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L Cook

Publications and source records attributed to L Cook.

At least 145 records · Page 8Linked to original sources
PubMed1983

Biochemical properties of short- and long-chain rat liver microsomal trans-2-enoyl coenzyme A reductase.

This study describes the biochemical properties of the rat hepatic microsomal NADPH-specific short-chain enoyl CoA reductase and NAD(P)H-dependent long-chain enoyl CoA reductase. Of the substrates tested, crotonyl CoA and trans-2-hexenoyl CoA are reduced by the short-chain reductase only in the presence of NADPH. The trans-2-octenoyl CoA and trans-2-decenoyl CoA appear to undergo reduction to octanoate and decanoate, respectively, catalyzed by both enzymes; 64% conversion of the C8:1 is catalyzed by the short-chain reductase, while 36% conversion is catalyzed by the long-chain enzyme. For the C10:1 substrate, 45% is converted by the short-chain reductase, while 55% is reduced by the long-chain reductase. trans-2-Hexadecenoyl CoA is a substrate for the long-chain enoyl CoA reductase only. Reduction of C4 and C6 enoyl CoA's was unaffected by bovine serum albumin (BSA), whereas BSA markedly stimulated the conversion of C10 and C16 enoyl CoA's to their respective saturated product. Reduction rates as a function of microsomal protein concentration, incubation time, pH, and cofactors are reported including the apparent Km and Vmax for substrates and cofactors. In general, the apparent Km's for the substrates ranged from 19 to 125 microM. The apparent Vmax for the short-chain enoyl CoA reductase was greatest with trans-2-hexenoyl CoA, having a turnover of 65 nmol/min/mg microsomal protein, while the apparent Vmax for the long-chain enzyme was greatest with trans-2-hexadecenoyl CoA, having a turnover of 55 nmol/min/mg microsomal protein. With respect to electron input, NADPH-cytochrome P-450 reductase, either alone, mixed with phospholipid, or incorporated into phospholipid vesicles, possessed no enoyl CoA reductase activity. Cytochrome c did not affect the NADPH-dependent conversion of the trans-2-enoyl CoA. In addition, anti-NADPH-cytochrome P-450 reductase IgG did not inhibit the reduction of trans-2-hexadecenoyl CoA in hepatic microsomes. Finally, the NADPH-specific short-chain and NAD(P)H-dependent long-chain enoyl CoA reductases were solubilized and completely separated from NADPH-cytochrome P-450 reductase by employing DE-52 column chromatography. These studies demonstrate the noninvolvement of NADPH-cytochrome P-450 reductase in either the short-chain (13) or long-chain enoyl CoA reductase system. Thus, the role of NADPH-cytochrome P-450 reductase in the microsomal elongation of fatty acids appears to be at the level of the first reduction step.

Animals↗
PubMed1983

Kinetic evidence for two separate trans-2-enoyl CoA reductases in rat hepatic microsomes: NADPH-specific short chain- and NAD(P)H-dependent long chain-reductase.

The rat hepatic microsomal conversion of crotonyl- and hexenoyl CoA to butyrate and hexanoate was supported only by NADPH, while both NADH and NADPH were effective cofactors in the conversion of trans-2-hexadecenoyl CoA to palmitate. Experiments using mixtures of long- and short-chain enoyl-CoA substrates and competition experiments support the conclusion that microsomes contain 2 distinct enoyl CoA reductases, (1) a long chain enoyl CoA reductase capable of accepting reducing equivalents from either NADH or NADPH, and (2) a NADPH-specific short chain enoyl CoA reductase.

Animals↗
PubMed1983

Structural and genetic heterogeneity of the receptor mediating translocation of immunoglobulin A dimer antibodies across epithelia in the rabbit.

Secretory component (SC), synthesized as a transmembrane protein, acts as the receptor that binds IgA dimers and mediates their transepithelial transport. Cleavage of the receptor (membrane SC) apparently occurs during transport and a fragment, the secreted form, is generated, which remains tightly bound to the IgA dimer. In the rabbit, variation in the size of membrane SC is observed with both a high and a low molecular weight family, each composed either of two or of four distinct polypeptides depending on the individual rabbit. The same degree of size heterogeneity is observed for secreted SC. Part of this size heterogeneity is related to genetic polymorphism. The milk of individual rabbits typed with anti-SC-allotype sera reveals three different banding patterns. The simplest pattern, found in t61/t61 and t62/t62 homozygotes, consists of an upper and a lower doublet. Since each band of these two doublets in the t62 allotype migrates slightly faster than its counterpart in the t61 allotype, a composite pattern is observed in the heterozygotes (t61/t62). Within a given allotypic group, all SC polypeptide chains expressed the identical allotypic specificity. The 2000 to 4000 difference in molecular weight between the two forms of a doublet probably reflects differences in the number of glycosylated asparagine residues, since individual bands of a doublet show identical peptide maps. High and low molecular weight families are also structurally related to each other as shown by one-dimensional peptide maps and identical NH2- and COOH-terminal amino acid sequences. These results indicate that the 25-kDa size difference between SC from the high and low molecular weight families reflects an intramolecular deletion.

Amino Acid Sequence↗
PubMed1983

Pharmacological effects of Ro 22-1319: a new antipsychotic agent.

Ro 22-1319, a novel pyrroloisoquinoline compound, was identified as a potential antipsychotic agent in a rat discrete avoidance procedure that is highly specific for such agents. Results in this test are highly correlated with the clinical potency of all types of antipsychotic agents. The avoidance-blocking potency of Ro 22-1319 (0.7 mg/kg) in this procedure approached that of haloperidol (0.4 mg/kg) and was 7- and 12-times greater than that of chlorpromazine and clozapine, respectively. Ro 22-1319 exhibited similar high potency in other rat and monkey avoidance procedures, rat motor activity, and antagonism of apomorphine emesis in dogs. High potency and antipsychotic-like activity have been demonstrated in monkey EEG and in an in vivo 3H-spiroperidol binding assay. Although studies of amphetamine antagonism in rats indicate antidopaminergic activity at nigrostriatal sites, Ro 22-1319 exhibited relatively weaker cataleptogenic and antistereotypic activity than haloperidol, and had minimal activity in a rat chronic stereotypy model of receptor supersensitivity. This profile suggests that Ro 22-1319 is an efficacious antipsychotic compound, almost as potent as haloperidol, with fewer or less intense extrapyramidal effects and low potential for tardive dyskinesia.

Amphetamine↗
PubMed1983

The induction of atrial flutter and fibrillation and the termination of atrial flutter by esophageal pacing.

In patients with Wolff-Parkinson-White syndrome (WPW), it is important to assess the ventricular response during atrial flutter or fibrillation since conduction across the accessory pathway during these atrial rhythms may cause hemodynamic impairment or life-threatening ventricular arrhythmias. We have recently reported the effective use of an esophageal electrode in pacing the atrium. In this study we prospectively assessed the ability to induce atrial flutter and fibrillation by esophageal pacing in 23 patients with WPW or other electrophysiological abnormalities. An esophageal bipolar electrode with 29 mm interelectrode distance was positioned in the esophagus to record the most rapid and largest esophageal electrogram (mean distance of 36.6 +/- 2.9 cm (SD) from the nares). Pacing was performed at cycle lengths of 40-340 ms (mean 166 +/- 72), pulse durations of 7.0-9.9 ms, and currents of 10-25 mA. Atrial flutter alone was induced in 6 patients, fibrillation alone in 11 patients, and both arrhythmias in 5 patients. In one patient neither flutter nor fibrillation was induced by esophageal pacing, and fibrillation was induced only with difficulty using intracavitary pacing. Of the 11 patients with flutter, the arrhythmia was terminated in 8 by esophageal pacing at cycle lengths of 160-220 ms (mean 176 +/- 18 ms). All patients tolerated the procedure well with only mild to moderate discomfort. Therefore, esophageal pacing appears to offer an effective, well tolerated method of initiating atrial fibrillation and flutter and terminating atrial flutter and offers a potentially useful noninvasive method of following patients serially.

Adolescent↗
PubMed1983

Methodologic approach to adverse events applied to bupropion clinical trials.

A strategy for identifying and classifying adverse events and for assessing their relationship to therapy and frequency of occurrence is presented. Data from clinical trials of bupropion (Wellbutrin), a novel antidepressant, are presented as an example. Bupropion was studied in four double-blind, placebo-controlled trials (N = 360) at dosages of 300-750 mg/day. The incidence and frequency of adverse events associated with bupropion were minimal, and correlated well with the known pharmacologic and clinical properties of this new antidepressant.

Akathisia, Drug-Induced↗
PubMed1982

Evidence for a second microsomal trans-2-enoyl coenzyme A reductase in rat liver. NADPH-specific short chain reductase.

Evidence for the existence of a previously unknown rat hepatic microsomal reductase, short chain trans-2-enoyl-CoA reductase (SC reductase) is presented. This reductase has a specific requirement for NADPH, is unable to utilize NADH, and catalyzes the conversion of crotonyl-CoA and trans-2-hexenoyl-CoA to butyric acid and hexenoic acid at a rate of 5 and 65 nmol per min per mg of microsomal protein, respectively. Highly purified NADPH cytochrome P-450 reductase incorporated into liposomes prepared from dilauroyl phosphatidylcholine in the presence or absence of cytochrome P-450 possesses no SC reductase activity. These liposomal preparations did, however, catalyze mixed function oxidations of benzphetamine and testosterone. Rabbit antibody to rat liver NADPH cytochrome P-450 reductase had little to no effect on the conversion of crotonyl-CoA and trans-2-hexenoyl-CoA, suggesting that the SC reductase accepts reducing equivalents directly from NADPH. When acetoacetyl-CoA was incubated with hepatic microsomes and either NADH or NADPH, no formation of butyrate was detected; however, when both cofactors were present, a rate of formation of 3 nmol of butyrate was determined per min per mg of microsomal protein. These results suggest the presence of a previously unknown short chain beta-ketoreductase which catalyzes the reduction of short chain beta-keto acids, only in the presence of NADH. Our results also indicate that the electrons from NADH to the beta-ketoreductase bypass cytochrome b5. The physiological significance is discussed in terms of lipogenesis and ketone body utilization by the liver.

Animals↗
PubMed1982

Electrophysiologic effects of disopyramide phosphate in patients with Wolff-Parkinson-White syndrome.

We evaluated the electrophysiologic effects of disopyramide phosphate in 12 patients with the Wolff-Parkinson-White syndrome. Electrophysiologic studies were performed during a control period and after administering i.v. disopyramide (four bolus doses of 9.5 mg/kg over 40 minutes superimposed on a continuous infusion at 1.0 mg/kg/hour). All patients were then restudied after 3 days on oral medication in doses of 800-1200 mg/day. In all patients we tried to induce reciprocating tachycardia and atrial fibrillation. The cycle length during reciprocating tachycardia was not changed by i.v. disopyramide, but increased after oral disopyramide, from 331 +/- 53 (+/- SD) to 370 +/- 68 msec (p less than 0.01). This increase occurred predominantly as a result of prolongation of retrograde conduction time in the accessory pathway. Despite prolonging cycle length during reciprocating tachycardia, disopyramide did not prevent its induction. The shortest and mean RR intervals during atrial fibrillation were used to assess antegrade refractoriness of the accessory pathway. Intravenous disopyramide prolonged the shortest RR from 169 +/- 18 to 226 +/- 24 msec (p less than 0.0001) and the mean RR from 255 +/- 58 to 329 +/- 62 msec (p less than 0.005). Oral disopyramide prolonged the shortest RR interval from 169 +/- 18 to 248 +/- 36 msec (p less than 0.0001) and the mean RR from 255 +/- 58 to 360 +/- 93 msec (p less than 0.001). After oral disopyramide, the episodes of atrial fibrillation were shorter and self-terminating. No acute hemodynamic side effects were observed, but five patients developed gastrointestinal or anticholinergic side effects on oral disopyramide. Seven patients elected to have surgical interruption of their accessory pathways and five have been successfully treated with oral disopyramide for 14-33 months. Disopyramide appears to have beneficial electrophysiologic effects in patients with Wolff-Parkinson-White syndrome. Prolongation of refractoriness in the accessory pathway markedly slows the ventricular response during atrial fibrillation and therefore prevents the development of life-threatening arrhythmias.

Administration, Oral↗
PubMed1981

Quantitative morphological analysis of interatrial muscle cells in the ferret heart.

Cells located in the interatrial septum of the ferret heart were examined and mean cell volume, surface area, length, width, as well as cell length/width and surface area/volume ratios were obtained. The muscle cells were from two different regions. One region was the area of the middle internodal tract while the other was from the area where the anterior and middle internodal tracts intermingled. Based on the data obtained, at least two different subpopulations of interatrial muscle cells could be defined. The larger cells had a mean cell length of 109.7 micrometer, a mean cell width of 13.1 micrometer, a length/width ratio of 8.61, a mean cell surface area of 5,057.6 micrometer2, a mean cell volume of 5960.8 micrometer3, and a surface area/volume ratio of 0.87. The smaller cells had a mean cell length of 58.0 micrometer, a mean cell width of 12.2 micrometer, a length/width ratio of 4.85, a mean cell surface area of 2494.1 micrometer2, a mean cell volume of 2553.6 micrometer3, and a surface area/volume ratio of 1.00. The large cell population had cells that were myofibril rich and also others that were myofibril poor. These quantitative data indicate that the regions of internodal pathways are not composed of a single specialized cell type, but rather are composed of at least two, if not more, cell types that intermingle with each other.

Animals↗
PubMed1981

Effects of diazepam on operant behavior in man.

The effects of diazepam (10 mg orally) on the responding of normal human volunteers was studied in a procedure that involved the maintenance of operant behavior by monetary reinforcement and its suppression by monetary loss (punishment). Diazepam produced an antipunishment effect as shown by an increase in behavior suppressed by monetary loss. An analogy to animal procedures that selectively detect antianxiety drugs is apparent.

Adult↗
PubMed1981

Detecting ductal shunting in premature infants by range-gated Doppler echocardiography.

Range-gated pulsed Doppler echocardiography has been reported to be a useful noninvasive bedside technic for detecting ductal left-to-right shunting in premature infants. We studied 30 premature infants with a birth weight of less than 1,500 gm, using a 5 MHz system developed by Advanced Technology Laboratories. An umbilical artery catheter was used to obtain a contrast aortogram. Twenty-three infants had both a positive flush aortogram and a continuous turbulence documented by Doppler echocardiography. A clinically audible murmur was present in 17 of these patients. In six infants there was no Doppler evidence of PDA. In five of this last group there was also a negative flush aortogram. The excellent correlation found between the Doppler and aortographic studies suggests that this noninvasive technic is very sensitive for detecting ductal left-to-right shunting, even in the absence of an audible murmur.

Aortography↗
PubMed1981

The use of a computerized algorithm to determine single cardiac cell volumes.

Single cardiac muscles cell volume data have been difficult to obtain, especially because the shape of a cell is quite complex. With the aid of a surface reconstruction method, a cell volume estimation algorithm has been developed that can be used on serial of cells. The cell surface is reconstructed by means of triangular tiles so that the cell is represented as a polyhedron. When this algorithm was tested on computer generated surfaces of a known volume, the difference was less than 1.6%. Serial sections of two phantoms of a known volume were also reconstructed and a comparison of the mathematically derived volumes and the computed volume estimations gave a per cent difference of between 2.8% and 4.1%. Finally cell volumes derived using conventional methods and volumes calculated using the algorithm were compared. The mean atrial muscle cell volume derived using conventional methods was 7752.7 +/- 644.7 micrometers3, while the mean computerized algorithm estimated atrial muscle cell volume was 7110.6 +/- 625.5 micrometers3. For AV bundle cells the mean cell volume obtained by conventional methods was 484.4 +/- 88.8 micrometers3 and the volume derived from the computer algorithm was 506.0 +/- 78.5 micrometers3. The differences between the volumes calculated using conventional methods and the algorithm were not significantly different.

Animals↗
PubMed1981

Pharmacology of midazolam.

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Anesthetics↗