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Biomedical subjects

M B Robinson

Publications and source records attributed to M B Robinson.

At least 55 records · Page 3Linked to original sources
PubMed1998

Super Profile analysis of socioeconomic variations in coronary investigation and revascularisation rates.

OBJECTIVES: To investigate socioeconomic variations in the utilisation of tertiary cardiology services. DESIGN: Cross sectional ecological study, using the Super Profile classification of enumeration districts, and ischaemic heart disease standardised mortality ratios as a proxy for needs. SETTING: The former Yorkshire Regional Health Authority area in England and its seven constituent district health authority areas. SUBJECTS: Patients with a primary diagnosis of ischaemic heart disease aged > or = 25 years who underwent investigation by angiography, or treatment by coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), as a primary procedure between April 1992 and March 1994 in an NHS hospital. MAIN RESULTS: There is an overall increasing trend in investigation and revascularisation rates from the affluent to the deprived in the region suggesting equity. However, the gradient is slight compared with the corresponding mortality gradient. Age specific analysis shows a more appropriate trend in rates for the under 65s, but a downward trend from affluence to deprivation for the elderly. Much of the regional trend is caused by very high rates in one geographically small but densely populated district that has two tertiary cardiology centres. In other districts, with higher heart disease mortality but much lower procedure rates, there is a decreasing trend from the affluent to the deprived suggesting considerable inequity. CONCLUSIONS: This study confirms wide socioeconomic variations in coronary investigation and revascularisation within the former Yorkshire Region, suggesting that in some districts need is not being met and that service utilisation is inequitable. Such inequities are over and above those that result from proximity to tertiary cardiology centres.

Adult↗
PubMed1998

Why is evaluation of the cost effectiveness of audit so difficult? The example of thrombolysis for suspected acute myocardial infarction.

BACKGROUND: Cost effectiveness analysis is an established technique for evaluation of delivery of health care, but its use to evaluate clinical audit is rarely reported. Thrombolysis for suspected acute myocardial infarction is a commonly used therapy of established effectiveness and an appropriate subject for audit in many healthcare settings. OBJECTIVE: To measure the cost effectiveness of audit of thrombolysis in some district general hospitals. MAIN OUTCOME MEASURE: Cost of audit per extra patient treated with thrombolysis (incremental cost effectiveness ratio). DESIGN: Prospective agreement with physicians to undertake repeated audits of a specific aspect of the management of patients with acute myocardial infarction. Baseline measurement of the proportion of these patients given thrombolysis in each hospital were made, as were three subsequent retrospective audits, giving time series of measurements. Costs were estimated from records of staff time and other resources used in each hospital; effectiveness was estimated by fitting the results to a model which assumed a uniform rate of increase over time in the proportion of eligible patients given thrombolysis which might be accelerated by regular audit. Upper and lower limits for main outcome measure were derived from sensitivity analysis of costs and logistic regression of time series data. SETTING: Five district general hospitals in North West Thames Regional Health Authority including one control hospital were used, starting in April 1991 when widespread medical audit was first introduced. RESULTS: Between the first and last audits, the proportion of patients with suspected acute myocardial infarctions receiving thrombolysis rose in three of the hospitals undertaking audit by 20% to 37% and fell by 6% in the fourth (although this hospital started with a rate in excess of 90%). The corresponding change in the control hospital was an increase of 15%. The differences between each of the auditing hospitals and control hospital were not significant, except in one case, where 51 extra treatments per year were attributable to audit (95% confidence intervals (95% CIs) 0.5 to 61 cases per year). Estimated overall costs in each hospital ranged from 3700 Pounds to 5200 Pounds for data collection, a series of four audit meetings, and subsequent actions. The central estimate of cost effectiveness in the three responsive hospitals ranged from 101 Pounds to 392 Pounds per extra case given thrombolysis, with very wide 95% CIs. In the fourth hospital audit had zero effectiveness as defined in this study. CONCLUSIONS: Methodological difficulties were encountered which need to be considered in future economic evaluations of clinical audit and related activities. These were: (a) adequate control for other factors influencing clinical behaviour; (b) uncertainties about the sustainability of changes in behaviour associated with audit; and (c) the relative infrequency in a single hospital of specific clinical events leading to small numbers for analysis. These difficulties constitute major challenges for the economic evaluation of clinical audit. They are most likely to be overcome in a large study which compares clinical audit with other interventions aiming for the same quality improvement, such as patient specific reminders or educational programmes.

Cost-Benefit Analysis↗
PubMed1997

Does medical audit lead to explicit standards? Experience with thrombolysis in four UK hospitals.

The setting of explicit standards against specific criteria is a recognized part of the medical audit cycle, but often in practice it has been neglected, implicit judgements being used instead. The conduct of a study to evaluate audit among physicians in four UK district general hospitals provided an opportunity to encourage the setting of explicit standards and observe the results. The subject chosen for audit by the participating physicians was the extent of use of intravenous thrombolysis in patients with suspected acute myocardial infarction (AMI). Standard setting was requested at initial peer review meetings held to review baseline results. This was followed up by a written request to lead consultants and subsequent telephone calls. Two out of the four participating hospitals set technical standards, which excluded patients with contra-indications from the denominator. The other two hospitals set population standards as requested, one with considerable reluctance and scepticism. Each hospital set separate standards for definite AMIs and for probable AMIs. Six out of the eight standards set were achieved in at least one of four audits conducted in each hospital. Time trends were difficult to interpret because of small numbers. The amount of discussion between the lead consultant and colleagues about standards was highly variable, but there was no clear relationship between the process for agreeing standards in a particular hospital and subsequent attainment.

Chest Pain↗
PubMed1997

Adenovirus-mediated in vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge.

The purpose of this study was to determine the time of onset, duration, and the efficacy of in vivo gene transfer in protecting the ornithine transcarbamylase deficient spf/Y mouse from an acute ammonium challenge. The animals were challenged with ammonia (10 mmol/kg NH4Cl) 1, 2, 7, 14, or 28 d after the administration of a recombinant adenoviral construct deleted in E1 and with a temperature sensitive mutation in E2. Although there was no protection with the control LacZ virus, the ornithine transcarbamylase (OTC)-containing vector provided partial protection from both behavioral symptoms (ataxia, seizures, and abnormal response to sound) and biochemical abnormalities (ammonium, aspartate, alanine, and glutamine) within 24 h and complete protection by 48 h. Mortality was also decreased. Animals receiving the vector 7 and 14 d before the ammonium load were also protected, whereas those treated 28 d before the challenge were not. OTC enzyme activity in liver of untreated spf/Y mice was 5% of control C3H mice. After gene transfer, activity was increased to near control levels through 14 d but had returned to baseline by 28 d. These studies indicate that adenovirus-mediated gene transfer confers a metabolic benefit within 24 h of administration and provides protection against an acute metabolic insult for at least 2 wk.

Adenoviridae↗
PubMed1996

Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors.

A murine model of ornithine transcarbamylase (OTC) deficiency was used in this study to evaluate the efficacy of recombinant adenoviruses for correcting the metabolic defect in liver. Recombinant adenoviruses deleted in E1 and containing a human OTC cDNA expressed little functional OTC enzyme in vivo and had no observable impact on the underlying metabolic abnormalities of the OTC-deficient mouse (i.e. elevated urinary orotate and serum glutamine). E1-deleted vectors were improved through the use of the strong constitutive promoter from cytomegalovirus driving the normal murine homolog of OTC cDNA and the ablation of E2a with a temperature-sensitive mutation. Infusion of this improved vector into the mouse model was associated with a complete normalization of liver OTC enzyme activity that persisted for at least 2 months with complete but transient correction in serum glutamine and urine orotic acid. These studies illustrate the utility of improved adenoviral vectors in the treatment of liver metabolic disease.

Adenoviridae↗
PubMed1996

Rapid stimulation of EAAC1-mediated Na+-dependent L-glutamate transport activity in C6 glioma cells by phorbol ester.

C6 glioma cells were used as a model system to study the regulation of EAAC1-mediated Na(+)-dependent L-[3H]glutamate transport. Although a 30-min preincubation with forskolin had no effect on transport activity, preincubation with phorbol 12-myristate 13-acetate (PMA) increased transport activity two- to threefold. PMA caused a time-dependent and concentration-dependent increase in EAAC1-mediated L-[3H]glutamate transport activity. A 2-min preincubation with PMA was sufficient to cause more than a twofold increase in transport activity and the protein synthesis inhibitor cycloheximide had no effect on the increase. These data suggest that this increase is independent of protein synthesis. The EC50 value of PMA for stimulation of transport activity was 80 nM. Kinetic analyses demonstrated that the increase in transport activity was due to a 2.5-fold increase in Vmax with no change in Km. PMA also increased the transport of the nonmetabolizable analogue, D-[3H] aspartate to the same extent. In parallel assays, PMA did not, however, increase Na(+)-dependent glycine transport activity in C6 glioma. The inactive phorbol ester alpha-phorbol 12,13- didecanoate, did not stimulate L-[3H]glutamate transport activity, and the protein kinase C inhibitor chelerythrine blocked the stimulation caused by PMA. Okadaic acid and cyclosporin A, which are phosphatase inhibitors, had no effect on the stimulation of transport activity caused by PMA. The Ca2+ ionophore A23187 did not act synergistically to increase PMA stimulation. In previous studies, PMA caused a rapid increase in amiloride-sensitive Na(+)/H+ transport activity in C6 glioma. In the present study, pre- and coincubation with amiloride had no effect on the stimulation of transport activity caused by PMA. These studies suggest that activation of protein kinase C causes a rapid increase in EAAC1-mediated transport activity. This rapid increase in Na(+)-dependent L-[3H]-glutamate transport activity may provide a novel mechanism for protection against acute insults to the CNS.

ATP-Binding Cassette Transporters↗
PubMed1996

Evaluation of the effectiveness of guidelines, audit and feedback: improving the use of intravenous thrombolysis in patients with suspected acute myocardial infarction.

OBJECTIVE: To determine the effectiveness of medical audit as a means of improving the use of intravenous thrombolytics in patients with suspected acute myocardial infarction. DESIGN: Time-series analyses of observations in four study hospitals conducting repeated audits and feedback compared to a control hospital. SETTING: Five district general hospitals in North West Thames Region between April 1991 and July 1992. SUBJECTS: 2593 patients admitted as emergencies with a suspected acute myocardial infarction. MAIN OUTCOME MEASURES: Proportion of eligible cases receiving intravenous thrombolytic therapy observed in each audit and proportion of patients in whom this therapy was used appropriately. RESULTS: In the baseline audits, the proportions of eligible cases receiving thrombolytic therapy in the four study hospitals were 94%, 60%, 58% and 57%, and 53% in the control hospital. After three further audits in each study hospital over the subsequent year, the observed proportions had changed to 88% (to 6%), 92% (+32%), 95% (+37%), and 7796 (+20%). Meanwhile the proportion in the control hospital rose to 68% (+15%). The trend over time was significant in the second and third hospitals but not in the other two study hospitals or the control hospital. Reclassification of those cases in which the reliability of the diagnosis was poor altered the extent but not the direction of observed trends. Generally, the appropriateness of use of thrombolytic therapy increased with increasing treatment rates. There was a suggestion, however, that continued auditing in the presence of high treatment rates may have led to a reduction in appropriateness. CONCLUSIONS: medical audit can be an effective means of improving the use of intravenous thrombolytics. It is possible that over auditing may result in greater inappropriate use.

Algorithms↗
PubMed1996

The glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures.

Because of the well-documented importance of glutamate uptake in protecting neurons against glutamate toxicity, we were interested in testing the effects of L-trans-pyrrolidine-2,4-dicarboxylate (PDC) on rat cortical cultures. This compound is a substrate for glutamate transporters and is a potent glutamate transport inhibitor that does not interact significantly with glutamate receptors. Using a 30 min exposure, and assessing neuronal survival after 20-24 h, PDC was neurotoxic in conventional astrocyte-rich cortical cultures, with an EC50 in these cultures of 320 +/- 157 microM. In astrocyte-poor cultures, an EC50 for PDC of 50 +/- 5 microM was determined. The neurotoxicity of PDC in both astrocyte-rich and astrocyte-poor cultures was blocked by the NMDA antagonist MK-801, but not by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). We tested the possibility that the neurotoxicity of PDC might be due to release of excitatory amino acids using several approaches. After pre-loading cells with the non-metabolizable analogue of glutamate, [3H]-D-aspartate, first we demonstrated that PDC caused significant efflux of [3H]-D-aspartate. This effect of PDC was dependent upon extracellular sodium. In contrast with glutamate neurotoxicity, PDC neurotoxicity was inhibited by removal of extracellular sodium. In the presence of 1 mM PDC, sodium caused neurotoxicity with an EC50 of 18 +/- 7.6 mM. Tetrodotoxin had no effect on either PDC neurotoxicity or on PDC-evoked [3H]-D-aspartate release. PDC-evoked release of [3H]-D-aspartate was demonstrable in astrocyte cultures with no neurons present. PDC also evoked release of endogenous glutamate. Finally, the neurotoxicity of PDC was blocked by coincubation with glutamate-pyruvate transaminase plus pyruvate to degrade extracellular glutamate. These results demonstrate the neurotoxicity of PDC, and suggest that the mechanism of this toxicity is the glutamate transporter-dependent accumulation of glutamate in the extracellular space.

Animals↗
PubMed1996

Comparison of Na+-dependent glutamate transport activity in synaptosomes, C6 glioma, and Xenopus oocytes expressing excitatory amino acid carrier 1 (EAAC1).

Several subtypes of sodium-dependent high affinity (SDHA) glutamate transporters have been pharmacologically differentiated in brain tissue. Recently, four distinct cDNAs (EAAC1, GLT1, GLAST, and EAAT4) encoding Na+-dependent glutamate transporters have been isolated, but the properties of some of these transporters do not fully match the properties of transport observed in brain tissue or astrocyte-enriched cultures. The purpose of the current investigation was to determine whether the pharmacological properties of EAAC1 parallel those observed in cortical or cerebellar synaptosomes, C6 glioma, or primary astrocyte-enriched cultures. EAAC1 cRNA was expressed in Xenopus oocytes, an expression system with no detectable endogenous Na+-dependent glutamate transport activity. EAAC1-mediated glutamate transport was >98% Na+ dependent, and the transport was saturable and consistent with a single site. Glutamate transport activates in EAAC1-injected oocytes and C6 glioma have similar Km values for glutamate (Km = 15-24 microM) and Na+ (apparent Km = 35-50mM), and these values markedly differ from those observed in rat synaptosomes (glutamate, Km = 1-5 microM; Na+, Km = 13-20 mM). Several excitatory amino acid analogues were tested as inhibitors of L-[3H] glutamate transport in oocytes expressing EAAC1 cRNA. The potencies of several compounds for inhibition of EAAC1-mediated transport differed from those previously observed in cerebellar synaptosomes and astrocyte-enriched cultures. Although EAAC1-mediated transport and cortical synaptosomal transport have similar pharmacological profiles, five excitatory amino acid analogues were > or= 3-fold more potent as inhibitors of transport into cortical synaptosomes than of transport into EAAC1-injected oocytes. For example, L-trans-pyrrolidine-2,4-dicarboxylate was approximately 5-fold more potent in cortical synaptosomes, and dihydrokainate was approximately 10-fold more potent in cortical synaptosomes than in EAAC1-injected oocytes. In contrast, all of the compounds examined inhibit transport observed in C6 glioma wtih potencies similar to that observed in oocytes injected with EAAC1 cRNA. Consistent with these data, C6 glioma expressed EAAC1- but not GLT1- and GLAST-like immunoreactivity. Although this immunoreactivity migrated as proteins of slightly different molecular masses in each system, treatment with N-glycosidase F shifted all proteins to a molecular mass consistent with that predicted from the cDNA sequence. In cortical synaptosomes, EAAC1-, GLT1-, and GLAST-like immunoreactives were apparent. These results indicate that (i) EAAC1 but not GLAST or GLT1 transporters are expressed in C6 glioma, (ii) synaptosomes contain a heterogeneous population of transporters, (iii) EAAC1 does not account for the pharmacology previously observed in cortical synaptosomes, and (iv) based on the pharmacology and tissue distribution of EAAC1, GLT1, GLAST, and EAAT4, it appears that there are additional glutamate transporter subtypes.

Amino Acid Transport System X-AG↗
PubMed1995

Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse.

Ornithine carbamoyltransferase deficiency (OCTD) is the most common inborn error of urea synthesis. An X-linked disorder, OCTD males commonly present with hyperammonemic coma in the newborn period. There is a high rate of mortality and morbidity, with most survivors sustaining severe brain damage and resultant developmental disabilities. Although ammonia is presumed to be the principal neurotoxin, there is evidence that other neurochemical alterations may also be involved. The OCTD sparse fur (spf/Y) mouse has proven to be a useful model of this disease with similar metabolic and neurochemical alterations to those found in the human disease. In this study, the levels of the tryptophan derived excitotoxin quinolinic acid were examined in the brains of spf/Y mice. In addition, the neuropathology was examined using both light and electron microscopic approaches. Consistent with reports in children with urea cycle disorders, the levels of tryptophan and quinolinic acid were increased two-fold in various brain regions of the spf/Y mouse. Quinolinic acid, an agonist at the N-methyl-D-aspartate (NMDA) receptors, is known to produce selective cell loss in the striatum. We found a significant loss of medium spiny neurons and increased numbers of reactive oligodendroglia and microglia in the striatum of spf/Y mice. These neurochemical and neuropathological observations are consistent with an excitotoxic influence on brain injury in OCTD. It leads us to suggest that administration of NMDA receptor antagonists may ameliorate brain damage in children with inborn errors of urea synthesis.

Ammonia↗
PubMed1995

Identification of 2-amino-2-methyl-4-phosphonobutanoic acid as an antagonist at the mGlu4a receptor.

2-Amino-2-methyl-4-phosphonobutanoic acid (MAP4) was tested for interactions with the mGlu4a receptor which when expressed in baby hamster kidney (BHK570) cells couples to inhibition of forskolin-stimulated cAMP production. MAP4 had no agonist activity at this receptor and caused a concentration-dependent inhibition of the reduction in forskolin-stimulated cyclic AMP formation elicited by L-2-amino-4-phosphonobutanoic acid (L-AP4). Inhibition by MAP4 was consistent with a competitive mechanism of action (Schild slope = 1.2) with a Ki of 190 microM. MAP4 is the first antagonist identified for the mGlu4a receptor.

Aminobutyrates↗
PubMed1995

Intrastriatal injections of the succinate dehydrogenase inhibitor, malonate, cause a rise in extracellular amino acids that is blocked by MK-801.

The effects of intrastriatal injections of a reversible inhibitor of succinate dehydrogenase, malonate, on the extracellular concentrations of amino acid neurotransmitters were examined using a microdialysis probe that was positioned a fixed distance from an injection cannula. Malonate (2 mumol) caused a 23 +/- 5-fold increase in extracellular glutamate (Glu), a 18 +/- 6-fold increase extracellular gamma-aminobutyric acid (GABA) and a modest increase in extracellular aspartate (Asp, 2.9 +/- 0.8-fold increase). Administration of the NMDA receptor antagonist MK-801 (5 mg/kg) prior to injection of malonate almost completely blocked these increases. This study provides direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular amino acid neurotransmitters and further evidence that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through an excitotoxic mechanism.

Amino Acids↗
PubMed1995

Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus.

L-Glutamic acid (L-Glu) and L-aspartic acid (L-Asp) activate several receptor subtypes, including metabotropic Glu receptors coupled to phosphoinositide (PI) hydrolysis. Quisqualic acid (Quis) is the most potent agonist of these receptors. There is evidence that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the Quis effect. The purpose of the current studies was to use Quis analogs and the recently identified metabotropic receptor antagonist, (+)-alpha-methyl-4-carboxy-phenylglycine((+)-MCPG), to define the structural properties required for interaction with the metabotropic receptors coupled to PI hydrolysis and to determine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or presence of the metabotropic receptor-specific agonist 1SR,3RS-1-amino-1,3-cyclopentanedicarboxylic acid (1SR,3RS-ACPD) in neonatal rat hippocampus. Some of the compounds that induce the Quis effect also stimulate PI hydrolysis, including Quis itself and 9 (homoquisqualic acid). Not all of the Quis analogs that stimulate PI hydrolysis, however, induce the Quis effect, including 7A (EC50 = 750 +/- 150 microM) and (RS)-4-bromohomoibotenic acid (BrHI) (EC50 = 130 +/- 40 microM). Although (+)-MCPG blocked PI hydrolysis stimulated by Quis (IC50 = 370 +/- 70 microM), it had no effect on the induction of the Quis effect. Other Quis analogs did not stimulate PI hydrolysis but rather blocked the effects of 1SR,3RS-ACPD. The IC50 values were 240 +/- 70 microM for 2, 250 +/- 90 microM for 3, and 640 +/- 200 microM for 4. Data for inhibition by 2 and 3 were consistent with non-competitive mechanisms of action. These studies provide new information about the structural features of Quis required for interaction with metabotropic receptors coupled to PI hydrolysis and provide evidence that the Quis effect is not mediated by (+)-MCPG sensitive subtypes of these receptors.

ATP-Binding Cassette Transporters↗
PubMed1995

Pharmacology of sodium-dependent high-affinity L-[3H]glutamate transport in glial cultures.

Pharmacological and molecular biological studies provide evidence for subtypes of sodium-dependent high-affinity glutamate (Glu) transport in the mammalian CNS. At least some of these transporters appear to be selectively expressed in different brain regions or by different cell types. In the present study, the properties of L-[3H]Glu transport were characterized using astrocyte-enriched cultures prepared from cerebellum and cortex. In both brain regions, the kinetic data for sodium-dependent transport were consistent with a single site with Km values of 91 +/- 17 microM in cortical glial cells and 66 +/- 23 microM in cerebellar glial cells. The capacities were 6.1 +/- 1.6 nmol/mg of protein/min in cortical glial cells and 8.4 +/- 0.9 nmol/mg of protein/min in cerebellar glial cells. The potencies of approximately 40 excitatory amino acid analogues for inhibition of sodium-dependent transport into glial cells prepared from cortex and cerebellum were examined, including compounds that are selective inhibitors of transport in synaptosomes prepared from either cerebellum or cortex. Of the analogues tested, 14 inhibited transport activity by > 50% at 1 mM concentrations. Unlike L-[3H]Glu transport in synaptosomes prepared from cerebellum or cortex, there were no large differences between the potencies of compounds for inhibition of transport measured in glial cells prepared from these two brain regions. With the exception of (2S,1'R,2'R)-2-(carboxycyclopropyl)glycine and L-alpha-aminoadipate, all of the compounds examined were approximately 10-200-fold less potent as inhibitors of L-[3H]Glu transport measured in glial cells than as inhibitors of transport measured in synaptosomes prepared from their respective brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Economic evaluation of quality assurance programmes.

Substantial investments are now being made in quality assurance programmes throughout the developed world. Proposes that economic evaluation is one approach to justifying these in terms of value for money. Three key elements are: comparison with some alternative course of action; measurement of costs; and measurement of consequences. Illustrates the difficulties of addressing these by a case-study--an audit programme aiming to increase the use of intravenous thrombolysis for acute myocardial infarction. Discusses the production of accurate costings; the wide confidence limits associated with regression analysis; and the numerous assumptions required in the modelling of effectiveness. Economic evaluation of quality assurance programmes may be useful in future, if the required data can be collected.

Cost-Benefit Analysis↗
PubMed1995

Type 4a metabotropic glutamate receptor: identification of new potent agonists and differentiation from the L-(+)-2-amino-4-phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats.

Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic transmission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent with the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present study, the pharmacology of mGluR4a expressed in baby hamster kidney 570 cells was characterized and compared with that previously reported for the lateral perforant pathway responses. The endogenous excitatory amino acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonists at mGluR4a. The cyclopropyl-AP4 analogue (Z)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP production with an EC50 of 0.58 microM, which is comparable to that of L-AP4 (EC50 = 0.43 microM). Two other cyclic analogues of L-AP4 were approximately 10-fold less potent as agonists at mGluR4a, i.e., (+/-)-1-amino-3-(phosphonomethylene)cyclobutanecarboxylic acid (EC50 = 4.4 microM) and (E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC50 = 7.9 microM). Comparison of the potencies of the compounds for activation of mGluR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold more potent in one of the systems. In addition, although the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L-AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4a does not mediate the effects of L-AP4 in the lateral perforant pathway, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the effects of L-AP4 in the lateral perforant pathway are mediated by a (+)-alpha-methyl-4-carboxyphenylglycine-sensitive receptor.

Aminobutyrates↗