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Biomedical subjects

A J Carter

Publications and source records attributed to A J Carter.

At least 55 records · Page 3Linked to original sources
PubMed1996

Clinical evaluation of a microsample coagulation analyzer, and comparison with existing techniques.

A new microsample coagulation analyzer (Hemochron Jr.) has recently been developed which performs a modified activated clotting time (ACT+) and an aPTT by using different reagents. The Hemochron Jr. measures the clotting time of a 5-microliter whole-blood sample by an optical detector and extrapolates the results to the activated clotting time (ACT+) or the plasma-activated partial thromboplastin time by using a validated regression analysis. We compared 124 simultaneous ACT+ and Hemochron ACTs, and 53 paired Hemochron Jr. aPTTs and hospital laboratory aPTTs, in 44 patients during coronary intervention. The Hemochron Jr. aPTT closely correlated with the lab aPTT (r = .79, P < .0001), and the test results were available much more rapidly than the lab aPTT (3.5 +/- 1.1 vs. 56.3 +/- 25.5 min, P = 0.0029). A comparison of duplicate ACT+ measurements did not identify a significant difference in the means (292 +/- 115 sec vs. 293 +/- 112 sec, P = 0.72). The ACT+ closely correlated with the Hemochron ACTs (r = .85, P < .0001). At baseline, the mean ACT+ (175 +/- 43 sec) exceeded the Hemochron ACT (144 +/- 36 sec) by 22% (P < .001). After heparin administration, the mean ACT+ (378 +/- 74 sec) exceeded the Hemochron ACT (332 +/- 65) by 12% (P < .001). The Hemochron Jr. provides a fast and reproducible methodology for measuring ACT and aPTT, using a small blood volume. Further studies are required to determine the optimal anticoagulation range when using the Hemochron Jr. during or after interventional procedures.

Anticoagulants↗
PubMed1996

Coronary stenting with a novel stainless steel balloon-expandable stent: determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model.

OBJECTIVES: This study evaluated the delivery characteristics and vascular response to placement of a novel balloon-expandable stent in swine with experimentally induced atherosclerosis. BACKGROUND: The Multi-Link stent is a balloon-expandable stainless steel stent with an interconnected ring structure designed to provide a high degree of compressive resistance while preserving longitudinal flexibility. The placement characteristics and vascular response to this stent in atherosclerotic coronary arteries have not been characterized. METHODS: We tested the delivery characteristics and vascular response to the Multi-Link stent in 19 miniature swine with experimentally induced coronary atherosclerosis created in 37 coronary artery segments by overstretch balloon injury and high cholesterol diet. Quantitative coronary angiography was used to define stent performance characteristics, such as lesion dilation and compressive resistance. Pathologic assessment of the stented arteries was used to evaluate the immediate and long-term vascular response to stent placement. RESULTS: Nineteen (95%) of 20 stents were successfully implanted in the left anterior descending (n = 11), left circumflex (n = 7) or right (n = 1) coronary artery. The baseline angiographic minimal lumen diameter of the stented coronary segment was 2.48 +/- 0.09 mm (reference diameter 2.87 +/- 0.06 mm, mean +/- SE) and increased to 2.82 +/- 0.05 mm (p < 0.001) after stent placement. The balloon-inflated stent diameter was 2.98 +/- 0.06 mm with minimal recoil to a final minimal lumen diameter of 2.82 +/- 0.06 mm at 15 min after implantation (p = 0.001). Angiographic and histologic follow-up at 72 h (n = 7), 14 days (n = 4) and 56 days (n = 8) demonstrated that all stents were patent, without evidence of migration, intraluminal filling defects or side branch occlusion. At 56 days, mean neointimal thickness was significantly greater at the stent wire sites in the region of the plaque where the media was absent than the stent wire sites, where the internal elastic lamina was intact with underlying normal media (0.48 +/- 0.01 vs. 0.27 +/- 0.02 mm, p < 0.0001). Compared with the nonstented atherosclerotic lesions, after 56 days the stented vessels had a mildly reduced lumen area when normalized to the proximal reference vessel (2.81 +/- 0.27 vs. 2.68 +/- 0.30 mm2, p = 0.07). The mean change in the area within the external elastic lamina relative to a normal proximal reference segment was significantly greater in stented vessels (1.45 +/- 0.34 mm2) than nonstented atherosclerotic vessels (0.44 +/- 0.28 mm2, p = 0.033). CONCLUSIONS: Morphologic data confirm that the principal beneficial effect of stent placement is vessel expansion and attenuation of constrictive remodeling. In vessels with eccentric atherosclerotic fibrocellular plaques, the presence of normal media underlying the stent determines the degree of neointimal formation. These data may be useful in understanding the mechanism of stent restenosis in patients with prior percutaneous transluminal coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1995

Comparison of bedside and hospital laboratory coagulation studies during and after coronary intervention.

The activated clotting time is routinely used to monitor anticoagulation during coronary intervention, whereas the hospital laboratory APTT guides pre- and postprocedure heparin therapy. An optimal coagulation test for patients undergoing percutaneous revascularization would provide a rapid and accurate assessment of anticoagulation throughout a broad range of heparin therapy. We studied the relationships of the bedside whole blood APTT, ACT, and the laboratory APTT in 166 patients undergoing coronary intervation. The whole blood APTT correlated closely with the laboratory APTT (range 18-80 sec) (r = .75), whereas the ACT and laboratory APTT had only a fair correlation (r = .42). Also, the whole blood APTT demonstrated a strong correlation with the ACT throughout the range of heparin therapy for intervention (r = .81). The diagnostic accuracy of the whole blood APTT, based on the receiver operating characteristic curve, was significantly better than that for the ACT in determining the anticoagulation status. The whole blood APTT obtained by bedside monitoring provides a rapid and accurate assessment of anticoagulation throughout the range of heparin dosing associated with coronary intervention. In situations in which an adequate assessment of residual anticoagulation is necessary, the whole blood APTT is superior to the ACT and probably should be the method of choice.

Angioplasty, Balloon, Coronary↗
PubMed1995

Antagonists of the NMDA receptor-channel complex and motor coordination.

Many structurally different, centrally active antagonists of the NMDA receptor-channel complex induce phencyclidine-like side effects in mammals which include head weaving, body rolling, sniffing and disturbances of motor coordination. The ability of these compounds to cause disturbances of motor coordination correlates directly with their ability to antagonize the NMDA receptor-channel complex in vivo. Although noncompetitive antagonists increase motility in rodents, whereas competitive antagonists do not, both classes of compounds appear to induce schizophrenia-like psychosis in human beings, and cause similar changes in a variety of different biogenic amine neurotransmitter systems in the limbic and motoric areas of the brain. The complex spectrum of behavioural effects observed after the administration of antagonists of the NMDA receptor-channel complex probably reflects the intricate nature of the interaction with positive and negative feedback loops of the motor circuit. Recent research indicates that the site of integration of this interaction could be the striatal medium spiny GABAergic neuron.

Animals↗
PubMed1995

Metabotropic glutamate receptor subtypes differentially influence neuronal recovery from in vitro hypoxia/hypoglycemia in rat hippocampal slices.

Hippocampal slices were transiently exposed to an oxygen- and glucose-free environment which causes a pronounced drop of both ATP and creatine phosphate, an anoxic depolarization, and an incomplete recovery of synaptically evoked population spike in the CA1 region after 1 h (48.5 +/- 3.6% of baseline values). This recovery could be markedly enhanced by the application of N-methyl-D-aspartate receptor antagonists. To examine the influence of metabotropic glutamate receptors on neuronal recovery from hypoxia/hypoglycemia, we applied various antagonists and agonists of the metabotropic glutamate receptors to the bath during the interval from 20 min before to 10 after hypoxia/hypoglycemia. The metabotropic glutamate receptor antagonists (+)-alpha-methyl-4-carboxyphenylglycine and L-2-3- amino-phosphonopropionic acid were both able to enhance the population spike recovery significantly. However, the mixed metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid also exhibited a protective effect on population spike recovery, leaving the anoxic depolarization and N-methyl-D-aspartate responses during the hypoxia/hypoglycemia untouched. With the help of more subtype-specific agonists, we found that an activation of phospholipase C coupled (class 1) metabotropic glutamate receptors prior to hypoxia/hypoglycemia may be responsible for the protective effect seen with 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid, because the specific class 1 metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid appeared to be highly protective, but only if it was applied 20 min before the hypoxia/hypoglycemia. An activation of class 2 metabotropic glutamate receptors by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, which inhibits adenylyl cyclase activity, led to a marked deterioration of the population spike recovery and even to a total prevention of the protective effect of the N-methyl-D-aspartate agonist D-2-amino-5-phosphonopentanoic acid. Our data suggest that prior activation of class 1 metabotropic glutamate receptors is beneficial, while their activation during hypoxia/hypoglycemia is detrimental. Furthermore, the activation of class 2 metabotropic glutamate receptors decreases the recovery from hypoxia/hypoglycemia.

Adenosine Triphosphate↗
PubMed1995

Preincubation with creatine enhances levels of creatine phosphate and prevents anoxic damage in rat hippocampal slices.

We have investigated the relationship between energy metabolism, NMDA-receptor antagonism, and anoxic damage in vitro. Anoxic damage was assessed by measuring protein synthesis, defined as the incorporation of [14C]lysine into perchloric acid-insoluble tissue extracts. The concentrations of energy metabolites were measured by ion-exchange HPLC. Anoxia caused an inhibition of protein synthesis, a reduction in phosphocreatine and adenosine triphosphate, and extensive neuronal damage. The reduction of protein synthesis depended on the duration of anoxia and the time allowed for recovery. Preincubation with the creatine dose-dependently (0.03-3 mmol/L) increased baseline levels of phosphocreatine, reduced the anoxia-induced decline in phosphocreatine and adenosine triphosphate, prevented the impairment of protein synthesis, and reduced neuronal death. Incubation with (R,S)-3-guanidinobutyric acid, a synthetic analogue of creatine that cannot be phosphorylated, did not prevent the anoxia-induced impairment of protein synthesis and did not enhance the levels of phosphocreatine and adenosine triphosphate. Incubation with a combination of both creatine and the noncompetitive NMDA antagonist MK-801 provided complete protection. These results indicate that energy status is a major factor controlling anoxic damage in the rat hippocampal slice.

Animals↗
PubMed1995

Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors.

Caffeine is a commonly used drug that increases arousal, a condition associated with increased cholinergic activity in the mammalian cerebral cortex including the hippocampus. We have used the technique of microdialysis in association with microbore high-performance liquid chromatography to investigate the effects of caffeine on the extracellular levels of acetylcholine in the hippocampus of awake, freely moving rats. The oral administration of caffeine dose-dependently (3-30 mg/kg) increased the extracellular levels of acetylcholine. This increase was completely blocked when the microdialysis probe was perfused with the Na(+)-channel blocker tetrodotoxin, and strongly attenuated when a Ca(2+)-free Ringer solution was used. The effect of caffeine on hippocampal acetylcholine release was concentration-dependently counteracted by local perfusion of an A1 receptor agonist, N6-cyclopentyladenosine (0.1-1 mumol/liter), but not by the A2 receptor agonist, CGS 21680 (10 mumol/liter). Neither agonist affected base-line acetylcholine release at these concentrations. These results demonstrate that acetylcholine release in the hippocampus is under tonic inhibitory control of the endogenous neuromodulator adenosine, and that orally administered caffeine enhances action potential-dependent vesicular acetylcholine release by antagonism of local A1 receptors. Hence, the data provide a possible link between adenosine A1 receptors in the hippocampus, increased cholinergic activity and the psychostimulant effects of caffeine.

Acetylcholine↗
PubMed1995

BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex.

We determined the ability of a new benzomorphan derivative [2R-[2 alpha, 3(R*),6 alpha]]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)- 6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride (BIII 277 CL) to inhibit the N-methyl-D-aspartic acid (NMDA) receptor-channel complex in vitro and in vivo. BIII 277 CL potently displaced [3H]MK-801 binding from the NMDA receptor-channel complex in synaptosomal membrane preparations from rat brain cortex (Ki = 4.49 nmol/l). It was much less effective at displacing [3H]dihydromorphine, [3H]naloxone and [3H]ditolyguanidine binding in similar membrane preparations: the Ki values were 3323, 8031 and 1017 nmol/l, respectively. BIII 277 CL did not exhibit any marked affinities for a variety of other central neurotransmitter receptors. BIII 277 CL antagonized NMDA-induced [3H]noradrenaline release (EC50 = 1.7 mumol/l) and NMDA-induced inhibition of protein synthesis in rat hippocampal slices (EC50 = 3.0 mumol/l). In mice, BIII 277 CL prevented NMDA-induced lethality (ID50 = 0.54 mg/kg s.c.) and, as expected, also caused disturbances in motor coordination in the same dose range (ED50 = 0.47 mg/kg s.c.). The duration of BIII 277 CL was much shorter than than of (+)MK-801 in both tests. Finally, BIII 277 CL (0.3 mg/kg s.c. 5 times over 24 h) reduced the cortical infarct area in mice that had been subjected previously to focal cerebral ischemia by unilateral occlusion of the middle cerebral artery. In summary, these results indicate that BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex which could be used for the treatment of acute thromboembolic stroke in humans.

Animals↗
PubMed1994

Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model.

OBJECTIVES: This study was performed to define the evolution of lesion morphology and its relation to thrombus formation and smooth muscle cell proliferation after experimental coronary stent placement. BACKGROUND: Restenosis after percutaneous revascularization may develop because of thrombus accumulation and smooth muscle cell proliferation. In animal models of restenosis, thrombus may assume a significant role in neointimal formation by providing an absorbable matrix into which smooth muscle cells proliferate. METHODS: Twenty-eight oversized stents were placed in the coronary arteries of 23 juvenile domestic pigs. The histologic degree of vessel injury, lesion morphometry and smooth muscle cell proliferation measured by immunolocalization with a monoclonal antibody to proliferating cell nuclear antigen (PCNA) were assessed at 24 h and 7, 14 and 28 days after stent placement. RESULTS: The area of thrombus was minimal at 24 h ([mean +/- SE] 0.44 +/- 0.12 mm2). Neointimal area at 7 days (0.72 +/- 0.20 mm2) was similar to the area of thrombus, followed by a significant increase at 14 days (3.15 +/- 0.39 mm2) and 28 days (3.30 +/- 0.28 mm2) (p < 0.0036, 24 h and 7 days vs. 14 and 28 days). At 14 and 28 days, neointimal thickness correlated with the histologic degree of vessel injury (p < 0.003). In arteries with severe injury, the increase in neointimal thickness is accounted for by replacement of the damaged media. The smooth muscle cell proliferation index was 18.6 +/- 3.5% at 7 days compared with 9.6 +/- 1.3% by 14 days (p = 0.0247) and declined to 1.1 +/- 0.97% by 28 days (p < 0.008, 7 and 14 days vs. 28 days). CONCLUSIONS: Early thrombus formation is minimal, and thrombus accounts for a small portion of subsequent neointimal formation. Smooth muscle cell proliferation and matrix formation are the major factors relating to neointimal formation in this proliferative model of restenosis. The evolution of neointimal formation after coronary stenting shows maximal smooth muscle cell proliferation at 7 days, with a decline to low levels by 28 days. Therefore, these data may be useful for developing effective therapies for restenosis.

Animals↗
PubMed1994

Microbore high-performance liquid chromatographic method for the measurement of dopamine and its metabolites: recommendations for optimal sample collection and storage.

A microbore high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of small quantities of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in microdialysis samples from rat striatum. The limit of detection of dopamine was in the low nmol/l range (10 fmol/40 microliters dialysate). Standard mixtures of dopamine and its metabolites were stored in tubes made of polypropylene, soda-lime glass or borosilicate glass. Dopamine and homovanillic acid were stable in all three types of container for 24 h providing they were kept at an acidic pH. However, 3,4-dihydroxyphenylacetic acid was only stable in tubes made of polypropylene or borosilicate glass. Basal levels of dopamine in the dialysate obtained from rats which had been chronically implanted with a microdialysis probe in the anterior striatum were stable for one to three days following probe implantation. However, the levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the dialysate decreased rapidly with time after the first day. This indicates that the synthesizing capacity of the neurons is compromised by the microdialysis probe after day one, and that microdialysis experiments in freely moving animals should be confined to the day immediately following probe implantation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Placement and angiographic patency of the Strecker coronary stent.

The Strecker stent is a newer, balloon-expandable vascular prosthesis consisting of a single tantalum filament knitted into a flexible mesh tube. To test the placement characteristics and patency of this device, we implanted 29 stents in the coronary arteries of 24 juvenile Yorkshire swine. Seventeen stents were placed in the left anterior descending artery, and 12 were placed in the left circumflex system. All stents were deployed successfully. Four animals died within the first 24 hr of anesthesia-related complications. The remaining animals were sacrificed at 24 hr, 1 week, 2 weeks, or 4 weeks. Follow-up angiography demonstrated the patency of all stents. There were no episodes of stent migration or side branch occlusion. The Strecker stent has several favorable characteristics, including its unique delivery system, ease of deployment, flexibility, radiopacity, and radial strength. There was 100% patency at up to 4 weeks in this animal model. Further studies are required to define whether the knitted mesh design offers any advantage over previous models.

Angioplasty, Balloon, Coronary↗
PubMed1994

Effect of alpha 1 adrenoceptor antagonists on prostatic pressure and blood pressure in the anesthetized dog.

OBJECTIVES: In the current study we have profiled a range of compounds at alpha 1 adrenoceptor subtypes in vitro and have assessed their effects in vivo using the anesthetized dog in an attempt to elucidate the predominant alpha 1 adrenoceptor subtype mediating contractile responses of the canine prostate. METHODS: The affinity of compounds for alpha 1 adrenoceptor subtypes was determined by displacement of [3H] prazosin binding from stably transfected rat 1 fibroblasts expressing alpha 1A, alpha 1B, and alpha 1C, adrenoceptor subtypes. The potency of these agents was then assessed in vivo using an anesthetized dog model allowing simultaneous measurement of prostatic pressure and blood pressure following intravenous (i.v.) administration of phenylephrine (1 to 128 micrograms/kg). RESULTS: All compounds examined in this study showed high and similar affinity for alpha 1 adrenoceptor subtypes, with the exception of 5-Methyl-urapidil, which was selective for alpha 1C (pKi = 9.3) over alpha 1B (pKi = 7.2) and alpha 1A (pKi = 8.1). Doxazosin, terazosin, alfuzosin, and tamsulosin were potent antagonists of phenylephrine responses and in vivo derived "pseudo pA2" determinations showed that the drugs did not discriminate between prostatic and vascular receptors. 5-Methyl-urapidil was also a potent antagonist of phenylephrine-induced responses but was selective for prostatic pressure ("pseudo pA2" = 8.7) over blood pressure ("pseudo pA2" = 7.2). CONCLUSIONS: Data in the present study suggest a predominant role of the alpha 1C adrenoceptor subtype in the contractile response of the canine prostate to phenylephrine in vivo. This model therefore provides a suitable means of assessing putative prostate-selective antagonists for the treatment of benign prostatic hyperplasia.

Adrenergic alpha-Antagonists↗
PubMed1994

Many agents that antagonize the NMDA receptor-channel complex in vivo also cause disturbances of motor coordination.

Antagonists of the NMDA receptor-channel complex may be useful for the treatment of thrombotic stroke, head injury and epilepsy. Their clinical use, however, could be limited by the incidence of side effects such as ataxia. I have therefore investigated the relationship between functional antagonism of the N-methyl-D-aspartate (NMDA) receptor-channel complex in vivo and disturbances of motor coordination. Antagonism of the NMDA receptor-channel complex was assessed by measuring a compounds ability to inhibit NMDA-induced lethality in mice, disturbances of motor coordination were measured by the rotarod technique. NMDA dose-dependently induced convulsions and ultimately caused death in mice (LD50 = 137 +/- 4 mg/kg i.p.). Noncompetitive NMDA antagonists of either an arylcyclohexylamine (phencyclidine, (+)/(-)-MK-801 [10-11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate] and ketamine) or a benzomorphan (dextrorphan and N-allylnormetazocine) structure, competitive antagonists (CGP 37849 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid monohydrate] and CGP 39551 [(R,S)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid 1-ethyl ester]) or a glycine site antagonist (L-687,414 [(3R,4R)-3-amino-4-methyl-1-hydroxy-pyrrolidin-2-one-(-)-tartrate salt]) inhibited NMDA-induced lethality after s.c. administration. These compounds also interfered with motor coordination. There was an excellent correlation (r = 0.97) between the two effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Aortic thrombosis in a dog with glomerulonephritis.

A Bearded Collie was presented with clinical signs of intermittent weakness, intermittent pain in the back legs and a bilateral absence of the femoral pulse. Further diagnostic investigations revealed proteinuria, hypoproteinaemia, hyperlipidaemia and azotaemia. A quantitative estimation of the proteinuria using a protein/creatinine ratio indicated a loss of 483 mg kg-1 of protein per day. A large caudal aortic thrombosis was demonstrated by means of non-selective angiography and ultrasonographic examination. Autopsy confirmed an extensive aortic thrombus extending from the level of the fourth lumbar vertebra to include both iliac and femoral arteries at the level of the stifle joints. A large thrombus, 4 cm in length, was also found in the pulmonary artery. Histopathological examination of the kidneys revealed a subacute to chronic membranoproliferative glomerulonephritis.

Animals↗
PubMed1991

Pramipexole, a dopamine D2 autoreceptor agonist, decreases the extracellular concentration of dopamine in vivo.

Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 micrograms/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 micrograms/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 micrograms/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor.

3,4-Dihydroxyphenylacetic Acid↗