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R J Walsh

Publications and source records attributed to R J Walsh.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and biological activity of trans(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: a new class of potassium channel opener.

The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.

Animals↗
PubMed1992

Prolactin enhancement of its own uptake at the choroid plexus.

The choroid plexus contains PRL receptors that function in part to transport PRL from the blood into the cerebrospinal fluid (CSF). The blood PRL concentration of female rats was altered by 1) three daily injections of haloperidol (chronic hyperprolactinemia) with or without bromocriptine administration 4 h before death, 2) bromocriptine alone for 4 h (acute hypoprolactinemia), and 3) a single vascular injection of ovine PRL (acute hyperprolactinemia). Changes in the uptake of PRL by the choroid plexus was assessed by quantitative in vivo autoradiography after the injection of radiolabeled PRL. Correlation of changes in PRL uptake at the choroid plexus with changes in PRL transport from blood to CSF was evaluated by subjecting CSF samples to sodium dodecyl sulfate-polyacrylamide gel electrophoresis after vascular injection of radiolabeled PRL. Autoradiography revealed that both chronic and acute hyperprolactinemia resulted in a significant increase in the uptake of radiolabeled PRL by the choroid plexus compared to that in untreated control animals. In contrast, bromocriptine had no effect on PRL uptake at the choroid plexus relative to that in control (untreated) animals. Chronic hyperprolactinemia, but not acute hyperprolactinemia, resulted in a significant increase in the transport of radiolabeled PRL from the blood to the CSF compared to that in untreated controls. The results are consistent with the up-regulation of PRL receptors in the choroid plexus by circulating PRL and the consequent augmentation of transport of PRL from blood to CSF.

Animals↗
PubMed1990

The distribution of lactogen receptors in the mammalian hypothalamus: an in vitro autoradiographic analysis of the rabbit and rat.

The hypothalamus contains a high concentration of lactogen receptors as detected with in vitro radioreceptor assay techniques. In an effort to define the location of the lactogen receptors relative to specific hypothalamic nuclei, an in vitro autoradiography technique was applied to frozen sections of rat and rabbit brains. Three lactogenic hormones, i.e. human growth hormone (hGH), ovine prolactin (oPRL), and rat prolactin (rPRL), were radiolabeled with iodine-125. Competition for observed binding sites was assessed with unlabeled hGH, oPRL, and bovine growth hormone (bGH). Analysis of the autoradiographs with a microcomputer-based densitometry system revealed that the rabbit hypothalamus contains specific lactogen binding sites within the supraoptic, paraventricular, suprachiasmatic, ventromedial, arcuate, and dorsomedial nuclei and the medial preoptic area. Unlabeled bGH was effective in competing for binding sites in all areas when hGH but not oPRL was used as the radiolabeled ligand, suggesting the presence of growth hormone receptors in the rabbit hypothalamus with a distribution similar to that of the lactogen binding sites. In contrast to the rabbit, no lactogen binding sites were detected in the rat hypothalamus regardless of the ligand used in the assay. All of the ligands were successful, however, in detecting lactogen receptors within the rat choroid plexus and liver. The results from the rabbits indicate that the influences of prolactin on hypothalamic activity are mediated via lactogen receptors that are widely distributed throughout the various pertinent hypothalamic nuclei. The broad distribution of lactogen receptors in the rabbit hypothalamus attests to the extensive influence of prolactin on hypothalamic regulatory systems. The results from the rat raise questions as to the nature of rat brain prolactin receptors in comparison to prolactin receptors in rat peripheral tissues.

Animals↗
PubMed1990

Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents.

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

Animals↗
PubMed1990

Computer-assisted instructions: a role in teaching human gross anatomy.

Eight computer-assisted instructions were developed concerning selected topics in human gross anatomy. The computer lessons were designed to be very flexible in terms of the selection of material to be presented and make extensive use of colour graphics to explain the anatomy. Voluntary testing with immediate and cumulative feedback is incorporated into the lessons so that the users can evaluate their own progress in mastering the subject material. In an effort to assess the value of the computer lessons, the programs were provided to a volunteer group of 48 first-year medical students from a class of 151 students. At the completion of the gross anatomy course, the student users were requested to complete an anonymous questionnaire regarding their impressions of the value of the computer lessons. In addition, test performance on multiple choice examinations was compared between the users of the computer-assisted instructions and their non-user classmates. The responses in the questionnaires revealed a very positive attitude regarding the value and usefulness of the computer-assisted instructions in learning human gross anatomy. The overall rating of the programs on a scale of 1.0 to 10.0 was 1.8 +/- 1.0 with 1.0 representing 'extremely helpful' and 10.0 being 'of no value'. A comparison of test scores showed no significant difference in test performance between the users of the computer-assisted instructions and the non-users. The results of the study suggest that while the computer lessons provide neither an advantage nor a disadvantage in test performance as evaluated by a multiple choice examination, students perceive the computer-assisted instructions as valuable educational tools in mastering the subject of human gross anatomy. The potential role of the computer-assisted instructions in curriculum development is discussed.

Anatomy↗
PubMed1990

Prolactin receptors in the primate choroid plexus.

The presence of prolactin receptors in the choroid plexus of primates has until now been assumed to be based on observations made on lower vertebrate animal models. An in vitro autoradiographic technique employing the principles of competitive binding was used to demonstrate the presence of specific prolactin binding sites in the choroid plexus of monkeys. Thus the primate choroid plexus resembles that of lower vertebrate mammals in that it possesses the prerequisite receptor for a prolactin blood-to-CSF transport mechanism.

Animals↗
PubMed1989

Magnesium-dependent non-specific binding of [125I]prolactin to myelinated tracts in the rat central nervous system.

An in vitro autoradiographic assay was used in identifying a magnesium-dependent, non-specific binding of [125I] prolactin to myelinated fiber tracts in the rat brain. Frozen tissue sections were incubated for 18 h at 4 degrees C in media which included [125I]prolactin alone or with a 500 fold excess of unlabelled prolactin. Magnesium in the incubation medium caused a non-specific binding of radiolabelled prolactin to the myelinated fiber tracts in the brain. In contrast, calcium did not facilitate prolactin non-specific binding to myelin. Hence, calcium should optimize the detection of specific prolactin binding sites in the brain by in vitro autoradiographic or radioreceptor assays.

Animals↗
PubMed1988

In vivo autoradiographic analysis of prolactin binding in brain and choroid plexus of the domestic ring dove.

The binding of intravenously administered prolactin to choroid plexus and brain tissue was determined radioautographically in the ring dove, a species that exhibits prolactin-induced alterations in brain function. An intense autoradiographic reaction was detected over the epithelial cells of the choroid plexus 5 min after the intravenous injection of 125I-ovine prolactin. A significant reaction was also observed over the infundibulum but no significant uptake of prolactin occurred in other brain areas. The binding of radiolabelled prolactin to infundibulum appeared to be non-specific, since excess unlabelled hormone did not reduce silver grain density. In contrast, 125I-ovine prolactin binding in choroid plexus was significantly reduced by excess unlabelled ovine prolactin or human growth hormone, but not by ovine luteinizing hormone. Specific binding to choroid plexus was also detected in vitro. The lack of significant brain uptake of prolactin in vivo is discussed in relation to recent in vitro evidence for specific binding sites for prolactin in several dove brain regions. Similarities between the binding results obtained in this avian species and those reported previously in mammals suggest that the two vertebrate groups exhibit similar patterns of prolactin interaction with neural target tissues.

Animals↗
PubMed1987

Prolactin causes increased turnover of dopamine in 10-day-old rat median eminence.

The present work examines the ability of prolactin to enter the CNS of the rat and effect its feedback stimulation of dopamine release prior to the appearance of prolactin receptors in choroid plexus (i.e., 10 days postnatal). An inhibitor of tyrosine hydroxylase was used to allow the assessment of dopamine turnover separate from synthesis and transport of the amine. Chronic but not acute hyperprolactinemia resulted in increased dopamine release relative to vehicle-treated controls, as shown by diminished fluorescence intensity in the median eminence. These results indicate that activation of the prolactin short-loop feedback system occurs by 10 days postnatal, prior to the appearance of prolactin receptors at the choroid plexus.

Animals↗
PubMed1987

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones.

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

Animals↗
PubMed1987

A receptor-mediated mechanism for the transport of prolactin from blood to cerebrospinal fluid.

PRL interacts with areas of the central nervous system which reside behind the blood-brain barrier. While vascular PRL does not cross this barrier, it is readily accessible to the cerebrospinal fluid (CSF) from which it may gain access to the PRL-responsive areas of the brain. Studies were undertaken to characterize the mechanism responsible for the translocation of PRL from blood to CSF. Rats were given external jugular vein injections of [125-I]iodo-PRL in the presence or absence of an excess of unlabeled ovine PRL (oPRL), human GH, bovine GH, or porcine insulin. CSF and choroid plexus were removed 60 min later. CSF samples were electrophoresed on sodium dodecyl sulfate-polyacrylamide slab gels and resultant autoradiographs were analyzed with quantitative microdensitometry. The data revealed that unlabeled lactogenic hormones, viz. oPRL and human GH, caused a statistically significant inhibition of [125I]iodo-PRL transport from blood to CSF. In contrast, nonlactogenic hormones, viz bovine GH and insulin, had no effect on [125I]iodo-PRL transport into the CSF. An identical pattern of competition was observed in the binding of hormone to the choroid plexus. Furthermore, vascular injections of [125I]iodo-PRL administered with a range of concentrations of unlabeled oPRL revealed a dose-response inhibition in the transport of [125I]iodo-PRL from blood to CSF. The study demonstrates that PRL enters the CSF by a specific, PRL receptor-mediated transport mechanism. The data is consistent with the hypothesis that the transport mechanism resides at the choroid plexus. The existence of this transport mechanism reflects the importance of the cerebroventricular system in PRL-brain interactions.

Animals↗
PubMed1986

The ontogeny of specific prolactin binding sites in the rat choroid plexus.

The development of prolactin receptors in the choroid plexus of the rat was examined using the in vivo autoradiographic approach employing the principle of competitive binding. Experimental animals were injected with [125I]prolactin alone (total binding) while control animals received [125I]prolactin and a 500-fold excess of unlabelled prolactin (non-specific binding). Newborns as well as animals 10, 14 and 18 days postnatal were studied. Three minutes following hormone injection animals received an intracardiac perfusion with fixative and tissues were prepared for quantitative light microscopic autoradiography. The choroid plexus first demonstrated specific binding of prolactin, i.e. a statistically significant difference in the autoradiographic reactions between experimental and control animals, at 14 days postnatal. The lactogen specificity of these binding sites was further defined by the ability of [125I]prolactin to be displaced by unlabelled human growth hormone, which is lactogenic in rats, and not by unlabelled insulin, which is structurally dissimilar to prolactin. Morphometric analyses were performed on electron micrographs of choroid plexus from 10- and 14-day postnatal rats. The volume densities of constituents known to be enriched in polypeptide hormone receptors were measured and compared. Small cytoplasmic vesicles and tubules were statistically significantly more abundant in 10-day-old rats than in 14-day-old animals. It is conjectured that these vesicles and tubules contain an intracellular pool of prolactin receptors whose decrease at 14 days parallels the expression of specific binding sites at the cell surface.

Adrenal Cortex↗
PubMed1985

NH2-terminal specificity and axonal localization of adrenocorticotropin binding sites in rat median eminence.

Adrenocorticotropin binding sites in the rat median eminence have been localized in vivo. These binding sites occur in the basalar zone, which is rich in axonal endings. Using competitive binding and quantitative light-microscope radioautography, we found that the median-eminence binding site, in contradistinction to the adrenal receptor, binds specifically the residue 4-10 region of the adrenocorticotropin molecule. Using quantitative electron-microscope radioautography and median-eminence deafferentation, we localized the binding sites to axon terminals in this region. In time-delayed uptake studies using light-microscope radioautography, we failed to observe concentration of radiolabel in neurons of the medial basal hypothalamus after the direct injection of radioiodinated adrenocorticotropin(1-24) into the median eminence.

Adrenal Glands↗
PubMed1979

Cytology of the arcuate nucleus in newborn male and female rats.

Five coronal levels of the arcuate nuclei in newborn male and female rats were examined with the transmission electron microscope. The nuclei from male and female neonates appear similar in all respects. All levels exhibit a significant population of round to oval cell profiles with large centrally located nuclei and scant cytoplasm which contains predominantly ribosomes, sparse mitochondria, and a few short cisternae of rough endoplasmic reticulum. These organelle-poor cell profiles resemble neuroblasts in other parts of the developing CNS. The arcuate nuclei of neonates also exhibit some cell profiles with the variety and quantity of organelles characteristic of mature neurons in the arcuate nuclei of adult rats. In addition, the neonatal arcuate nuclei show a paucity of synapses with apparent immaturity of those present, and numerous structures identified as growth cones. Definitive macroglia are not present in the arcuate nuclei of newborn rats.

Animals↗
PubMed1978

Prolactin binding sites in the rat brain.

The principles of the competitive-binding assay were used in conjunction with light microscopic radioautography to demonstrate specific prolactin binding sites localized on ependyma of the rat choroid plexus, a previously unknown prolactin target tissue.

Animals↗
PubMed1978

The age of the menopause of Australian women.

The mean age of the menopause by probit analysis in a group of apparently healthy Australian women was 50.4 years. No relationship was found between this value and the age of the menarche or the number of children born or the age at the time of birth of the first child. The mean duration of the menstruating life was 26.3 years with a range of from 17 to 44 years.

Adult↗