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Biomedical subjects

A J Page

Publications and source records attributed to A J Page.

At least 19 recordsLinked to original sources
PubMed2005

Inhibition of mechanosensitivity in visceral primary afferents by GABAB receptors involves calcium and potassium channels.

GABA(B) receptors inhibit mechanosensitivity of visceral afferents. This is associated with reduced triggering of events that lead to gastro-esophageal reflux, with important therapeutic consequences. In other neuronal systems, GABA(B) receptor activation may be linked via G-proteins to reduced N-type Ca(2+) channel opening, increased inward rectifier K(+) channel opening, plus effects on a number of intracellular messengers. Here we aimed to determine the role of Ca(2+) and K(+) channels in the inhibition of vagal afferent mechanoreceptor function by the GABA(B) receptor agonist baclofen. The responses of three types of ferret gastro-esophageal vagal afferents (mucosal, tension and tension mucosal receptors) to graded mechanical stimuli were investigated in vitro. The effects of baclofen (200 microM) alone on these responses were quantified, and the effects of baclofen in the presence of the G-protein-coupled inward rectifier potassium channel blocker Rb(+) (4.7 mM) and/or the N-type calcium channel blocker omega-conotoxin GVIA (0.1 microM). Baclofen inhibition of mucosal receptor mechanosensitivity was abolished by both blockers. Its inhibitory effect on tension mucosal receptors was partly reduced by both. The inhibitory effect of baclofen on tension receptors was unaffected. The data indicate that the inhibitory action of GABA(B) receptors is mediated via different pathways in mucosal, tension and tension mucosal receptors via mechanisms involving both N-type Ca(2+) channels and inwardly rectifying K(+) channels and others.

Action Potentials↗
PubMed2005

Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function.

AIMS: Members of the acid sensing ion channel (ASIC) family are strong candidates as mechanical transducers in sensory function. The authors have shown that ASIC1a has no role in skin but a clear influence in gastrointestinal mechanotransduction. Here they investigate further ASIC1a in gut mechanoreceptors, and compare its influence with ASIC2 and ASIC3. METHODS AND RESULTS: Expression of ASIC1a, 2, and 3 mRNA was found in vagal (nodose) and dorsal root ganglia (DRG), and was lost in mice lacking the respective genes. Recordings of different classes of splanchnic colonic afferents and vagal gastro-oesophageal afferents revealed that disruption of ASIC1a increased the mechanical sensitivity of all afferents in both locations. Disruption of ASIC2 had varied effects: increased mechanosensitivity in gastro-oesophageal mucosal endings, decreases in gastro-oesophageal tension receptors, increases in colonic serosal endings, and no change in colonic mesenteric endings. In ASIC3-/- mice, all afferent classes had markedly reduced mechanosensitivity except gastro-oesophageal mucosal receptors. Observations of gastric emptying and faecal output confirmed that increases in mechanosensitivity translate to changes in digestive function in conscious animals. CONCLUSIONS: These data show that ASIC3 makes a critical positive contribution to mechanosensitivity in three out of four classes of visceral afferents. The presence of ASIC1a appears to provide an inhibitory contribution to the ion channel complex, whereas the role of ASIC2 differs widely across subclasses of afferents. These findings contrast sharply with the effects of ASIC1, 2, and 3 in skin, suggesting that targeting these subunits with pharmacological agents may have different and more pronounced effects on mechanosensitivity in the viscera.

Acid Sensing Ion Channels↗
PubMed2002

Vagal mechanoreceptors and chemoreceptors in mouse stomach and esophagus.

We used a novel in vitro mouse vagus-gastro-esophageal preparation to study the properties of peripheral vagal afferent endings. We found two types of mechanoreceptive fiber, mucosal receptors and tension receptors. These were distinguished by their sensitivity to mucosal stroking with von Frey hairs and circular tension applied via a claw-cantilever system. A comparison was made with gastro-esophageal afferents found in a similar preparation of ferret tissue. Responses of mouse tension receptors to circular tension were significantly greater than ferret tension and tension/mucosal receptors. Similarly the responses of mouse mucosal receptors to mucosal stroking were significantly greater than ferret mucosal and tension/mucosal receptors. Forty-seven percent of mouse mucosal receptors and 50% of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. These included alpha,beta-methylene ATP (10(-6) to 10(-3) M), 5-hydroxytryptamine (10(-6) to 10(-3) M), and hydrochloric acid (10(-2) to 10(-1) M). Drug responses were concentration dependent. One hundred percent of mucosal receptors and 61% of tension receptors tested responded to bile (1:8 to 1:1 dilution). A third type of fiber was recruited by bile. These fibers were mechanically insensitive and silent prior to bile exposure. In conclusion, we have shown three types of gastro-esophageal vagal afferent fibers in the mouse: mucosal mechanoreceptors, tension receptors, and specific chemoreceptors activated by bile.

Animals↗
PubMed2000

P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation.

1. Using an in vitro single unit recording technique we studied the changes in mechanical and chemical sensitivity of vagal afferent fibres in acute oesophagitis, with particular attention to inflammatory products such as purines. 2. Histologically verified oesophagitis was induced by oesophageal perfusion of 1 mg ml-1 pepsin in 150 mM HCl in anaesthetized ferrets for 30 min on two consecutive days. Controls were infused with 154 mM NaCl. 3. The number of action potentials evoked in oesophageal mucosal afferents by mucosal stroking with calibrated von Frey hairs (10-1000 mg) was stimulus dependent. In oesophagitis responsiveness was reduced across the range of stimuli compared with controls. 4. Topical application of the P2X purinoceptor agonist alphabeta-methylene ATP had no direct excitatory effect on afferents. In oesophagitis, but not in controls, there was a significant increase in responses to stroking with von Frey hairs during superfusion with alphabeta-methylene ATP (1 microM). 5. Mucosal afferents responded directly to one or more chemical stimuli: 26 % (5/19 afferents) responded in controls, and 47 % (7/15 afferents) in oesophagitis. There were no differences in responsiveness to bradykinin (1 microM), prostaglandin E2 (100 microM), 5-hydroxytryptamine (100 microM), capsaicin (1 mM) or hydrochloric acid (150 mM) between control and oesophagitis groups. 6. We conclude that a sensitizing effect of a P2X purinoceptor agonist on mechanosensory function is induced in oesophagitis. This effect is offset by a decrease in basal mechanosensitivity.

Action Potentials↗
PubMed2000

Acute effects of capsaicin on gastrointestinal vagal afferents.

Capsaicin is an important tool for investigation of thin afferent fibres, but its acute effects on subtypes of vagal afferent endings are unknown. In the gastrointestinal tract, these subtypes are: muscle endings (thought to be purely tension sensitive), mucosal endings (sensitive to stroking and chemical stimuli) and endings in the oesophagus with both properties. Acute capsaicin sensitivity was investigated in ferrets using in vivo and in vitro methods. Single-fibre activity was recorded from 63 vagal afferents: 12 Adelta-fibres, 15 C-fibres and 36 unclassified fibres with endings in the oesophagus (n=42), stomach (n=19) and duodenum (n=2). Responses to capsaicin occurred independently of motility changes and were therefore due to direct activation of the receptor ending. In the oesophagus in vivo, two of 10 tension receptors and one of one mucosal receptor responded to intraluminal application of 3.25 mM capsaicin. In the stomach and duodenum, five of 14 tension receptors and two of four mucosal receptors responded to close-systemic (32-164 nmol) capsaicin. In an in vitro gastro-oesophageal preparation, three of five tension, four of 21 mucosal and two of eight tension/mucosal receptors responded to topical application of 1mM capsaicin. Occurrence of responses was therefore unrelated to location of endings and isolation of tissue. Responsiveness was also unrelated to conduction velocity. Capsaicin caused desensitization of responses to further capsaicin application in 37% of afferents. It additionally caused cross-desensitization to mechanical stimuli, which was also seen in afferents that did not respond directly to capsaicin. In conclusion, capsaicin acutely activates all subtypes of gut vagal afferents in vivo and in vitro, although responsiveness is restricted to 30% of fibres and follows no specific pattern. Acute desensitization may be induced with or without a response.

Animals↗
PubMed2000

Aorto-atrial fistula after operated type A dissection.

The development of a fistula between the aorta and right atrium is a rare complication of ascending aortic dissection and has a high mortality if not diagnosed and surgically treated. Clinical diagnosis is best supported by specialised imaging. In addition it may present technically very challenging problems. We report the first case which follows aortic root replacement for an acute type A dissection. Aorto-right atrial fistula (AoRAF) rarely complicates ascending aortic dissection. We report the first case to follow corrective surgery for aortic dissection.

Aortic Dissection↗
PubMed1999

GABA(B) receptors inhibit mechanosensitivity of primary afferent endings.

The modulatory effects of baclofen on the sensitivity of peripheral afferent endings to mechanical stimulation were investigated using an in vitro ferret gastroesophageal vagal afferent preparation. Changes in sensitivity of three types of gastroesophageal vagal afferent endings previously categorized as mucosal, tension, and tension-mucosal (TM) receptors according to their mechanoreceptive field characteristics were investigated. Baclofen (30-200 microM) dose dependently reduced responses of mucosal afferents to mucosal stroking with calibrated von Frey hairs (10-1000 mg). This was reversed by the GABA(B) receptor antagonist SCH50911 (1 microM). TM afferent responses to mucosal stroking (10-1000 mg) were unaffected by baclofen (30-200 microM). However, baclofen (30-200 microM) significantly inhibited the response of 11 of 18 TM afferents to circumferential tension. This was reversed by SCH50911 (1 microM). Baclofen (100 and 200 microM) significantly inhibited the response of all tension receptor afferents to circumferential tension in the lower range (1-3 gm) but not in the higher range (4-7 gm). This inhibition was reversed by SCH50911 (1 microM; n = 3). This study provides the first direct evidence for the inhibitory modulation of peripheral mechanosensory endings by the G-protein-coupled GABA(B) receptor. Inhibition was dose-dependent, pharmacologically reversible, and selective to certain aspects of mechanosensitivity. These findings have important relevance to strategies for selective reduction of sensory input to the CNS at a peripheral site.

Afferent Pathways↗
PubMed1998

An in vitro study of the properties of vagal afferent fibres innervating the ferret oesophagus and stomach.

1. A novel preparation of the oesophagus with attached vagus nerve from the ferret maintained in vitro was used to study the properties of single vagal afferent nerve fibres with identified receptive fields. 2. Recordings were made from three types of gastro-oesophageal vagal afferent fibres that were classified on the basis of their sensitivity to mechanical stimulation. There were those responding to mucosal stroking (mucosal receptors), to circular tension (tension receptors) and those responding to mucosal stroking and circular tension, which we have termed tension/mucosal (TM) receptors. 3. The conduction velocities for mucosal, TM and tension receptor fibres were 6.38 +/- 1.22 m s-1 (n = 22), 6.20 +/- 1.49 m s-1 (n = 13) and 5.33 +/- 0.86 m s-1 (n = 22), respectively. 4. Receptive fields of afferents showed random topographical distribution by fibre type and conduction velocity. They were found mainly distal but also occasionally proximal to the point of vagal dissection. 5. Twenty-eight per cent of mucosal, 63% of TM and 43% of tension receptors responded to one or more drugs or chemical stimuli applied to the receptive field. 6. In conclusion, this experimental preparation provides evidence for the existence of three types of oesophageal vagal afferent fibre, namely mucosal, tension and the newly identified tension/mucosal receptors.

Animals↗
PubMed1998

Oesophagitis-induced changes in capsaicin-sensitive tachykininergic pathways in the ferret lower oesophageal sphincter.

Prolonged oesophageal acidification may impair lower oesophageal sphincter (LOS) function in reflux disease. The aim of this study was to investigate aspects of altered LOS innervation in a model of oesophagitis. Oesophagitis was induced by acid (HCl, 0.15 M) and pepsin (0.1% w/v) infusions in anaesthetized ferrets. LOS muscle strip responses to the following stimuli were measured in vitro from control and acid/pepsin-treated ferrets: electrical field stimulation (EFS; 1-50 Hz), potassium chloride KCl; 20 mM), substance P, [beta-Ala8]-neurokinin A 4-10, [Sar9, Met (O2)11]-substance P (all 10(-10) to 10(-6) M) and capsaicin (10(-8) to 10(-6) M). LOS relaxation occurred in response to all stimuli except [beta-Ala8]-neurokinin A 4-10, which evoked contraction. In muscle strips from acid/pepsin-treated animals there were no differences in amplitude or sensitivity of relaxation following EFS, KCl or substance P vs controls. However, the inhibitory response to capsaicin was increased four-fold (10(-8) M; P < 0.05) and an increased sensitivity of the inhibitory response to [Sar9, Met (O2)11]-substance P occurred (pD2 = 8.64 +/- 0.12 acid/pepsin-treated vs 7.94 +/- 0.24 control, P < 0.05). We conclude that in acute oesophagitis, increased sensitivity of capsaicin-activated inhibitory pathways occurs in which activation of NK-1 receptors plays an integral role in the ferret LOS.

Animals↗
PubMed1994

Maze 3 for atrial fibrillation: two cuts too few?

The Maze procedure has been developed as a surgical approach to the management of patients with atrial fibrillation refractory to medical treatment. The recent modification of the technique (Maze 3) achieves good rate control with coordinated AV contractions. However, the procedure involves cuts that completely isolate a block of left atrial (LA) wall, including the four ostia of the pulmonary veins. The electrical and mechanical activity of this isolated LA block are dissociated from the rest of the atrium, and the area may, in fact, continue to fibrillate. This may provide a nidus for the development of mural thrombus. The weight and endocardial surface area of the LA block and of the entire LA were estimated in ten formalin fixed hearts from trauma victims with no evidence of cardiac disease. In these samples, the LA block represented 35% of the endocardial surface area of the entire LA and 29% of the weight. The LA block is of sufficient size to allow macroreentrant circuits to form and has the potential to fibrillate if isolated from the rest of the atrium. We modified the Maze 3 procedure to recruit the otherwise isolated LA block by using two additional cuts around each pair of pulmonary veins as they enter the LA. The first patient who underwent the modified procedure demonstrated sinus rhythm on Holter monitoring postoperatively and remained in sinus rhythm following burst atrial pacing at 300 and 420 beats/min each for 30 seconds. In addition, atrial contractions were found to contribute 19% of the cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗
PubMed1993

Homeless families and their children's health problems. A Utah urban experience.

Descriptive information was obtained about homeless families in the Intermountain West and their children's health care needs were defined to help professionals develop programs tailored to meet the unique needs of this population. We collected data during the well-child visits of 306 children in 161 families living at the Travelers Aid Society family shelter. The results reveal 2 types of homeless families, episodic and long term. Each requires different levels of assistance. This study's profile of mobile, predominantly white, 2-parent families with few children (mean of 1.2) differs considerably from that of studies conducted on the East and West coasts. The families' nomadic life-style (73.1% came from 32 states other than Utah) present important public health issues, especially because of the recent resurgence of tuberculosis and declining levels of childhood immunizations. The children's health problems were similar to those reported nationally: delayed immunizations, dental decay, anemia, and impaired vision.

Adolescent↗
PubMed1984

Electrocardiographic changes following electroconvulsive therapy.

This paper reports a study of the effects of ECT (electroconvulsive therapy) upon cardiac function (as judged by electrocardiographic changes) in 24 patients who were given 139 treatments in all. Of the 24 patients 13 were studied over a 24-h period using monitoring equipment. No potentially dangerous arrhythmias were encountered. Modified ECT was found to give rise to sinus tachycardia, which was considerably more prolonged than previously reported. The tachycardia was shown in some cases to be accompanied by a depression of the ST segment and may hence be potentially harmful to those with pre-existing ischaemic heart disease. In such patients consideration should be given to the prior administration of beta-adrenergic blocking drugs and/or oxygen.

Adult↗
PubMed1984

The Birmingham Trial of permanent pacing in patients with intraventricular conduction disorders after acute myocardial infarction.

Patients surviving 2 weeks after myocardial infarction who had persistent conduction disorder (right bundle branch block alone or associated with left anterior or posterior hemiblock [LPH] or LPH alone) were allocated at random to permanent pacing or control groups. Throughout follow-up, up to 5 years, there was no significant difference in survival: at 2 years 14 of 23 (61%) of paced patients had died compared with 11 of 27 (41%) control patients. Progression of conduction disorder was not observed and measurement of infranodal conduction time (HV interval) did not predict outcome. Ventricular tachyarrhythmias were an important cause of death in these patients and pacing appears to offer no benefit.

Bundle-Branch Block↗
PubMed1981

Oral prostaglandin E2 in ductus-dependent pulmonary circulation.

Prostaglandin E2 (PGE2) was administered orally, in doses of 12-65 microgram/kg at intervals of 1-4 hours, to 12 neonates in whom the pulmonary circulation depended on patency of the ductus arteriosus. After an oral dose, both oxygen saturation (SaO2) and plasma PGE2 concentration increased consistently within 15-30 minutes, reaching values comparable to those during i.v. infusions. Treatment continued for 5 days to 4 months. In eight infants, PGE2 withdrawal resulted in a decrease of SaO2, from a mean of 75 +/- 7% to 57 +/- 10% (+/- SD). The ductus remained responsive for long periods--in four infants, for over 3 months. Consequently, surgery could be delayed until the infants and their pulmonary arteries had grown. Side effects during oral therapy were similar to those during i.v. infusion but were less severe in this series. The effectiveness and simplicity of oral PGE2 administration have advantages over i.v. administration, especially for long-term treatment.

Administration, Oral↗
PubMed1980

The straight back syndrome.

The straight back syndrome, consisting of loss of normal upper thoracic spinal curvature associated with cardiac murmurs and radiographic cardiomegaly is considered a form of 'pseudoheart disease' which has been attributed to squashing of the heart in the reduced AP diameter of the chest. During an 18-month period 31 patients referred to a cardiologist were found to have a straight back. Forty-five relatives were subsequently examined and 27 were found also to have a straight back. Palpitations and chest pain were the commonest symptoms. On the lateral chest radiograph the distance from the middle of the anterior border T8 to a vertical line connecting T4 and T12 was found to be significantly reduced compared to controls, and a value less 1.2 cm is indicative of a straight back. Of the 58 subjects with the syndrome, 39 (67 per cent) had clinical and/or echocardiographic evidence of mitral valve prolapse. Respiratory function testing revealed no significant abnormality. HLA typing showed no association with an particular HLA antigen but indicates that the straight back syndrome is inherited as an autosomal dominant condition and suggested that the antigenic determinants may be located on chromosome 6. We conclude that the straight back syndrome should no longer be considered a form of pseudoheart disease and patients should be investigated for associated mitral valve prolapse and their relatives screened.

Adolescent↗
PubMed1979

Plasma noradrenaline concentrations at different vascular sites during rest and isometric and dynamic exercise.

1. Blood samples were obtained simultaneously from femoral artery and vein, pulmonary artery and antecubital vein at rest and during isometric and dynamic exercise in six patients during cardiac catheterization and plasma noradrenaline was measured radioenzymatically. 2. Analysis of variance indicated that differences between vascular sites were not significant, whereas differences between patients (P less than 0.001) and differences between activities (P less than 0.001) were significant. 3. Mean systemic arterial concentrations tended to be lower than pulmonary arterial concentrations during each activity, although the difference was not significant. 4. We conclude that forearm venous plasma noradrenaline concentrations are representative of those from other sites.

Adult↗