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Biomedical subjects

D G Morgan

Publications and source records attributed to D G Morgan.

At least 91 records · Page 5Linked to original sources
PubMed1989

Ultrastructure of an arterial lesion induced in rats by fenoldopam mesylate, a dopaminergic vasodilator.

Fenoldopam mesylate (FM) is a dopaminergic vasodilator with demonstrated efficacy and a favourable safety profile in hypertensive and congestive heart failure patients. FM produced a novel arterial lesion in renal and splanchnic arteries of rats, but not dogs or monkeys. The studies reported here were undertaken to investigate the ultrastructure of the arterial lesion induced in rats by FM in an attempt to shed light on its pathogenesis. Rats were infused intravenously with FM, either 50 micrograms/kg/min for 1 or 4 h, or 5 or 100 micrograms/kg/min for 24 h. Control rats were infused for 4 or 24 h with vehicle alone. Perfusion-fixed tissue from the stomach and pancreas of control and drug-treated rats was examined by transmission electron microscopy. No arterial lesions were seen in rats infused with the drug for 1 or 4 h, or in control rats. All drug-treated rats infused with 5 or 100 micrograms/kg/min of FM for 24 h had lesions in subserosal gastric arteries and interlobular pancreatic arteries. In areas of mild arterial damage, medial smooth muscle cells contained intracytoplasmic pseudovacuoles, autophagic vacuoles, and electron-dense, myofilamentous inclusions. More severe lesions were characterized by overt medial necrosis and haemorrhage. The endothelium of affected arteries was invariably intact, except in areas of severe medial damage. The internal elastic lamina and connective tissue elements within the arterial wall were unaffected. These findings suggest that medial smooth muscle cells are the primary site of damage caused by fenoldopam mesylate in splanchnic arteries of the rat. This iatrogenic arterial lesion could provide an interesting model to study the response of medial smooth muscle to pharmacologically mediated injury.

Animals↗
PubMed1989

Role of dopaminergic and adrenergic receptors in the pathogenesis of arterial lesions induced by fenoldopam mesylate and dopamine in the rat.

Fenoldopam mesylate (FM), a selective, postjunctional, dopaminergic (DA1) vasodilator, causes a novel lesion of large caliber splanchnic arteries (100 to 800 microns) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (less than 100 microns) of the splanchnic, cerebral, coronary, and renal vascular beds. Dopamine, an alpha- and beta-adrenoceptor and dopaminergic agonist, is used clinically, principally as a pressor agent. Because these arterial lesions were believed to result from the pharmacologic activity of these two compounds, the role of vascular receptor subtypes in their pathogenesis was investigated. Rats were coexposed to either FM or dopamine and a variety of receptor antagonists (alpha, beta, DA1, DA2, and 5HT2). In rats coexposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased; PBZ, however, prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. SK&F 83566-C, a selective DA1 dopaminergic receptor antagonist, prevented the induction of FM and dopamine-induced hemorrhagic lesions of large caliber arteries. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. The other receptor antagonists tested did not prevent arterial injury. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Activation of the postjunctional, dopaminergic (DA1) receptor is causally associated with the induction of novel hemorrhagic lesions of large caliber splanchnic arteries in the rat.

Animals↗
PubMed1988

Crystallization and preliminary X-ray diffraction analysis of 11 S acetylcholinesterase.

The 11 S form of acetylcholinesterase from Electrophorus electricus was purified by affinity chromatography. The protein was crystallized from polyethylene glycol solutions. One crystal form proved suitable for x-ray diffraction studies. Preliminary x-ray analysis demonstrates that the space group of this crystal is F222. The unit cell dimensions are a = 141.0 +/- 0.2, b = 202.4 +/- 0.2, and c = 237.4 +/- 0.1 A. The diffraction is anisotropic, extending to at least 3.5 A along the a* and b* axes, but becoming weak beyond about 6 A along the c* axis. Crystal density measurements suggest that one complete 11 S tetramer occupies the asymmetric unit of the crystal.

Acetylcholinesterase↗
PubMed1988

Three-dimensional structural analysis of tetanus toxin by electron crystallography.

Two-dimensional crystalline arrays of native tetanus toxin have been formed at the interface between a solution of the toxin and a phospholipid monolayer containing a ganglioside. Electron crystallographic analysis has been used to study these periodic arrays. The arrays obey the symmetry of plane group p12(1), with a = 126 A and b = 84 A, and a thickness of 90 A (1 A = 0.1 nm). The three-dimensional structure of tetanus toxin in negative stain is reconstructed to a nominal resolution of 14 A from multiple tilt images. The molecule presents an asymmetric three-lobed structure and could interact with the monolayer in two possible orientations.

Crystallography↗
PubMed1988

Effects of radioligand oxidation and ascorbate-induced lipid peroxidation on serotonin-1 receptor assay: use of ascorbate and ethylenediamine tetraacetic acid buffers to prevent (3H)-5-HT binding artifacts.

The effects of ascorbic acid and ascorbate-induced lipid peroxidation upon (3H)-5-HT binding were examined in total membrane fractions prepared from mouse cortex and hippocampus. Low concentrations of ascorbic acid promoted lipid peroxidation of membranes as assessed by malondialdehyde production relative to intermediate concentrations of ascorbate. The actual concentration of ascorbate required for expression of pro-oxidative and antioxidative properties was dependent upon assay conditions such as temperature and ionic constituents. Ascorbate-induced lipid peroxidation was completely prevented by addition of 1 mM ethylenediamine tetraacetic acid (EDTA) and enhanced by GTP at concentrations typically used in binding assays. Marked lipid peroxidation was associated with loss of (3H)-5-HT binding sites with little effect upon affinity of the receptor for the ligand. In contrast, mild lipid peroxidation occurring during the binding assay with the ligand present was associated with a decreased affinity for (3H)-5-HT and the appearance of a curvilinear Scatchard plot. Under assay conditions that prevented ascorbate-induced lipid peroxidation, Scatchard analysis indicated only a single high-affinity binding site for (3H)-5-HT even when assayed with an expanded range of ligand concentrations. Preparation of ligand and assay of (3H)-5-HT binding in the absence of ascorbate resulted in shallow, markedly curvilinear Scatchard plots. These data support the continued use of ascorbate in (3H)-5-HT binding assays to prevent ligand degradation and the addition of 1 mM EDTA to prevent lipid peroxidation from occurring during the binding assay.

Animals↗
PubMed1988

Cryo electron microscopy of unstained, unfixed RecA-cssDNA complexes.

Complexes of RecA protein with phi X174 circular single-stranded DNA (cssDNA) with and without ATP gamma S were rapidly frozen and embedded in a thin layer of vitreous ice. The electron micrographs of these frozen-hydrated complexes clearly show visible helicity. Quantitative image analyses of these micrographs reveal the helical pitch and the axial rise between DNA bases of these complexes. Both of these structural parameters of RecA-cssDNA complexes increase significantly when ATP gamma S is present. These observations agree qualitatively but not quantitatively with those from negative stained specimens and confirm the general model that the interactions among RecA molecules and between RecA and DNA could change according to the functional states of the RecA-cssDNA complex.

DNA, Single-Stranded↗
PubMed1988

The effect of longterm treatment with auranofin and gold sodium thiomalate on immune function in the dog.

Although gold compounds are recognized as effective immunomodulatory agents in the treatment of rheumatoid arthritis (RA), their mechanism of action is controversial. We examined the effect of longterm treatment with 0.6-3.6 mg/kg auranofin (AF) per os q24h, or intramuscular injections of 0.5-2.0 mg/kg gold sodium thiomalate (GSTM) q3d, on 13 variables of immune function in normal dogs. None of the changes in these variables previously attributed to treatment with AF or GSTM could be demonstrated after 6-7 years' dosing. As gold compounds are effective in treating spontaneous RA in dogs, these proposed actions may not be responsible for the remittive effects of chrysotherapy in this disease.

Animals↗
PubMed1987

Hypothalamic monoamines and their catabolites in relation to the estradiol-induced luteinizing hormone surge.

Monoamines and non-conjugated catabolites (serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG), norepinephrine (NE), and dopamine (DA] were measured in the medial basal hypothalamus (MBH) and preoptic area (POA) of ovariectomized (OVX) and OVX estradiol (E2)-treated rats using high-performance liquid chromatography with electrochemical detection. These E2 treatments were sufficient to induce an LH surge. The use of MHPG/NE ratios as estimates of NE release was validated in the rat hypothalamus by the major decreases of MHPG after injection of the alpha 2-adrenergic agonist, clonidine, and by MHPG increases after the alpha 2-antagonist, yohimbine. The ratio, MHPG/NE, decreased between morning and afternoon in the MBH but not in the POA; there were no differences between OVX and E2-treated rats. Previous studies using a variety of methods indicate that NE turnover increases during LH surges. The present data suggest that unconjugated MHPG is not a sensitive measure of NE release in the rat hypothalamus, but can detect the large changes produced by stimulating or inhibiting the alpha 2-adrenergic autoreceptor. The ratios of DOPAC/DA and 5-HIAA/5-HT in the MBH decreased consistently between morning and afternoon in OVX rats, with or without E2 treatment. This suggests that the release of DA and 5-HT decreases during the day regardless of steroidal milieu.

Animals↗
PubMed1987

Alteration of calmodulin distribution does not accompany dopaminergic supersensitization of the mouse striatum.

Membrane-bound calmodulin increases following dopaminergic supersensitization of the rat striatum. To assess the generality of this relationship, mice were treated with two different supersensitization paradigms. Calmodulin levels and subcellular distribution were determined by radioimmunoassay. Chronic haloperidol treatment increased striatal D2 dopamine receptor density by 25% but had no effect on membrane-bound calmodulin levels. Similarly, 6-hydroxy-dopamine (6-OHDA) lesions depleted striatal dopamine content greater than 95% without affecting membrane-bound calmodulin. In contrast, soluble calmodulin levels decreased by 15% in the 6-OHDA-lesioned striatum, suggesting that soluble calmodulin is enriched in presynaptic dopaminergic terminals. We conclude that dopaminergic supersensitization can occur in the mouse striatum in the absence of any change in calmodulin distribution.

Animals↗
PubMed1987

Age-related differences in susceptibility to renal ischemia in rats.

These experiments were designed to determine the influence of age on the response of the kidney to ischemia. Renal ischemia was induced in female Fischer-344 rats, 3-4 or 37-38 months old, by renal arterial and venous occlusion followed by 0, 1, 24, or 96 hr of reflow. Age-matched controls were sham operated but were not subjected to ischemia. A transient postischemic increase in blood urea nitrogen (BUN) and serum creatinine was observed in young rats. In old rats, BUN and serum creatinine remained markedly elevated through 96 hr postischemia. In vitro renal cortical slice accumulation of organic ions was inhibited to a greater extent in old rats than in young rats 96 hr postischemia. Histologically, renal tubular damage was more severe in old than in young rats 24 and 96 hr postischemia. Tubular regenerative activity was similar in old and young rats at 96 hr, but restoration of tubular architecture was more complete in young rats. Organic ion accumulation by renal cortical slices from naive old rats was inhibited by in vitro anoxia (treatment with 100% N2) to a greater extent than tissue from young rats. These data suggest that old rats are more susceptible to renal ischemia than are young rats and these differences in susceptibility may reflect intrinsic age-related differences in basal renal metabolism.

Aging↗
PubMed1987

The hematopathology of cefonicid- and cefazedone-induced blood dyscrasias in the dog.

Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized. A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months. Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias. Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology. Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals. The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue. The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible. These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.

Animals↗
PubMed1987

The dopamine and serotonin systems during aging in human and rodent brain. A brief review.

During nonpathological aging, quantitative changes occur in the pre- and post-synaptic elements of both the dopamine and serotonin systems. The level of dopamine in the human striatum declines up to 50% with age, while smaller and more variable changes are found in rodent brain (0-30%). Postsynaptically, the density of D-2 dopamine receptors also declines by 25-50% in both human and rodent striata. Conversely, D-1 receptors have been reported to increase with age in human, and to remain stable in rodent brain. In the serotonin system, the concentration of serotonin remains stable during nonpathological aging in both rodents and humans. The density of S-2 serotonin receptors declines 20-50% with age in human frontal cortex and hippocampus, and by 30% in mouse cortex. The density of S-1 serotonin receptors is unchanged throughout the mouse lifespan, but declines by 30-50% in human frontal cortex. In rodents, the up-regulation of D-2 receptors in response to antagonist (neuroleptic) treatment is impaired in old animals. Conversely, the down-regulation of D-2 receptors in response to chronic agonist (bromocriptine) treatment is equivalent at all ages. Similarly, the down-regulation of S-2 receptors to antidepressant (amitriptyline) treatment in mice is constant over the lifespan. Attempts to up-regulate serotonin receptors with antagonists have, thus far, been unsuccessful.

Aging↗
PubMed1987

Genotypic influences on pituitary responsiveness to haloperidol in mice.

Previous studies from this laboratory demonstrated that CBA/J mice have impaired striatal dopaminergic supersensitivity in response to subchronic haloperidol administration. Others have speculated that the peripheral hyperprolactinemia produced by haloperidol is necessary for the striatal dopamine receptor supersensitization produced by dopamine antagonists. In the present experiments, we tested the hypothesis that the impaired supersensitization response to haloperidol in CBA/J mice was secondary to an impaired hyperprolactinemic response by comparing the CBA/J mice with other mice that show normal supersensitization responses: the BALB/cJ and C57BL/6J strains. Acute haloperidol treatments increased serum prolactin levels 60 min later in all three strains, with the greatest response in CBA/J mice. After longer haloperidol treatment (2 or 21 days), serum prolactin remained elevated in CBA/J and, to a lesser extent, in C57BL/6J mice; levels remained low throughout treatment in BALB/cJ mice. Although, the basal density of pituitary dopamine receptors [( 3H]spiperone or D-2 binding sites) was greater in CBA/J than BALB/cJ mice, only BALB/cJ mice showed increased pituitary D-2 binding sites following chronic haloperidol administration. Taken together with previous studies of dopamine and noradrenaline receptors in these mouse strains, we conclude that CBA/J mice have a generalized impairment in their supersensitization responses to pharmacologic blockade of receptors. These data do not support the involvement of prolactin in haloperidol-induced dopamine receptor up-regulation.

Animals↗
PubMed1987

Dopamine and serotonin systems in human and rodent brain: effects of age and neurodegenerative disease.

The nonpathological age-related changes in the dopamine- and serotonin-containing neurotransmitter systems in human and rodent brain are reviewed. The dopamine system exhibits age-related declines both presynaptically and postsynaptically. Presynaptically, both the levels of dopamine and the number of midbrain dopamine-containing neurons decline by up to 50% at advanced ages in the absence of neurological disease. Postsynaptically, the density of D-2 dopamine receptors decreases by 40%, while D-1 dopamine receptors either increase (man) or remain stable (rodents). Additional reductions of dopamine levels and D-2 receptors have been reported in Alzheimer's disease (AD), but these changes are relatively small, and not consistently observed. The levels of serotonin appear stable during normal aging, and presynaptic markers such as (3H)imipramine binding may actually increase. In human brain, the two major classes of serotonin receptor (S-1 and S-2) decrease by 30 to 50% over the lifespan. In AD, both presynaptic and postsynaptic markers of the serotonin system are reduced, including a loss of the serotonin-containing raphe neurons. The additional loss of serotonin receptors in AD approaches 80% when compared with young normals. A hypothesis is presented to explain the typically young age at onset of schizophrenia (usually before 30 years of age) and the older age at onset of parkinsonism (rarely before 50 years of age) within the context of normal age-related declines in the dopamine system occurring in the absence of neurological disorders. The possibility that chronic cocaine abuse might accelerate the development of parkinsonism is discussed.

Aging↗
PubMed1987

The role of conventional pathology and toxicology in evaluating the immunotoxic potential of xenobiotics.

Investigating the immunotoxic potential of candidate drugs as part of a preclinical safety evaluation poses several problems. These include the need for practical, validated tests, the difficulty in establishing the toxicologic significance of positive findings, and a poor understanding of the predictive value such findings hold for drug effects in man. A key component of this investigation is the toxicologic profile generated through preclinical toxicity and safety studies. As this "routine" assessment becomes increasingly comprehensive and sophisticated, most toxicologically significant drug-associated effects are revealed. Such findings may serve as "triggers" for investigating possible immune mechanisms. Decisions to test specifically for immunotoxicity may also be influenced by the molecular structure and pharmacologic profile of the compound, as well as the intended use of the drug. Examples of such indications and follow-up studies are discussed in this review. We are presently poorly equipped to effectively screen drugs indiscriminately for an immunotoxic potential. We are better prepared, however, to investigate whether a drug-associated change is due to an adverse effect on the immune system. This problem-oriented approach to immunotoxicology challenges us as diagnosticians and immunopathologists, and requires a close working relationship among the toxicologic pathologist, the basic immunologist, the immunopharmacologist, and the clinician.

Animals↗
PubMed1986

Regional serotonin receptor studies: chronic methysergide treatment induces a selective and dose-dependent decrease in serotonin-2 receptors in mouse cerebral cortex.

Compared with the well described supersensitization responses of dopaminergic and beta-adrenergic receptors to pharmacologic antagonists and denervation, the regulation of serotonin-1 (S-1) and serotonin-2 (S-2) receptors is poorly understood. In an effort to modulate S-1 and S-2 receptors in mouse brain, male C57BL/6J mice were treated chronically with methysergide, a serotonin antagonist with nanomolar affinity for both S-1 and S-2 receptors. Methysergide treatment had no influence on the affinity or density of S-1 receptors as measured by binding of (3H)-5-HT in cerebral cortex, hippocampus or hypothalamus. In contrast, the S-2 receptor specific binding of (3H)-spiperone in the cerebral cortex decreased in a dose dependent fashion, a direction of change opposite to that usually seen in catecholamine pathways chronically exposed to antagonists. The effect was selective for the S-2 serotonergic receptor since the D-2 dopaminergic receptor specific binding of (3H)-spiperone in the caudate nucleus was unaffected by drug treatment. These results suggest that either serotonin receptors respond atypically to chronic receptor blockade by antagonist or that in vivo, methysergide may have additional pre-synaptic effects on serotonin uptake or release.

Animals↗
PubMed1986

Extensive postmortem stability of RNA from rat and human brain.

The postmortem stability of brain RNA was measured in rat and human samples for up to 48 hr. Whole rat brains, cooled at a rate approximating that of human brains awaiting autopsy, were collected at intervals from 0 to 48 hr after death and frozen. These samples were compared with freshly obtained, unfrozen rat brains. Two potentially independent characteristics of these RNA populations were measured: the recovery or yield of RNA/gram tissue (quantity) and the integrity or extent of degradation (quality). Total RNA yields were similar after all postmortem delays. Hybridization of [32P]-labeled cDNA probes to nitrocellulose filter blots of electrophoretically separated rat brain RNA failed to reveal degradation of the specific rat brain mRNAs during the postmortem period. Similarly, in vitro translation of these same rat total RNA samples produced high molecular weight translation products with no differences between long and short postmortem times. Human cerebral cortex RNA was prepared by the same methods as those used for rat brain from a neurosurgical sample and four other donors with postmortem intervals from 7 to 36 hr. Typically, the yield of total RNA from human brain was 40-50% of the yield from rat brain. When analyzed by RNA gel blot hybridization studies, as for rat brain RNA, human cortical RNA appeared slightly degraded. However, the degree of apparent RNA degradation was not related to the postmortem interval. In vitro translation products of human cortical RNA revealed high molecular weight peptides at all postmortem intervals, but slightly less [35S]incorporation into these bands was found at the longer postmortem intervals relative to the shorter times. Together, these results demonstrate an extensive stability of brain RNA that invites aggressive use of molecular genetic techniques for the study of human neurodegenerative diseases.

Animals↗