l on placebo, P = 0.90 when adjusted for baseline values. There was a correlation between fibrinogen and the UC disease activity index (UCDAI) at weeks 0 and 10, P = 0.036 and 0.033, respectively, and between fibrinogen and sigmoidoscopic grade at each assessment, P = 0.014, 0.021 and 0.034. Changes in fibrinogen did not correlate with changes in disease severity. CONCLUSIONS: There was no significant effect of nicotine enemas, in either direction, on plasma fibrinogen-this was raised in moderately active UC and correlated with the sigmoidoscopic grade of colitis and the UCDAI; however, fibrinogen was not sufficiently sensitive to be of practical clinical value.

Colitis, Ulcerative↗
PubMed2005

Comparative study of enema retention and preference in ulcerative colitis.

BACKGROUND: Therapeutic enemas are often used to treat active colitis but their retention may be limited because of urgency to defecate. Some preparations may be better retained and tolerated than others because of their physical properties. AIM: To compare patient preference and retention of four therapeutic enemas, including a nicotine enema, in patients with ulcerative colitis (UC). METHODS: Twenty four patients with active UC received the four trial enemas-corticosteroid, 5-amino salicylate (5-ASA), and nicotine liquid enemas and a corticosteroid foam, in a randomised order, taking one enema on each of four successive nights. Patients scored them 1 to 4 for ease of administration and retention, degree of abdominal bloating, and for their overall preference. RESULTS: Fifteen patients rated nicotine their overall favourite or second favourite, compared with 14 for corticosteroid foam and 11 for 5-ASA and corticosteroid liquids, but this was not significant (p = 0.302). Overall, there was no significant difference in overnight retention. However, the nicotine enema tended to be less well retained in patients with milder urgency but a higher proportion retained it overnight with more severe urgency (p = 0.031 compared with 5-ASA enema). CONCLUSION: There was no significant difference in patient preference or overall duration of retention for the four enemas.

Adrenal Cortex Hormones↗
PubMed2004

Nicotine enemas for treatment of ulcerative colitis: a study of the pharmacokinetics and adverse events associated with three doses of nicotine.

BACKGROUND: Transdermal nicotine is of value in active ulcerative colitis but causes adverse events because of systemic absorption. Nicotine enemas may give rise to fewer adverse events. AIM: To assess the pharmacokinetics of nicotine enemas in three doses. METHODS: Thirteen volunteers, all non-smokers but three ex-smokers, were given enemas on separate occasions containing 3, 6 and 9 mg of nicotine, in ascending dose order. Adverse events were recorded and blood samples taken over 8 h for measurement of serum nicotine and cotinine. RESULTS: Enemas were retained by most subjects. Eleven of 14 adverse events were 'early'--30-105 min after the enema, corresponding to maximum plasma nicotine concentrations; three events were later, 4-8 h after the enema and unrelated to the tmax. 'Early' adverse events occurred in eight subjects--six with 9 mg. The three highest plasma nicotine concentrations were with 9 mg and associated with headache, nausea and sweating. Only one had adverse events with 3 mg and withdrew from the study. Nicotine Cmax with 6 and 9 mg doses were respectively two and three times the value with 3 mg. Peak nicotine concentrations occurred 44-50 min after the enema. CONCLUSION: The 6 mg dose of nicotine probably represents the dose to use in clinical practice - for the highest therapeutic dose with a low risk of adverse events.

Adult↗
PubMed2004

Differential effect of nitric oxide synthase inhibition on sigmoid colon longitudinal and circular muscle responses to nicotine and nerve stimulation in vitro.

BACKGROUND: Nicotine has been shown to release nitric oxide from nerves in human sigmoid colon. This effect has been used to investigate the innervation and functional relationship of the longitudinal and circular muscle layers. METHODS: Strips of longitudinal and circular muscle were obtained from 19 patients with colorectal cancer. The strips from ten patients were subjected to electrical field stimulation (EFS) in vitro using stimulus parameters for selective stimulation of nerves. The effect of nicotine 1-10 micromol/l on EFS responses was then measured in the presence and absence of a nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME) 200 micromol/l. The effect of nicotine on spontaneous activity was investigated in the muscle strips from the other nine patients. RESULTS: Both longitudinal and circular strips responded to EFS with contraction. The time to achieve a peak contractile response (time to peak; TTP) was significantly longer (P<0.001) in circular strips. L-NAME reduced the mean(s.e.m.) TTP in circular muscle from 23.3(2.0) to 17.2(1.5) s (P=0.007) and altered its pattern of response to resemble that of longitudinal muscle. Nicotine 10 micromol/l reduced the contraction to EFS in circular (P<0.001) but not in longitudinal (P=0.347) muscle. The nicotine-induced reduction in circular muscle contraction was blocked by L-NAME 200 micromol/l (P=0.005). CONCLUSION: These findings suggest that nitric oxide release on neural stimulation is greater in circular than in longitudinal muscle.

Colon, Sigmoid↗
PubMed2003

Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a disease largely of non-smokers, in which nicotine is of therapeutic value. The mode of action is unknown, but may involve nicotinic acetylcholine receptors (nAChRs) in the bowel wall. AIM: To investigate the presence of nAChRs in rectal mucosa, and the effect of smoking and nicotine on their expression. DESIGN: Prospective case-control study. METHODS: In situ hybridization (ISH) and immunocytochemistry (ICC) were used to show alpha3 nAChRs in colonic mucosa. Rectal mucosa was examined from controls (n=55) and patients with inactive UC (n=62), both smokers and non-smokers, by ICC, using two antibodies to show the density and distribution of receptors in the mucosa. Non-smokers with UC (n=43) were given transdermal nicotine or placebo patches for 6 months, and rectal biopsies, taken before and after treatment, were examined by ICC to show nAChRs. RESULTS: In normal colon, ISH and ICC showed alpha3 subunit in a wide variety of cells, including mucosal epithelium. In rectal biopsies, neither smoking nor nicotine influenced the expression of alpha3 immunoreactivity in epithelium, either in controls or UC. However, controls had a significantly greater density of immunodetectable mucosal epithelium alpha3 subunit, compared with UC patients. DISCUSSION: The presence of nAChRs in colonic epithelium may be pertinent to the beneficial effect of nicotine in UC, but since neither smoking nor nicotine treatment is associated with any change in the expression of epithelial alpha3 nAChRs, the effect may be due to functional changes in the receptor. The decreased number of alpha3 nAChRs in UC compared with controls may be related to an increased cell turnover in UC.

Administration, Cutaneous↗
PubMed2002

Naloxone treatment for irritable bowel syndrome--a randomized controlled trial with an oral formulation.

BACKGROUND: Opioids change gut motility and secretion, causing delayed intestinal transit and constipation. Endorphins play a role in the constipation troubling some patients with irritable bowel syndrome; hence naloxone, an opioid antagonist, may have a therapeutic role. AIM: To assess the efficacy and safety of an oral formulation of naloxone in irritable bowel syndrome patients with constipation. METHODS: A randomized, double-blind, placebo-controlled trial was performed. Patients fulfilling the Rome II criteria for irritable bowel syndrome (constipation-predominant and alternating types) were randomized to receive 8 weeks of treatment with naloxone capsules, 10 mg twice daily, or identical placebo. RESULTS: Twenty-eight patients entered the study, which was completed by 25. 'Adequate symptomatic relief' was recorded in six of 14 on naloxone and three of 11 on placebo. Whilst the differences were not significant, improvements in severity gradings and mean symptom scores for pain, bloating, straining and urgency to defecate were greater with naloxone than placebo for all parameters. In addition, quality of life assessments improved to a greater extent in patients taking naloxone. CONCLUSIONS: Preliminary results suggest that naloxone is well tolerated and beneficial in patients with irritable bowel syndrome and constipation. A larger clinical trial is needed to provide sufficient statistical power to assess efficacy.

Administration, Oral↗
PubMed2002

Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.

AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.

Acute Disease↗
PubMed2001

Immediate and six-month results of the profile of the Amplatzer septal occluder as assessed by transesophageal echocardiography.

Catheter closure of secundum atrial septal defect (ASD) using the Amplatzer septal occluder (ASO) is a potential alternative for open surgical repair. However, the large profile of the device obtained immediately after closure continues to raise some concerns regarding its long-term safety. To evaluate the changes in the profile of the device after being deployed, transesophageal echocardiography was performed in 70 patients (17 men and 53 women) who underwent catheter closure of ASDs immediately after and at 6-month follow-up. The median age at closure was 16 years (range 1.9 to 75) and the median size of the ASD as assessed by transesophageal echocardiography was 14 mm (range 3 to 25). The thickness (profile) of the device was assessed in the 4-chamber, short- and long-axis views of the interatrial septum, and measured at its middle and at the junction of the waist with the disc at its 2 ends. Seventy-three devices were deployed in the 70 patients. The median size of the device was 19 mm (range 8 to 34). Complete closure was achieved in 81.4% and 91.4% immediately after and at 6-months follow-up, respectively. The thickness of the device at its middle decreased from 12.2 +/- 4.3, 12.2 +/- 3.7, and 12.5 +/- 4.3 mm in the 4-chamber, short- and long-axis views to 6.5 +/- 2.0, 6.3 +/- 1.9, and 6.5 +/- 2.2 mm, respectively. The thickness of the device at its superior, inferior, anterior, and posterior edges also decreased by 41.8% +/- 14.0% to 43.7% +/- 9.8%. The changes in the thickness were related to device size. Larger devices were thicker after being deployed. We conclude that the thickness of the ASO decreases by 42% to 48% within 6 months after deployment, resulting in a lower profile.

Adolescent↗
PubMed2001

Myelopoiesis in the zebrafish, Danio rerio.

Genome-wide chemical mutagenesis screens in the zebrafish (Danio rerio) have led to the identification of novel genes affecting vertebrate erythropoiesis. In determining if this approach could also be used to clarify the molecular genetics of myelopoiesis, it was found that the developmental hierarchy of myeloid precursors in the zebrafish kidney is similar to that in human bone marrow. Zebrafish neutrophils resembled human neutrophils, possessing segmented nuclei and myeloperoxidase-positive cytoplasmic granules. The zebrafish homologue of the human myeloperoxidase (MPO) gene, which is specific to cells of the neutrophil lineage, was cloned and used to synthesize antisense RNA probes for in situ hybridization analyses of zebrafish embryos. Granulocytic cells expressing zebrafish mpo were first evident at 18 hours after fertilization (hpf) in the posterior intermediate cell mass (ICM) and on the anterior yolk sac by 20 hpf. By 24 hpf, mpo-expressing cells were observed along the ICM and within the developing vascular system. Thus, the mpo gene should provide a useful molecular probe for identifying zebrafish mutants with defects in granulopoiesis. The expression of zebrafish homologues was also examined in 2 other mammalian hematopoietic genes, Pu.1, which appears to initiate a commitment step in normal mammalian myeloid development, and L-Plastin, a gene expressed by human monocytes and macrophages. The results demonstrate a high level of conservation of the spatio-temporal expression patterns of these genes between zebrafish and mammals. The morphologic and molecular genetic evidence presented here supports the zebrafish as an informative model system for the study of normal and aberrant human myelopoiesis. (Blood. 2001;98:643-651)

Amino Acid Sequence↗
PubMed2001

Altered subcellular distribution of transcriptional regulators in response to Abeta peptide and during Alzheimer's disease.

Recent studies have shown that various cell cycle proteins are expressed in post-mitotic neurons within affected brain regions during Alzheimer's disease (AD). Cell cycle proteins have been proposed to function in mechanisms of neuronal cell death during AD. To further explore the role of cell cycle proteins in neurodegeneration associated with AD, we utilized PC12 cells to examine the subcellular distribution of cell cycle transcriptional regulators, including the retinoblastoma gene product (pRb), E2F1 and FAC1, during beta-amyloid (Abeta)-induced neurodegeneration. Moreover, we examined the immunolocalization of pRb and E2F1 in non-demented control and AD brain tissue. We found that pRb exhibited increased levels of Ser795 phosphorylation in response to Abeta in the nucleus of PC12 cells and also in the nucleus of a subset of neurons during AD. E2F1 was distributed throughout the cytoplasm and neurites of PC12 cells in response to Abeta and in the cytoplasm of cells in AD brain. FAC1 exhibited a rapid redistribution from the cytoplasm to the perinuclear region in PC12 cells treated with Abeta. These data indicate that altered phosphorylation and subcellular distribution of transcriptional regulators occur in response to Abeta-induced neurotoxicity and during AD.

Adult↗
PubMed2001

Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine.

INTRODUCTION: Constipation is a common side-effect of opioid therapy; in addition to their analgesic effect, opioids reduce intestinal secretion and motility with an increase in whole-gut transit time. Naloxone, a specific opioid antagonist, reverses these effects but may also cause symptoms of opioid withdrawal in patients on long-term therapy. AIM: To use an enteric-release formulation, designed to produce a topical effect in the gut, with minimum systemic effects. METHODS: Naloxone 10 mg b.d. and codeine 30 mg b.d. were used with identical placebo capsules in four sets of studies; 12 male volunteers were given the drugs alone and in combination, with a control study involving double placebo, during each of four study periods. Whole-gut transit time was calculated and compared for each treatment period. RESULTS: Naloxone, both alone and with codeine, significantly shortened the mean whole-gut transit time compared with the control period, respectively, from 53.1 to 42.1 h (P=0.005) and to 40.7 h (P=0.024). Urgency to defecate was reported by two volunteers on naloxone alone and by three on combination therapy. CONCLUSIONS: The results show that the naloxone formulation counteracts the effect of codeine on intestinal transit, suggesting that it may have useful clinical applications.

Administration, Oral↗
PubMed2001

Enteric-release glyceryl trinitrate in active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Mucosal ischaemia may contribute to the pathogenesis of Crohn's disease. Microvascular abnormalities have been found in colonic resection specimens, and mucosal levels of constitutive nitric oxide synthase are reduced. AIM: To assess the efficacy of a novel, enteric-release formulation of the nitric oxide donor, glyceryl trinitrate, aimed at increasing the mucosal circulation and relaxing smooth muscle in the affected bowel. METHODS: The trial was randomized, double-blind and placebo-controlled. Baseline disease activity was assessed by a structured symptom diary, with blood tests and a quality of life assessment. Patients with a Crohn's disease activity index of > or = 150 and < 450 were randomized to receive 12 weeks of either glyceryl trinitrate (initially 6 mg twice daily, increasing to 9 mg twice daily after 6 weeks) or an identical placebo. Assessments were repeated at 6 and 12 weeks. RESULTS: Seventy patients (22 male) entered the study; 34 were given glyceryl trinitrate and 36 placebo. At 12 weeks, there were no differences between the treatment groups in terms of Crohn's disease activity index, pain, stool frequency, inflammatory markers or quality of life scores. CONCLUSIONS: Enteric-release glyceryl trinitrate did not benefit patients with mild to moderately active Crohn's disease. Whilst ischaemia may contribute to the pathogenesis of Crohn's disease, our results fail to provide supportive evidence for this hypothesis.

Administration, Oral↗
PubMed2001

Schiff base-mediated co-stimulation primes the T-cell-receptor-dependent calcium signalling pathway in CD4 T cells.

In addition to macromolecular interactions that provide co-stimulation during antigen-presenting cell (APC) and CD4+ T-cell conjugation, covalent chemical events between specialized ligands have been implicated in T-cell co-stimulation. These take the form of transient Schiff base formation between carbonyls and amines expressed on APC and T-cell surfaces. Small Schiff base-forming molecules, such as tucaresol, can substitute for the physiological donor of carbonyl groups and provide co-stimulation to T cells, thereby functioning as orally active immunopotentiatory drugs. The Schiff base co-stimulatory pathway in T cells has been partially characterized in terms of changes in Na+ and K+ transport, and activation of the mitogen activated protein kinase (MAPK) ERK2. In the present study, the effects of Schiff base co-stimulation by tucaresol on the T-cell receptor (TCR)-dependent pathway leading to Ca2+ release were investigated. Schiff base co-stimulation by tucaresol was found to prime for enhanced TCR-dependent phospholipase C-gamma phosphorylation, inositol 1,4,5-triphosphate production, and Ca2+ mobilization that correlated with functional enhancement of interleukin-2 production in primary T cells. The effects on Ca2+ occurred comparably in Jurkat and primary CD4+ T cells responding to anti-CD3 monoclonal antibody. Enhancement of the Ca2+ response required a 10-min priming period and was prevented by prior covalent ligation of cell-surface free amino groups by sulpho-N-hydroxy succinimido-biotin; clofilium-mediated inhibition of tucaresol-induced changes in intracellular K+; and selective inhibition of the MAPK pathway. The data are consistent with a priming mechanism in which late co-stimulation-triggered events exert a positive influence on early TCR-triggered events. In additional studies of murine T cells expressing trans-gene TCRs, tucaresol was likewise shown to prime for enhanced Ca2+ mobilization in response to physiological TCR-engagement by MHC-peptide complexes.

Amines↗
PubMed2001

Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit.

BACKGROUND & AIMS: The megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disease of childhood that presents early with intestinal hypoperistalsis, hydronephrosis, and hydroureters. Transgenic mice that lack the alpha3 subunit containing nicotinic acetylcholine (nAChR) have a phenotype similar to that of MMIHS. METHODS: We examined the expression of this subunit in control and MMIHS tissue derived from patients using in situ hybridization (ISH) and immunocytochemistry (ICC). RESULTS: In controls, both techniques showed a wide distribution of alpha3 nAChRs present in ganglion cells, muscle, and epithelium. By contrast, most MMIHS tissue gave negative staining with ISH and variable results with ICC. CONCLUSIONS: These observations are consistent with a lack of alpha3 nAChRs contributing to the pathogenesis of MMIHS.

Abnormalities, Multiple↗
PubMed2001

Atrial natriuretic peptide blockade exacerbates high altitude pulmonary edema in endotoxin-primed rats.

High altitude pulmonary edema (HAPE) is associated with increases in pulmonary arterial and hydrostatic pressures and an increase in pulmonary vascular permeability. There is evidence to suggest that inflammatory mediators may cause some forms of HAPE, and Salmonella enteritidis endotoxin (ETX) is known to activate neutrophils and inflammatory mediators, such as TNF-alpha and IL1-beta. Since HAPE has been produced in rats primed with ETX, we hypothesized that ANP release and action may ameliorate HAPE and that ANP blockade may exacerbate HAPE in ETX-primed rats exposed to high altitude (HA). Plasma ANP, right atrial ANP mRNA, and indexes of lung injury were measured in rats primed with endotoxin (ETX) (0.1 mg/kg BW, i.p.) and exposed to simulated HA (4267 m; P(B) = 440 mmHg) for either 12 or 24 h. Catheters were chronically inserted into the right carotid artery, pulmonary artery, and jugular vein for assessment of hemodynamic parameters in response to ETX and/or HA. In addition, some rats were injected with an antibody against ANP (alphaANP) prior to normoxic (NX) or HA exposure. Pulmonary arterial pressure increased in the alphaANP group (50 +/- 20%; p < or = 0.05) and in the HA + alphaANP (51 +/- 15%; p < or = 0.05) group at 12 h compared to NX sham rats injected with normal rabbit serum. In addition, systemic arterial pressure was significantly lower in the HA + ETX rats compared to HA + ETX + alphaANP rats (p < or = 0.001). Plasma ANP levels were significantly higher at 12 and 24 h in ETX, HA, and HA + ETX groups (p <or = 0.05) compared to NX controls. There was an inverse relationship (p <or = 0.001) between plasma ANP levels and lung wet to dry (W/D) weight when data from NX, ETX, HA, and HA + ETX groups were pooled. The HA + alphaANP rats had significantly higher lung W/D ratios (p < 0.001) compared to sham rats. These results support the hypothesis that ANP, at physiological levels, modulates the development of pulmonary edema in HA-exposed ETX-primed rats.

Altitude Sickness↗
PubMed2001

Role of vascular smooth muscle in the development of high altitude pulmonary hypertension: an interspecies evaluation.

There is a marked variability in the degree of pulmonary hypertension induced by long-term exposure to altitudes above 3000 m among low altitude species, ranging from hyporesponders (sheep and dogs) to hyper-responders (cattle and pigs). The amount of inherent muscularization of small pulmonary arteries appears to be a determinant of this hypertensive response, as does the presence or absence of collateral ventilation. Hyper-responders also exhibit marked pulmonary vascular hypertrophy when exposed to long-term hypoxia. Humans exhibit similar inter- and intra-population variability. Animal species indigenous to high altitudes exhibit less variable, attenuated pulmonary hypertensive responses with little pulmonary vascular hypertrophy. This attenuated response is also apparent among human high altitude populations, particularly in Andean and Tibetan populations. Thus, successful adaptation to high altitudes is evident in species that do not sustain the acute cardiopulmonary compensations that occur upon initial exposure to high altitude.

Altitude↗
PubMed2001

Elevating dietary salt exacerbates hyperpnea-induced airway obstruction in guinea pigs.

Previous studies have indicated that increased dietary salt consumption worsens postexercise pulmonary function in humans with exercise-induced asthma (EIA). It has been suggested that EIA and hyperpnea-induced airway obstruction (HIAO) in guinea pigs (an animal model of EIA) are mediated by similar mechanisms. Therefore, the purpose of this study was to determine whether altering dietary salt consumption also exacerbated HIAO in guinea pigs. Furthermore, the potential pathway of action of dietary salt was investigated by blocking leukotriene (LT) production during HIAO in guinea pigs. Thirty-two male Hartley strain guinea pigs were split into two groups. One group (n = 16) of animals ingested a normal-salt diet (NSD) for 2 wk; the other group (n = 16) ingested a high-salt diet (HSD) for 2 wk. Thereafter, animals were anesthetized, cannulated, tracheotomized, and mechanically ventilated during a baseline period and during two dry gas hyperpnea challenges. After the first challenge, the animals were administered either saline or nordihydroguaiaretic acid, a LT inhibitor. Bladder urine was analyzed for electrolyte concentrations and urinary LTE(4). The HSD elicited higher airway inspiratory pressures (Ptr) than the NSD (P < 0.001) postchallenge. However, after infusion of the LT inhibitor and a second hyperpnea challenge, HIAO was blocked in both diet groups (P < 0.001). Nonetheless, the HSD group continued to demonstrate slightly higher Ptr than the NSD group (P < 0.05). Urinary LTE(4) excretion significantly increased in the HSD group compared with the NSD group within treatment groups. This study has demonstrated that dietary salt loading exacerbated the development of HIAO in guinea pigs and that LT release was involved in HIAO and may be moderated by changes in dietary salt loading.

Airway Obstruction↗