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A Barnett

Publications and source records attributed to A Barnett.

At least 109 records · Page 6Linked to original sources
PubMed1986

D-1 dopamine receptors in the rat brain: a quantitative autoradiographic analysis.

The distribution of dopamine D-1 receptors has been determined in the rat brain by a quantitative in vitro light-microscopic autoradiographic method. The binding of [N-methyl-3H]-SCH 23390 to slide-mounted tissue sections takes place with characteristics expected of a substance that recognizes D-1 receptors. The binding is saturable, has high affinity, and exhibits an appropriate pharmacology and stereospecificity in several discrete microscopic brain regions as determined by quantitative autoradiography. The highest density of D-1 receptors occurs in the caudate-putamen, accumbens nucleus, olfactory tubercle, and the substantia nigra pars reticulata. High concentrations of D-1 receptors were associated with the intercalated and medial nuclei of the amygdala, entopeduncular nucleus, and major island of Calleja. Furthermore, moderate to low concentrations were observed in several other structures, such as the frontal cortex, subthalamic nucleus, and several thalamic, hypothalamic, and hippocampal areas. The distribution of D-1 receptors correlates very well with projection areas of dopaminergic pathways. This technique furnishes a powerful assay for the accumulation of detailed pharmacologic and anatomical data about D-1 receptors, and the results suggest possible CNS sites of action of D-1 dopamine receptor selective compounds.

Animals↗
PubMed1986

AGEPC, a vasodilator phospholipid with profound circulatory actions.

Acetyl-glyceryl-ether-phosphoryl-choline (AGEPC) is a potent platelet activating factor which induces profound circulatory changes. AGEPC is synthesized in a variety of cell types including platelets, neutrophils, macrophages, basophils and endothelial cells. Biological responses include platelet activation, neutrophil activation, release of arachidonic acid metabolites and systemic anaphylaxis. Circulatory responses to AGEPC were evaluated in the present investigation. Intravenous administration of AGEPC (30 micrograms/kg/min) to anesthetized dogs reduced blood pressure, cardiac output, myocardial contractile force, renal blood flow and glomerular filtration. Intracoronary administration of AGEPC (0.3-3 micrograms) reduced blood pressure, coronary blood flow, and myocardial contractile force. Administration of AGEPC into the femoral vascular bed increased femoral artery blood flow. The data suggest that the circulatory response to AGEPC in the dog is complex and depends on the site of administration. The predominant response is hypotension mediated at least in part through myocardial depression. Intramuscular injection of AGEPC (10-30 micrograms/kg) to conscious spontaneously hypertensive rats (SHRs) reduced systemic blood pressure and increased heart rate. In pithed rats, AGEPC decreased pressor responses to sympathetic stimulation, angiotensin II and phenylephrine. Chronotropic responses were unchanged. Thus, antihypertensive doses of AGEPC reduced pressor responsiveness nonspecifically, but do not affect pre- or post-junctional adrenergic mechanisms. High concentrations of AGEPC (100 microM) relaxed phenylephrine contracted rabbit aortic rings. Relaxation was dependent on an intact endothelium. Lyso-GEPC produced similar actions. In light of the low potency of AGEPC and the activity of lyso-GEPC, physiological significance to endothelium dependent relaxation by AGEPC in rabbit aortic rings is unlikely. The physiological role of AGEPC in circulatory homeostasis is unclear at present. AGEPC may play a hypotensive role in some forms of experimental hypertension. In addition, AGEPC may mediate part of the circulatory derangements associated with cardiac anaphylaxis. Lastly, AGEPC may be involved in circulatory control during states of platelet and/or neutrophil activation such as myocardial ischemia and shock.

Animals↗
PubMed1985

Autoradiographic demonstration of the selectivity of two 1-N-trifluoroethyl benzodiazepines for the BZD-1 receptors in the rat brain.

Receptor autoradiographic techniques have been used to demonstrate the selectivity of two trifluoroethyl-containing benzodiazepines for one of the subtypes of benzodiazepine receptor. Indirect localization of the binding sites for quazepam and halazepam was accomplished by using the ability of these compounds to displace [3H]-flunitrazepam binding. The appropriate binding parameters were selected on the basis of initial studies aimed at identifying the binding characteristics of several benzodiazepine compounds in comparison with the triazolopyridine CL218,872. Autoradiographic analysis of the benzodiazepine sites displaceable with quazepam and halazepam revealed the two benzodiazepine compounds preferentially labeled receptor sites in regions of the brain dominated by the type 1 benzodiazepine receptor subtype. Thus, quazepam and halazepam preferentially bind to benzodiazepine type-1 receptors in lamina IV of the cerebral cortex, the zona incerta, substantia nigra and the cerebellum.

Animals↗
PubMed1985

Acute blood pressure and urinary responses to single dose combinations of captopril and diuretics in conscious spontaneously hypertensive rats.

The present studies involved oral administration of captopril alone or in combination with individual diuretics in conscious, freely-moving spontaneously hypertensive rats (SHR). Both blood pressure (BP) and urinary fluid and electrolyte excretion were concomitantly measured. Captopril, 10 mg kg-1, caused a decrease in BP (-18 +/- 3 mm Hg) which was not significantly different from control (-10 +/- 2 mm Hg). Diuretics alone also failed to alter BP. However the BP-lowering effect of captopril was readily potentiated by concomitant administration of a single oral dose of frusemide (10 and 30 mg kg-1) in proportion to the magnitude of urinary loss. Hydrochlorothiazide at 1 and 3 mg kg-1 oral and metolazone at 0.3 and 1 mg kg-1 oral induced fluid loss similar to frusemide at 10 mg kg-1 and all produced comparable BP reduction in combination with captopril (25-32 mm Hg). Triamterene did not increase fluid excretion and was ineffective. In SHR with bilateral ureteral ligation, the synergistic effect of frusemide was abolished while that of hydrochlorothiazide still occurred with a delayed onset. It is concluded that concomitant measurement of BP and urinary excretion in conscious, freely-moving SHR is a useful technique for studying new antihypertensive drugs. Using this preparation it was found that enhancement of the acute hypotensive response to captopril with concomitant diuretic therapy occurs within 10 min and is primarily related to the fluid and Na loss, regardless of the diuretic agent used.

Animals↗
PubMed1985

Pharmacological effects of SCH 30497--a novel analgesic substance.

SCH 30497 (2-[3-(1,2,3,6-tetrahydro-4-2(methylphenyl)-pyridin-1-yl) -propyl]-1,2,4-triazolo[4,3-a] pyridin-3-(2H)-one) was tested for analgesic effects in the rat, mouse and squirrel monkey. SCH 30497 showed dose-related analgesic effects in the rat yeast-paw test; at peak times the ED7sec (95% confidence limits) in mg/kg via the oral, subcutaneous, intramuscular and intravenous routes of administration were as follows, respectively: 4.7 (2.1-9.8), 5.7 (3.4-9.6), 6.4 (4.1-9.8) and 1.4 (0.6-3.2). SCH 30497 was also analgesic in the acetic acid-induced writhing test in mice (ED50 = 1.9 mg/kg p.o.) and the squirrel monkey shock titration test (ED50 = 14.5 mg/kg p.o.). It was inactive in the mouse (100 mg/kg p.o.) and rat (40 mg/kg p.o.) tail-flick tests. Thus, SCH 30497 was efficacious versus chemical, mechanical and electrical nociceptive stimuli. Naloxone antagonism of the analgesic effects of SCH 30497 was species specific with significant inhibition observed only in the rat and not in the mouse or monkey. SCH 30497 did not produce Straub tail or hyperactivity in mice. Twice daily dosing at 30 mg/kg p.o. to rats for 5 days failed to produce tolerance; in separate experiments, daily injections for 10 days at 20 or 100 mg/kg p.o. failed to induce signs of dependence following naloxone challenge. SCH 30497-induced analgesia was not attenuated in rats previously made tolerant to narcotics by implantation of a morphine pellet. SCH 30497 showed a weak ability to displace 3H-Met5-enkephalin from its binding sites on rat brain membranes (IC50 = 48 microM). SCH 30497 (100 microM) did not affect prostaglandin synthesis in vitro. In vivo, the drug did not have anti-inflammatory or ulcerogenic effects up to 80 mg/kg p.o. Acute behavioral, neurological and autonomic side effects were primarily depressant in rodents and occurred at doses greater than 15 times those that were analgesically relevant. Moderate doses in the monkey (2.5 times the ED50) and high doses in mice produced convulsions. It is hypothesized that SCH 30497-like drugs represent a new class of analgesics based on this unique pharmacological spectrum of activity.

Acetates↗
PubMed1984

Characterization of the binding of 3H-SCH 23390, a selective D-1 receptor antagonist ligand, in rat striatum.

A novel benzazepine, SCH 23390, has recently been described as a very potent and selective dopamine D-1 receptor antagonist based on its potent inhibition of dopamine sensitive adenylate cyclase and its selective displacement of 3H-piflutixol from rat striatal receptor sites. In the present study, the in vitro binding of 3H-SCH 23390 to specific striatal receptor sites has been characterized. Binding was saturable and stereospecific, and the results of both saturation and competition studies are consistent with the binding of 3H-SCH 23390 to a single striatal site. A KD of 0.53 nM was obtained through Scatchard analysis. Relative potencies of a variety of neuroleptics in competing with 3H-SCH 23390 and also 3H-spiperone support an interpretation that the single site to which 3H-SCH 23390 binds is the D-1 dopamine receptor. Also, the binding capacity of 3H-SCH 23390 (69 pmoles/gm wet weight) is in agreement with published values for the binding capacities of 3H-piflutixol and 3H-flupentixol. These data, coupled with the low level of non-specific binding encountered with this radioligand (4-8% of total binding at normally employed ligand concentration of 0.3 nM), its high specific activity and its negligible binding to plastic and glass surfaces make it ideally suited for studying interactions with this receptor.

Animals↗
PubMed1984

Selective affinity of 1-N-trifluoroethyl benzodiazepines for cerebellar type 1 receptor sites.

In binding studies with rat brain membranes, 1,4-benzodiazepines containing a trifluoroethyl moeity at the 1-N position, including halazepam and quazepam, had significantly higher affinities for binding sites in cerebellum than in cortex. This selectivity for cerebellar sites is not a property of benzodiazepines without the trifluoroethyl moiety, but is similar to that seen with the triazolopyridazines. Since halazepam and quazepam, like the triazolopyridazines, have behavioral effects in animals at doses much lower than those that cause ataxia, it is tempting to attribute this separation of pharmacologic activities to differential activity at subpopulations of benzodiazepine receptors. Further work is necessary to clarify this possibility.

Animals↗
PubMed1984

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine.

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)- 5-H-benzo [5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement of in vivo 3H-mepyramine binding in mouse brain and in vitro 3H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally. SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.

Animals↗
PubMed1984

Partial preservation of motor function by inhibition of arachidonate metabolism in rats with phospholipase A2-induced caudate lesions.

Dexamethasone pretreatment prevents motor impairment manifested by ipsilateral rotation and phospholipid alterations resulting from phospholipase A2-induced caudate nucleus lesions in rats. If motor function preservation is attributed solely to the antiprostaglandin activity of dexamethasone, then indomethacin (an inhibitor of cyclooxygenase) and phenidone (an inhibitor of both lipoxygenase and cyclooxygenase) should also diminish rotation. Phenidone offered dose-related, partial protection whereas indomethacin did not. Histologic sections of rat brain indicated that a positive correlation existed between the size of the caudate lesion and number of rotations for the various treatments. Because dexamethasone produced essentially complete protection, it is hypothesized that dexamethasone protects caudate motor function by interfering with breakdown of membrane phospholipids, as well as by preventing formation of arachidonate and its products.

Animals↗
PubMed1984

Effects of SCH 32651 on resting and stimulated acid secretion in guinea-pig isolated fundic mucosa.

Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea-pig isolated fundic mucosa were studied. SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1-10 microM), the IC50 being 4.4 microM. Cimetidine and atropine at concentrations up to 100 microM were inactive. Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 microM), methacholine (1 microM) or dibutyryl cyclic AMP (0.5 mM) plus theophylline (1 mM) in a concentration-dependent manner. The IC50S against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 microM, 0.71 microM and 2.9 microM, respectively. In contrast, atropine and cimetidine each at 100 microM, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. SCH 32651 0.1 mM in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H+ in the same solution. The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+-ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+-ATPase which is a final step in the acid secretory process triggered by various stimuli.

Animals↗
PubMed1984

Inhibitory effect of captopril on renal responses to frusemide in sodium-restricted rats.

Indomethacin (10 mg kg-1 orally) caused a moderate inhibition of the renal responses to frusemide (30 mg kg-1 orally) only in Na+-deficient rats, suggesting that renal prostaglandins (PG) are necessary for optimal effects of frusemide during Na+ restriction. Captopril (1, 3 and 10 mg kg-1 orally) also inhibited frusemide-induced diuresis and natriuresis in Na+-deficient rats; the large effect of captopril at 10 mg kg-1 was accompanied by arterial hypotension. In normal rats, captopril did not disturb blood pressure or affect the renal effects of frusemide. By comparison, minoxidil (10 and 20 mg kg-1 orally) caused hypotension and reduced the natriuretic effects of frusemide in both normal and low-Na+ states. Since circulating angiotensin II (AII) is a stimulus for PG synthesis during Na+ restriction, it is suggested that captopril may impair the renal responses to frusemide through hormonal and haemodynamic changes resulting from inhibition of A II formation.

Animals↗
PubMed1984

Antibody-induced membrane fusion in Paramecium.

Immobilization of cells by specific immune serum involves crosslinking between immunoglobulin G (IgG) and the i-antigen in the cell membrane. Globular material is seen to accumulate at the ciliary tips by phase-contrast and fluorescence microscopy in a manner analogous to 'capping' in more typical eukaryotes. When immobilized cells of Paramecium are examined by scanning electron microscopy, the fused ciliary tips are seen to be distended, discoidal membranes. Transmission electron microscopy often reveals several ciliary axonemes enclosed within a single, enlarged membrane that is oriented with the ferritin-labelled second antibody directed against the i-antigen antibody on the outer surface only. Fixed cells or living cells treated with immune Fab do not show membrane changes, but do bind antibody. Membrane fusion occurs only if cells are alive and the i-antigen is directly or indirectly cross-linked by intact immune IgG.

Animals↗