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Biomedical subjects

B M Lewis

Publications and source records attributed to B M Lewis.

At least 19 recordsLinked to original sources
PubMed1994

Piperidinyltetralin sigma ligands.

Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).

Aggression↗
PubMed1987

The effects of neonatal hypothyroidism on brain catecholamine turnover in adult rats: assessment by a steady-state method.

The effects of hypothyroidism in utero, and continuing into postnatal life, on the central turnover of catecholamines, noradrenaline and dopamine were studied in rats. Rats were rendered hypothyroid in utero by treating pregnant females with methimazole in the drinking water. In two groups goitrogen treatment continued for 3 or 10 weeks postnatally. Methimazole treatment in utero did not produce significant changes in noradrenaline, dopamine or tyrosine content in either the hypothalamus or striatum. Three weeks' postnatal treatment reduced tyrosine specific radioactivity in the anterior hypothalamus and dopamine specific radioactivity in the striatum. Ten weeks' treatment increased dopamine content and reduced noradrenaline synthesis in the mediobasal hypothalamus and a reduction in tyrosine content in the anterior hypothalamus. These data suggest that hypothyroidism restricted to intrauterine life does not produce permanent changes in adult catecholamine neuronal function. Long term hypothyroidism produced localized changes, suggesting a specific rather than general effect.

Animals↗
PubMed1987

Dopamine stimulates release of thyrotrophin-releasing hormone from perfused intact rat hypothalamus via hypothalamic D2-receptors.

We have studied the effect of dopamine together with agonist and antagonist drugs of different specificities on the release of TRH from the perfused, intact hypothalamus of the adult rat in vitro. Dopamine produced a dose-related stimulatory effect on TRH release with maximal effect being achieved at 1 mumol/l (increase over basal, 118 +/- 16.5 (S.E.M.) fmol TRH; P less than 0.001 vs basal). This effect was mimicked by the specific D2-agonist drugs bromocriptine (0.1 mumol/l) and LY 171555 (0.1 mumol/l) (increase over basal values, 137.5 +/- 13.75 fmol and 158.6 +/- 10.7 fmol respectively; P less than 0.001 vs basal), but not by the D1-agonist SKF 38393A. The stimulatory effect of dopamine (1 mumol/l) was blocked in a stereospecific manner by the active (D) but not by the inactive (L) isomers of the dopamine antagonist butaclamol. Similar blockade was achieved with the specific D2-antagonist domperidone (0.01 mumol/l) whereas the D1-antagonist SCH 23390 was only effective when used at a concentration 100 times greater. Lower concentrations (0.01 mumol/l) of this D1-antagonist did not block the stimulatory effect of dopamine. High-performance liquid chromatography characterization of the material secreted within the hypothalamus showed one single peak of immunoreactive material which coeluted with synthetic TRH. These data suggest that dopamine exerts a stimulatory role in the control of hypothalamic TRH release by acting at specific D2-receptors.

Animals↗
PubMed1986

Hypothalamic D2 receptors mediate the preferential release of somatostatin-28 in response to dopaminergic stimulation.

We have studied the effect of dopamine (DA) together with agonist and antagonist drugs of varying specificity on the release of immunoreactive forms of somatostatin (SS) from the perfused, adult rat hypothalamus in vitro. Levels of SS increased from 14.7 +/- 3.7 pg (mean +/- SE) under basal conditions to 137 +/- 23.0 pg after exposure to 10(-6) M DA. This dopaminergic effect was mimicked by the specific D2 agonists bromocriptine (10(-7) M) and LY 171555 (10(-6) M) but not by the D1 agonist SKF 38393A (10(-6) M). The stimulatory action of DA (10(-6) M) was blocked by the active (d) but not the inactive (l) isomer of butaclamol (10(-7) M). Similar blockade was achieved with the specific D2 antagonists metoclopramide (10(-8) M) and domperidone (10(-8) M), whereas the D1 antagonist SCH 23390 partially blocked the stimulation of DA but only when used at X100 greater concentration (10(-6) M). SCH 23390 (10(-8) M) did not affect the dopaminergic stimulation of SS release. HPLC characterization of the immunoreactive forms of SS yielded two peaks which corresponded to SS-28 and SS-14. The ratio of these forms varied significantly under different conditions. In the basal state the ratio of SS-28 to SS-14 was 1:4.4; in response to stimulation with DA, the ratio was 1:1.7 and in response to depolarization with 60 mM K+ the ratio was 1:3.1. In conclusion, the stimulatory action of DA on SS release is mediated via hypothalamic D2 receptors. Furthermore dopaminergic stimulation increases the molar ratio of SS-28 to SS-14 in the total immunoreactive SS which is released.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Effects of thyroid status on brain catecholamine biosynthesis in adult rats: assessment by a steady-state method.

Effects of thyroid status on brain catecholamine turnover in adult rats were investigated using a steady-state method. Rats were treated for 3 weeks with s.c. injections of L-thyroxine (0.4 mg/kg), aminotriazole in drinking water (0.1%, w/v) or vehicle. After 2 weeks of treatment rats were implanted chronically with lateral intracerebroventricular (i.c.v.) cannulae. They were injected i.c.v. with [3H]tyrosine 1 week later. Catecholamine and tyrosine content and specific activity were measured in mediobasal hypothalamus, anterior hypothalamus and striatum, using high-performance liquid chromatography with electrochemical detection. Thyroxine treatment resulted in a significant increase in noradrenaline and dopamine synthesis localized to the mediobasal hypothalamus. Conversely, aminotriazole treatment resulted in a significant decrease in noradrenaline synthesis localized to the mediobasal hypothalamus. The localization of these changes in catecholamine turnover to the mediobasal hypothalamus suggests that they may be specific functional effects which are of importance in the overall integrated control of thyroid function.

Amitrole↗
PubMed1985

An in vivo steady-state method for the determination of catecholamine biosynthesis in the rat brain using high-performance liquid chromatography with electrochemical detection.

A technique is described for the measurement of steady-state catecholamine (CA) synthesis in the rat brain in vivo, using [3H]tyrosine incorporation with high-performance liquid chromatography (HPLC) and electrochemical detection. Adult male rats chronically implanted with lateral intracerebroventricular (i.c.v.) cannulas, were injected i.c.v. with [3H]tyrosine. CA and tyrosine content and specific activity were measured in mediobasal hypothalamus, anterior hypothalamus and striatum. A time-dependent increase in CA synthesis occurred in all tissues over 20 min post-i.c.v. injection. The technique described may prove to be useful in the assessment of central neurotransmitter turnover in various physiological and pharmacological settings.

Animals↗
PubMed1983

Measurement of arterial blood gases at the transition from exercise to rest.

Arterial blood gas samples obtained 5-20 s after stair-climbing exercise were compared with samples taken during the last 30 s of exercise in 137 subjects. Arterial partial pressure of CO2 (PaCO2) did not change significantly, and in 110 subjects the two samples were within the analytical variation (+/- 2 Torr), supporting the cardiodynamic hypothesis of respiratory regulation. Exceptions to this response were 10 subjects who hyperventilated (PaCO2 less than 34) during exercise and 15 with severe obstruction [forced expiratory volume in 1 s (FEV1) less than 70% forced vital capacity (FVC), and FVC less than 70% of predicted] in whom PaCO2 increased significantly. Overall, arterial partial pressure of O2 (PaO2) increased an average of 3.49 Torr (P less than 0.001). In the two groups in which PaCO2 increased, postexercise PaO2 did not rise. In addition, duration of exercise affected PaO2 response. PaO2 increased significantly more after brief (less than 2 min) periods than after longer (4-6 min) exercise, and this difference increased only when subjects with normal or borderline ventilatory function were analyzed. In 13 subjects in whom a second sample was taken 30-45 s after exercise, the increase in PaO2 was progressive and again the difference between short and long exercise was evident. Regulation of respiration to maintain PaCO2 and changes in O2-CO2 kinetics, leading to an increase in the gas exchange ratio at the exercise-rest transition, are the most likely explanations of these data which establish that the usual response to stopping exercise in normal subjects and most patients is an unchanged PaCO2 and a variable increase in PaO2.

Aged↗
PubMed1981

Pitfalls of spirometry.

Many spirograms cannot be interpreted properly even when the technician is expert. The criteria of an interpretable spirogram are (1) full inspiration, (2) quick attainment of highest flow, (3) continuous decrease in flow with expiration, (4) smooth, gradual termination, and (5) expiration lasting three seconds or more. Violation of these criteria leads to "pseudo-obstruction" when expiration is not forceful, to "concealed obstruction" when the graphic record is started late and to two kinds of "pseudo-restriction," one due to inadequate inspiration and the other to premature termination of expiration. A "decision tree" for dealing with large volumes of spirometric data is presented.

Diagnostic Errors↗
PubMed1980

Routine pulmonary function tests during bleomycin therapy. Tests may be ineffective and potentially misleading.

Forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) studies in two patients with proved interstitial fibrosis after low doses of bleomycin were contrasted with these measurements in 21 patients who received bleomycin without toxicity. The FVC decreased significantly (20% or more) in both fibrosis patients and in seven others. In one fibrosis patient and in three others the results could be explained by weakness. The DLco fell in both patients with fibrosis and in 12 others. Correction for decrease in hemoglobin level accounted for the change in one of the toxic patients and seven of the others, but hemoglobin correction made two insignificant changes significant and increased therapy values above control four times. Since these tests have many false-positive results and can be affected by weakness and anemia leading to false-negative results their use is ineffective and may be misleading.

Bleomycin↗
PubMed1978

The treatment of hypertension with verapamil.

In a randomised double blind cross over trial, verapamil produced significant dose dependent reductions in blood pressure in 23 patients. There were minimal side-effects. All patients had some contraindication to the use of beta blocker therapy, and the role of verapmil in this situation is discussed.

Adult↗
PubMed1978

Adipose tissue cellularity: effect on insulin and thyroxine.

The influence of insulin and thyroxine on the cellularity of adipose tissue in the rat epididymal fat pad has been studied. Incorporation of (3H) thymidine into the DNA of fat cells and stroma was measured together with fat cell size and number in rats pre-treated with either one of these hormones. There was an increase in fat pad weight in insulin treated rats which was due to 'lipid filling' of existing adipocytes and not increased proliferation of new fat cells. Thyroxine treated rats showed a decrease in fat pad weight caused by a decrease in size of individual fat cells. Cell number remained unaffected by either treatment.

Adipose Tissue↗
PubMed1975

The effect of age on deoxyribonucleic acid synthesis in rat adipose tissue.

1. Rats of four different age groups were injected intraperitoneally with labelled thymidine and killed 1, 7 or 12 days later. 2. The epididymal fat-pads were separated into fat-cells and stromal elements by collagenase digestion. 3. The incorporation of labelled thymidine into the deoxyribonucleic acid (DNA) of both fractions was greatest in the 6-week-old animals. Uptake was significantly decreased in 12- and 15-week-old animals and was lowest in 22-week-old rats.

Adipose Tissue↗