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A J Fox

Publications and source records attributed to A J Fox.

At least 127 records · Page 7Linked to original sources
PubMed1996

Receptors mediating tachykinin-evoked depolarisations of neurons in the neonatal rat spinal cord.

We have examined the contribution of NK1, NK2 and NK3 receptors to the depolarisation of the neonatal rat spinal cord in vitro evoked by exogenously applied tachykinine. Potential changes were recorded extracellularly from a lumbar ventral root. The NK1 receptor selective agonists substance P methly ester (SPOMs), septide and/Sar9/-substance P-sulphone (/Sar9/-P-sulphone), perfused onto the cord for 20 s, evoked ventral root potentials (VRPs) with similar EC50 values of 7.2 nM (95% confidence limits, 4.4-10.9 nM), 4.6 nM (1.8-9.3 nM) and 3.1 nM (1.6-5.1 nM), respectively. The NK3 receptor selective agonist senktide also evoked VRPs with an EC50 of 12.0 nM (5.1-23.4 nM), whilst the NK2 receptor selective agonist/beta-AlaB/-neurokinin A(4-10) (/beta-AlaB/-NKA(4-10)) was much less potent (EC50 = 228.3 nM, 95% confidence limits 138.0-350.0 nM). The non-peptide NK1 receptor selective antagonist RP67580 inhibited responses to SPOMe, septide and/Sar9/-SP-sulphone to varying degrees with IC50 values against each of 16.0 nM (10.7-23.4 nM), 19.8 nM (8.9-37 nM) and 58.0 nM (41-89 nM), respectively. The NK1 receptor antagonist CP-96,345 similarly inhibited responses to these agonists, although with higher IC50 estimates of 0.84 microM (0.51-1.40 microM) against SPOMe, 0.79 microM (0.50-1.17 microM) against/Sar9/-SP-sulphone and 0.37 microM (0.27-0.51 microM) against septide. Further analysis of the activity of RP67580 yielded a significantly higher pKB estimate for antagonism of responses to septide (7.67 +/- 0.04) than of responses to/Sar9/-SP-sulphone (7.18 +/- 0.05). In both cases Schild analysis indicated competitive antagonism. RP67580 also reversibly inhibited responses to /beta-AlaB/-NKA(4-10). However, in this case the Schild alope was significantly different from unity (0.44 +/- 0.55; P < 0.001), although the potency of the antagonist appeared similar to that seen with the NK1 receptor agonists (pA2 = 7.52). There was no effect of RP67580 against responses to senktide or of the inactive isomer RP67581 against septide-evoked VRPs. The NK2 receptor antagonist MEN 10,376 at concentrations up to 1 microM produced a partial but reversible inhibition of responses to a submaximal concentration of /beta-AlaB/-NKA(4-10) (0.3 microM) with a maximum reduction in VRP amplitude of 25.6 +/- 7.3%. A similar inhibitory effect was seen against septide-evoked VRPs (30.2 +/- 5.6% inhibition), although there was no effect against responses to submaximal concentrations of /Sar9/-SP-sulphone or senktide. In contrast, the non-peptide NK2 receptor antagonist SR 48,968 (1 microM) produced a maximal 48.0 +/- 7.7% inhibition of/beta-AlaB/-NKA(4-10)-evoked VRP's with no effect against responses to a submaximal concentration of septide. These data show that NK1 and NK3 receptor activation mediates depolarisation of the neonatal rat spinal cord, and suggest the presence of two NK1 receptor populations showing preference for septide and/Sar9/-SP-sulphone. Depolarisations mediated by /beta-AlaB/-NKA(4-10), previously described as a selective NK2 receptor ligand, are mediated predominantly via an action at NK1 receptors with a lesser involvement of NK2 receptors.

Animals↗
PubMed1995

Gun control.

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Canada↗
PubMed1995

Stimulation of guinea-pig tracheal afferent fibres by non-isosmotic and low-chloride stimuli and the effect of frusemide.

1. Inhalation of low-chloride or non-isosmotic solutions evokes cough or reflex bronchoconstriction in humans that is inhibited by frusemide (furosemide), whilst capsaicin-evoked cough is unaffected. Here we have examined the responses of single vagal afferent fibres innervating the isolated guinea-pig trachea to these stimuli, and tested the effect of frusemide on fibre responses. 2. Both distilled water and hypertonic saline applied for 30 s onto identified receptive fields produced marked excitation of all A delta and C fibres tested. Isotonic glucose, a low-chloride solution, was a less potent stimulant and caused excitation in 37% of A delta fibres and 69% of C fibres. There was no difference in the distribution of low-chloride sensitive and insensitive receptive fields. 3. In the presence of frusemide, responses of A delta fibres to isotonic glucose were significantly inhibited to 34.2 +/- 6.2% of the pre-drug control level. However, frusemide was without effect either on responses of A delta fibres to distilled water or hypertonic saline, or on responses of C fibres to capsaicin. 4. These data support a role for tracheo-bronchial A delta and C fibres in airway reflexes evoked by hypotonic, hypertonic and low-chloride stimuli. The protective effect of frusemide against airway responses to low-chloride but not to non-isosmotic solutions may reflect an action on sensory nerve endings.

Animals↗
PubMed1995

Lack of relationship between leukoaraiosis and carotid artery disease. The North American Symptomatic Carotid Endarterectomy Trial.

OBJECTIVE: Leukoaraiosis (LA) (white matter changes) is frequently observed on computed tomographic scans of the brain of elderly patients at risk of stroke. A localized vascular-ischemic cause has been suggested for its underlying mechanism. Our aim was to assess whether high-grade carotid stenosis is associated with LA. DESIGN/SETTING: Patients enrolled in the North American Symptomatic Carotid Endareterectomy Trial (also known as NASCET) were evaluated for LA using a recently proposed grading scale. Ordinal regression analysis was used to assess the association between the severity of carotid artery stenosis and the extent of LA observed on computed tomographic scans. The patients' brain hemisphere was selected as the unit of analysis. RESULTS: Of the 2394 brain hemispheres contributed to the analyses, 352 (14.7%) had signs of LA. After controlling for known stroke risk factors in the ordinal regression analysis, only the history of stroke and increasing age were significantly related to LA. Severity of stenosis was observed to be unrelated (odds ratio [severe vs mild stenosis] = 1.08; 95% confidence interval, 0.73-1.62; P = .952) as were a history of hypertension and a history of myocardial infarction. CONCLUSION: Leukoaraiosis is not associated with severe carotid artery stenosis.

Aged↗
PubMed1995

Therapeutic embolization in the treatment of intractable epistaxis.

OBJECTIVE: To determine the effectiveness of therapeutic embolization in the treatment of intractable epistaxis. DESIGN: Cohort. SETTING: Tertiary care hospital. PATIENTS: Consecutive referred sample of 57 patients with intractable epistaxis. INTERVENTION: Percutaneous transfemoral catheterization and angiography of the internal maxillary arteries. Embolization of the most distal branches with 0.1- to 0.9- cm3 medium-sized polyvinyl alcohol particles on the suspected side of bleeding. OUTCOME: Outcome was successful if no further interventional treatment was required for epistaxis. RESULTS: Anatomical abnormalities precluded embolization in three patients. Three of the remaining 54 patients required supplementry embolization. Including these three patients, 52 (96%) of 54 patients had successful control epistaxis. The major neurologic complication rate was 6% (three of 54 patients), with no permanent deficits. CONCLUSIONS: Therapeutic embolization is an effective and safe technique and should be considered as the primary treatment modality in severe epistaxis.

Adolescent↗
PubMed1995

Human antibody response to meningococcal transferrin binding proteins: evidence for vaccine potential.

During iron-limited growth Neisseria meningitidis expresses two transferrin binding proteins, TBP1 and TBP2, with molecular masses of approximately 98 and 65-90 kDa depending on strain. Mixtures of TBP1 and TBP2 (TBP1 + 2) from three meningococcal strains were purified using affinity chromatography and used to determine anti-TBP antibodies in human sera by ELISA. Sera were obtained from healthy individuals, asymptomatic carriers of N. meningitidis and cases of meningococcal disease. Healthy individuals had little detectable antibody to TBPs but sera from carriers and cases exhibited a response demonstrating that TBPs are expressed in vivo during both carriage and disease. The ELISA absorbances produced by each of the individual sera to TBPs from the three meningococcal strains were compared and very high correlation coefficients were obtained, indicating that human anti-TBP antibodies, in contrast to mouse and rabbit antibodies, are cross-reactive between strains. Antibodies to separately purified TBP1 and TBP2 were also detected in both cases and carriers. The IgG and IgM response to TBP1 + 2 was greater in cases than carriers but the mean IgA response was the same. This demonstration of an antibody response that is cross-reactive between TBP types greatly strengthens the case for inclusion of TBPs in a meningococcal vaccine to protect against all serogroups and serotypes.

Animals↗
PubMed1995

Quantitative and qualitative changes in AMPA receptor expression during spinal cord development.

Synaptic activity in early postnatal life is important for the acquisition of mature structural and functional properties of neurons. Previous studies indicate that the mature molecular features of spinal motor neurons emerge during a period of activity-dependent development in early postnatal life. Since glutamatergic synaptic transmission provides the major excitatory drive into motor neurons, glutamate receptors are likely to play a central role in motor neuron activity-dependent development. To gain insight into this process, we have used receptor autoradiography, immunoblotting and immunohistochemistry to determine the distribution, temporal expression and potential subunit composition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype glutamate receptors in the developing rat spinal cord. Using two different ligands, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and [3H]-6-cyano-7-nitroquinoxaline-2,3-dione, we find that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites in the adult are largely restricted to the substantia gelatinosa. In marked contrast, during early postnatal life, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites are transiently expressed at high levels in the ventral horn. This parallels previous findings on the developmental regulation of N-methyl-D-aspartate receptor expression. Using alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit-specific antibodies we show by immunoblot analysis and immunohistology that, to varying degrees, the expression patterns of glutamate receptor subunit 1 and glutamate receptor subunits 2/3 are significantly developmentally regulated. The most conspicuous change is the downregulation of glutamate receptor 1 expression within motor neurons over the first three weeks of postnatal life. The qualitative and quantitative changes we observe in glutamate receptor expression in early postnatal life are likely to have a major impact on the electrophysiological properties of young motor neurons and thus may contribute to their activity-dependent development.

Animals↗
PubMed1995

Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig.

We have examined the effects of low pH and the selectivity of the capsaicin antagonist capsazepine on single sensory fibres innervating the guinea-pig trachea in vitro, and on the whole isolated vagus nerve. Application of a pH 5 solution for 1 min to the exposed receptive fields of single fibres caused excitation of all C-fibres tested but had no effect on A delta-fibres. Capsazepine (1 microM) perfused onto the receptive field for 5 min produced a reversible inhibition of both low pH- and capsaicin (60 nM)-evoked firing of C-fibres. In contrast, capsazepine had no effect on responses of C-fibres to bradykinin (0.1 microM) or of A delta-fibres to hypertonic saline. Perfusion of tissues with zero-calcium Krebs' solution containing trypsin produced denudation of the epithelium. In these tissues responses to low pH and capsaicin were unchanged and, moreover, the inhibitory effect of capsazepine against low pH and capsaicin was maintained. C- and A delta-fibre responses to bradykinin and hypertonic saline were similarly unaffected by epithelium removal. Perfusion of the whole guinea-pig vagus nerve with capsaicin (0.3 microM) or pH 5 buffer caused depolarization. However, in this preparation prior perfusion with capsazepine (1 microM) abolished responses to capsaicin whilst low pH-evoked depolarization was unchanged. These data show that capsazepine is a specific antagonist of proton- and capsaicin-evoked activation of the peripheral endings of sensory nerves in the guinea-pig airways, and suggest the release by protons of an endogenous ligand for the capsaicin receptor that does not originate from the epithelium.

Afferent Pathways↗
PubMed1995

Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs.

Acidic solutions mimick many of the effects of capsaicin (Cap), including pain, bronchoconstriction, cough, and sensory neuropeptide release. Evidence from the use of the Cap antagonist capsazepine suggests that in some cases protons act at the Cap receptor. In the present study, we have investigated whether cough evoked by Cap and citric acid (CA) is mediated specifically via the Cap receptor on airway sensory nerves. We have examined the effects of capsazepine on Cap-, CA-, and hypertonic saline-induced cough and also on CA-induced nasal irritation in awake guinea pigs. Capsazepine was nebulized for 5 min before cough challenges with Cap for 5 min and CA for 10 min. Control animals were pretreated with vehicle alone. Capsazepine (100 microM) inhibited the cough response to 30 microM Cap from 0.77 +/- 0.14 coughs/min in control animals to 0.23 +/- 0.08 coughs/min (P < 0.05) and to 80 microM Cap from 1.4 +/- 0.23 to 0.3 +/- 0.11 coughs/min (P < 0.01). There was no effect, however, of lower concentrations of capsazepine (5 and 10 microM) against Cap-evoked cough. At a concentration of 100 microM, capsazepine also inhibited the coughing induced by 0.25 M CA from 1.8 +/- 0.26 to 0.93 +/- 0.31 coughs/min (P < 0.05) but not that induced by 0.5 M CA. Nasal irritation induced by 0.25 M CA, but not by 0.5 M CA, was also inhibited by capsazepine from 2.47 +/- 0.37 to 0.75 +/- 0.31 nose wipes/min (P < 0.05). This inhibitory effect of capsazepine did not appear to reflect a nonspecific suppression of the cough reflex, since cough evoked by exposure to hypertonic (7%) saline for 10 min was unaffected by pretreatment with capsazepine (100 microM). These data show that capsazepine is a specific inhibitor of Cap- and CA-induced cough in guinea pigs. Moreover, they suggest that low pH stimuli evoke cough and nasal irritation by an action at the Cap receptor, either directly or through the release of an intermediate agent.

Animals↗
PubMed1995

Accuracy and prognostic consequences of ultrasonography in identifying severe carotid artery stenosis. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

BACKGROUND AND PURPOSE: The accuracy of routine ultrasonography in detecting severe carotid artery stenosis was evaluated in comparison with cerebral angiography. The precision of ultrasonographic criteria in predicting the risk of stroke was also assessed. METHODS: A total of 1011 symptomatic carotid bifurcations were studied in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Given that all patients were considered for entry into the trial, the chance of a verification bias affecting the analyses was minimized. The ultrasonographic data consisted of peak systolic velocities and frequency changes from both the internal and common carotid arteries. Angiographic stenosis was calculated as in NASCET. Receiver operating characteristic (ROC) curves were constructed from the ultrasonographic data for the detection of 70% or greater stenosis on the basis of an angiographic assessment. Kaplan-Meier stroke-free survival curves were used to predict the risk of stroke. RESULTS: The areas under the ROC curves ranged from 0.74 to 0.75 (95% confidence interval [CI], 0.69 to 0.79). The sensitivities and specificities ranged from 0.65 to 0.71. The risk of stroke at 18 months declined sharply as the degree of angiographically defined stenosis declined from 99% to 70%. No pattern of decline was apparent on the basis of the ultrasonographic data. CONCLUSIONS: The results indicate that the accuracy of ultrasonography is moderate when flow parameters are used to assess the degree of stenosis. Ultrasonography should be used as a screening tool to exclude patients with no carotid artery disease from further testing. Conventional angiography remains an essential investigation before assigning the risk of stroke and deciding appropriate treatment for extracranial carotid artery disease.

Blood Flow Velocity↗
PubMed1995

Prognosis for patients following a transient ischemic attack with and without a cerebral infarction on brain CT. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

BACKGROUND: Although cerebral infarctions are commonly observed on brain CTs of patients with TIAs, their prognostic importance is unknown. METHOD: The association between appropriately sited brain infarctions (ie, lesions located in the anterior circulation of the brain and ipsilateral to the symptomatic stenosed carotid artery) visualized on CT and the risk of subsequent stroke was assessed by Cox proportional hazards regression in 164 patients presenting with TIA (and no history of previous stroke) and severe angiographically defined carotid stenosis (70 to 99%) from the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: Patients with a TIA and CT-verified brain lesions were older and were more likely to have higher degrees of carotid stenosis and carotid plaque ulceration, a longer duration of symptoms, and a history of hypertension. With regard to prognosis, after adjusting for all known risk factors (patient characteristics) in a regression analysis, the presence of ischemic lesions observed on CT was not associated with an increased risk of ipsilateral stroke at 2 years (adjusted hazard ratio = 1.00; 95% CI: 0.39 to 2.58; p value = 0.99). CONCLUSION: Considered in combination with other patient characteristics, the mere presence of an appropriately sited cerebral infarction on CT does not alter the prognosis (risk of ipsilateral strokes) of severely stenosed patients with TIA. Therefore, there is no clinical rationale in differentiating patients with TIA on the basis of CT findings alone.

Aged↗
PubMed1995

Magnetic resonance imaging of brain death.

OBJECTIVE: To demonstrate the magnetic resonance imaging (MRI) appearance of the brain in patients with clinical brain death. PATIENTS AND METHODS: High-field (1.5-T) MRI was performed on five patients who were subsequently proven clinically brain dead. Conventional T1-weighted and T2-weighted imaging was performed. RESULTS: MRI exhibited similar features for all of the patients: loss of the subarachnoid spaces of the brain; slow flow in the intracavernous and cervical internal carotid arteries; and loss of flow void in the small and large intracranial arteries, as well as in the major intracranial venous sinuses. The differentiation between grey and white matter in the brain was preserved, although the brain had a "supernormal" appearance due to the absence of cerebrospinal fluid and arterial pulsations. These findings have not been observed in MRI of comatose patients who were not clinically brain dead. CONCLUSION: With the advent of MRI-compatible ventilators and noninvasive monitoring, which facilitate imaging of patients under intensive care, MRI may offer another method of confirming the clinical diagnosis of brain death.

Adolescent↗
PubMed1995

Symptomatic pulmonary complications from liquid acrylate embolization of brain arteriovenous malformations.

PURPOSE: To describe symptomatic pulmonary emboli from brain arteriovenous malformation embolization with liquid acrylates and to analyze the reasons for these complications and describe preventive techniques. METHODS: The clinical records of 182 patients embolized with acrylate glue since 1978 for treatment of brain AVMs were searched for evidence of symptomatic pulmonary complications. Originally iso-butyl-2-cyanoacrylate and more recently n-butyl-2-cyanoacrylate were used in all patients. Arteriovenous malformation morphology, amounts and techniques of glue injection, and clinical and radiologic investigations in the symptomatic patients were recorded. RESULTS: Three patients had pulmonary symptoms within 48 hours of glue injection. One patient with a left frontal arteriovenous malformation had embolization with an isobutyl-2-cyanoacrylate/pantopaque/acetic acid mixture; severe pleuritic chest pain developed 2 days later. One patient with a left temporal and one with a left cerebellar arteriovenous malformation had embolization with n-butyl-2-cyanoacrylate/lipiodol mixtures; a cough, pleuritic chest pain, and bloody sputum developed in both within 24 hours. Two patients experienced a significant drop in PO2. No flow-arrest techniques were used for any of the injections in these three patients. All patients demonstrated significant changes on chest x-ray and CT chest examinations. All were treated conservatively and recovered spontaneously. CONCLUSIONS: Symptomatic pulmonary complications can occur after acrylate glue injection, particularly when delivery systems without flow arrest are used in high-flow vascular brain lesions. Techniques using acetic acid to delay polymerization time and "sandwich" techniques in which glue is pushed with dextrose are also more susceptible to this complication.

Acetates↗
PubMed1994

Can bruits distinguish high-grade from moderate symptomatic carotid stenosis? The North American Symptomatic Carotid Endarterectomy Trial.

OBJECTIVE: To determine whether cervical bruits, alone or combined with other clinical characteristics, can distinguish high-grade (70% to 99%) carotid artery stenoses from less severe stenoses in patients with symptoms of cerebrovascular disease. DESIGN: Cross-sectional comparison of clinical observations with contemporaneous angiography. SETTING: The North American Symptomatic Carotid Endarterectomy Trial (NASCET), a multicenter randomized controlled trial of carotid endarterectomy. PATIENTS: All patients enrolled in the NASCET from its inception in 1988 to November 1991. RESULTS: A focal ipsilateral carotid bruit had a sensitivity of 63% and a specificity of 61% for high-grade stenosis and, when absent, only lowered the probability for high-grade stenosis from a pretest value of 52% to a post-test probability of 40%. When combined with four other clinical characteristics (an infarction on computed tomography of the head, a carotid ultrasound scan suggesting more than 90% stenosis, a transient ischemic attack rather than a minor stroke as a qualifying event, and a retinal rather than a hemispheric qualifying event), the predicted probabilities of high-grade stenosis ranged from a low of 18% (when none of the features was present) to a high of 94% (when all the features were present. CONCLUSIONS: Cervical bruits alone were not sufficiently predictive of high-grade symptomatic carotid stenosis to be useful in selecting patients for angiography; they were absent in over one third of patients with high-grade stenosis. When combined with other clinical variables, patients with high or low probabilities of 70% to 99% stenoses could be identified, but this prediction model still missed many individuals with high-grade stenosis, even in this training set of selected patients.

Angiography↗
PubMed1994

Early endarterectomy for severe carotid artery stenosis after a nondisabling stroke: results from the North American Symptomatic Carotid Endarterectomy Trial.

PURPOSE: The timing of carotid endarterectomy (CE) after a recent nondisabling stroke remains controversial. Delaying surgery in such cases may needlessly place patients at risk for a recurrent stroke that may be major and disabling. This study examines the prognostic implications of performing early endarterectomy compared with delayed endarterectomy in patients from the North American Symptomatic Carotid Endarterectomy Trial. METHOD: This retrospective, subgroup analysis involved 100 surgical patients with severe (70% to 99%) angiographically defined carotid artery stenosis, who were diagnosed with a nondisabling hemispheric stroke at entry into the trial. Forty-two CEs were performed within 30 days (early group, ranging 3 to 30 days), and 58 were performed beyond 30 days (delayed group, range 33 to 117 days) after stroke. The risk of subsequent stroke after CE was compared between the two groups. RESULTS: Baseline clinical characteristics were comparable in both the early and delayed groups. In the delayed group more lesions were identified ipsilateral to the symptomatic side on the preoperative computed tomography scans. The postoperative (30 days after endarterectomy) stroke rate was 4.8% in the early group and 5.2% in the delayed group, yielding a relative rate of 0.92 (95% confidence interval, 0.16 to 5.27; p = 1.00). No deaths occurred after operation in either group. At the end of 18 months, the rates of any stroke or death were 11.9% and 10.3% for the early and delayed groups, respectively, resulting in a relative rate of 1.15 (95% confidence interval, 0.38 to 3.52; p = 1.00). No association was found between an abnormal preoperative computed tomography scan result and the subsequent risk of stroke when early operation was used. CONCLUSION: Early CE for severe carotid artery stenosis after a nondisabling ischemic stroke can be performed with rates of morbidity and mortality comparable to those who receive delayed endarterectomy. Delaying the procedure by 30 days for patients with symptomatic high-grade stenosis exposes them to a risk of a recurrent stroke, which may be avoidable by earlier surgery.

Aged↗
PubMed1994

Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.

Animals↗
PubMed1994

Further comments on the measurement of carotid stenosis from angiograms. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

BACKGROUND AND PURPOSE: Three different methods for estimating the percentage of reduction in the diameter of the internal carotid artery (ie, stenosis) have been proposed in the literature. Further comparisons of the methods were carried out with the intent of recommending a current standard for determining the percentage of stenosis from angiograms. METHODS: Angiograms from 112 patients were obtained. For each angiogram, stenosis was estimated in the manner of the European Carotid Surgery Trial (ECST method), the North American Symptomatic Carotid Endarterectomy Trial (NASCET method), and by a method using the common carotid artery lumen diameter (CC method). RESULTS: Although there is much discrepancy among the estimates of stenosis arising from the three different methods for any particular patient, it is possible to predict (on average) the percentage of stenosis from one method to another. The relationship between the NASCET and CC methods is linear, with a mean ratio of distal internal carotid artery to common carotid diameter of 0.62 (SD of 0.11). The variability in the diameter of the common carotid artery lumen stabilizes only beyond 2.5 common carotid diameter units (approximately 20 to 30 mm by conventional angiography) proximal to the bifurcation. Unexpectedly, the relationships between both the ECST and NASCET methods and ECST and CC methods were parabolic (P < .001). The reasons underlying these departures from linearity are uncertain. CONCLUSIONS: The comparability of our results with those reported in the literature regarding the CC and NASCET methods provides further evidence of the reproducibility of methods measuring anatomic features that can be visualized on an angiogram. Disease of the internal carotid artery is one of the important causes of ischemic symptoms. Measuring the narrowest portion of the internal artery relative to the normal portion of the same artery, well beyond the bulb, is a logical method. Moreover, benefits of carotid endarterectomy for patients with 70% to 99% stenosis as determined by the NASCET method have been well established in a clinical trial. Converting from the NASCET method to the CC method, given that the CC method is neither superior nor easier to calculate, is not recommended.

Angiography↗