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Biomedical subjects

M P Maguire

Publications and source records attributed to M P Maguire.

At least 19 recordsLinked to original sources
PubMed1997

Nitric oxide modulates human chorionic gonadotropin-induced ovulation in the rabbit.

OBJECTIVE: To examine the potential role of the L-arginine:nitric oxide pathway in hCG-induced ovulation in the rabbit. DESIGN: Randomized, controlled animal study. SETTING: University research laboratory. INTERVENTION(S): Nitric oxide synthase, the enzyme that produces nitric oxide (NO), was immunohistochemically localized in the ovary. NG-nitro-L-arginine methyl ester (L-NAME), an analogue of L-arginine, which inhibits the enzyme NO synthase, and the inactive D-enantiomer were administered in vivo and/or in vitro via an isolated, perfused ovary preparation during the periovulatory period. MAIN OUTCOME MEASURE(S): Rate of follicular rupture (ovulatory efficiency). RESULT(S): Immunohistochemical staining for NO synthase was localized specifically to the granulosa cell layer of the follicle and the endothelium and adventitia of ovarian blood vessels. In vivo administration of L-NAME significantly reduced the percentage of large follicles that ovulated in response to hCG (treated 24.6%, control 68.1%). Similarly, exposure of the in vitro-perfused ovary to L-NAME significantly reduced follicular rupture (treated 32.8%, control 64.2%). In contrast, addition of an equimolar concentration of D-NAME to the perfusion medium had no significant effect on the rate of ovulation (treated 83.3%, control 61.3%). CONCLUSION(S): The stereospecific inhibition of follicular rupture by the arginine analogue suggests that NO production by the ovary is an important feature of the normal physiologic processes of the periovulatory period.

Animals↗
PubMed1997

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

Animals↗
PubMed1995

Characterization and localization of nitric oxide synthase in the human prostate.

OBJECTIVES: To characterize nitric oxide synthase (NOS), which catalyzes nitric oxide (NO) production, in the human prostate using biochemical and immunohistochemical techniques. METHODS: NOS catalytic assay and NOS immunohistochemistry were performed on histologically verified nonmalignant prostate tissue obtained from the peripheral and transition zones of seven radical prostatectomy specimens. RESULTS: Biochemical analysis revealed NOS activity in the human prostate, with a greater amount in the peripheral zone than in the transition zone (P < 0.01). In both prostate zones, NOS was immunohistochemically localized to nerve fibers and ganglia coursing throughout the smooth musculature of the stroma and to subepithelial nerve plexuses. NOS immunoreactivity was also localized to glandular epithelium. CONCLUSIONS: The presence, activity, and distribution of NOS were described in two regions of the human prostate. The present evidence implicates NO in the automatic innervation and physiology of the human prostate. It is proposed that NO may modulate smooth muscle tone and secretory functions in the human prostate, although functional studies are needed to support these hypotheses.

Amino Acid Oxidoreductases↗
PubMed1995

Localization of nitric oxide synthase in the reproductive organs of the male rat.

Nitric oxide synthase (NOS), which catalyzes the production of nitric oxide (NO), was characterized within the reproductive tract of adult male Sprague-Dawley rats by means of biochemical and immunohistochemical techniques. Tissues examined included the testis, epididymis (caput, corpus, and cauda regions), vas deferens, ejaculatory duct, seminal vesicle, and coagulating gland. NOS activity was measured by use of an assay based on the stoichiometric conversion of [3H]-L-arginine to [3H]-L-citrulline and NO, catalyzed by NOS. Low levels of NOS activity were detected in the testis and seminal vesicle (< 0.5 fmol [3H]-L-citrulline formed/min/mg protein in each tissue). The highest levels of NOS activity were present in the cauda segment of the epididymis and in the vas deferens, each having a sevenfold greater amount of NOS activity than the testis (p < 0.05). Intermediate levels of NOS activity were detected in the coagulating gland (0.863 +/- 0.248 fmol [3H]-L-citrulline formed/min/mg protein), caput epididymidis (0.457 +/- 0.180 fmol [3H]-L-citrulline formed/min/mg protein), and corpus epididymidis (0.631 +/- 0.215 fmol [3H]-L-citrulline formed/min/mg protein). NADPH diaphorase histochemistry and NOS immunohistochemistry localized NOS to neuronal fibers coursing throughout the smooth musculature and subepithelial regions of the epididymis, vas deferens, and ejaculatory duct. Endothelial cells and nerve plexuses within the adventitia of blood vessels supplying reproductive tissues were also positive for NOS. Additional localizations of NOS were within epithelial cells of the epididymis and coagulating gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Localization of nitric oxide synthase in spinal nuclei innervating pelvic ganglia.

We employed retrograde axonal tracing techniques and nitric oxide synthase (NOS) and choline acetyltransferase (ChAT) immunohistochemistry to identify NOS-containing neuronal populations within the lumbosacral spinal cord and determine whether these project to the major pelvic ganglion in the adult male Sprague-Dawley rat. Immunohistochemical localizations of NOS included neurons situated at the L5 to S2 segments of the spinal cord, which corresponded to the sacral parasympathetic nucleus. Another prominent locus for NOS was a group of neurons identified in the L1 segment corresponding to the dorsal commissural nucleus. These regions correlated directly with preganglionic parasympathetic and sympathetic neuronal origins, respectively, which were established with ChAT colocalizations. Retrograde tracing verified the projection of these neurons to the pelvis. Additional neuronal localizations of NOS were observed throughout the intermediolateral cell column, involving the superficial laminae of the dorsal horn, in the region surrounding the central canal and occasionally in the medial area of the ventral horn. These results indicate that the regulation of pelvic visceral activity may involve NO-based neuronal mechanisms operating at the level of the lumbosarcal spinal cord.

Amino Acid Oxidoreductases↗
PubMed1995

The effect of androgen on nitric oxide synthase in the male reproductive tract of the rat.

OBJECTIVE: To determine if nitric oxide synthase activity within the male reproductive tract is regulated by androgen. DESIGN: Nitric oxide synthase activity was measured in the reproductive organs of three groups of mature rats: unoperated controls, 1-week castrates, and 1-week castrates given T capsules at the time of surgery. The presence of nitric oxide synthase activity was confirmed by using the nitric oxide synthase-specific inhibitor N-nitro-L-arginine methyl ester (L-NAME). RESULTS: After castration, nitric oxide synthase activity was significantly reduced by 88%, 73%, and 54% in the caput, corpus, and cauda epididymidis, respectively. In the penis, nitric oxide synthase activity decreased 45% and nitric oxide synthase protein decreased 57% after castration. In the seminal vesicle and lateral prostate, nitric oxide synthase activity increased significantly after castration from nondetectable levels in controls. Nitric oxide synthase activity in the coagulating gland and ventral and dorsal prostate did not change after castration. The changes in nitric oxide synthase activity in all organs after castration were prevented by T replacement. Additionally, the activity measured in every organ in all three treatment groups was > 90% inhibited by L-NAME. CONCLUSION: These data demonstrate that androgen differentially affects nitric oxide synthase activity in the male reproductive tract. To the best of our knowledge this is the first time that nitric oxide synthase activity has been shown to be influenced by androgen in any tissue.

Amino Acid Oxidoreductases↗
PubMed1994

A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives.

A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The compounds were generally prepared either by a Friedlander condensation between an aryl-acetaldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupling between an aryl bromide or triflate and an organostannane or organozinc chloride. The presence of 6,7-dimethoxy groups on the quinoline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-position contributed substantially to activity. The lipophilic groups generally consisted of monocyclic aromatics or small alkynyl, alkenyl, and alkyl groups. Optimum activity of ca. < or = 20 nM (IC50) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl (17m), 3-fluorophenyl (17b), 4-hydroxyphenyl (24), 6-methoxypyridin-3-yl (15o), 5-pyridin-2(1H)-one (23), trans-beta-styryl (15e), thiophene-3-yl (2e), 5-chlorothiophene-2-yl (15f), or cyclopentenyl (17n) groups. Most of the compounds in the series were tested for inhibition of cell-free epidermal growth factor receptor tyrosine kinase activity and found to be inactive.

3T3 Cells↗
PubMed1994

Genetic evidence of Mutator-induced deletions in the short arm of chromosome 9 of maize. II. wd deletions.

Analyses of 113 putative Mutator-induced events involving the yg2 locus of chromosome 9 revealed that 11 of these events were deletions that produce albino seedlings when homozygous. This phenotype is characteristic of wd (white deficiency) deletions. All 11 wd-Mu deletions failed to complement wd1 and pyd1 (pale-yellow deficiency). Nine of the wd-Mu deletions were analyzed cytologically. Two were found to be terminal deletions and seven were internal deletions. Two of the seven had normal pairing throughout the terminal region involved in the pyd1 and wd1 deletions. Because genetic tests established that deletions were present in these two stocks, these deletions were probably too short to disrupt the pairing of the homologous chromosomes. Mechanisms by which the Mutator system might generate these deletions are discussed.

Chromosome Deletion↗
PubMed1994

The relationship of homologous synapsis and crossing over in a maize inversion.

Frequency of homologous synapsis at pachytene for a relatively short heterozygous inversion was compared to the frequency of crossover occurrence within the inversion and to the frequency of the presence of a recombination nodule within the homologously synapsed inverted region. Crossover frequencies were estimated from bridge-fragment frequencies at anaphase I and anaphase II. Recombination nodules (RNs) were observed in electron micrographs. Results show very similar frequencies of homologous synapsis and the occurrence of reciprocal recombination within the inverted region, consistent with the interpretation that establishment of homologous synapsis in this case is related to at least commitment to the form of resolution of crossover intermediates which gives rise to reciprocal recombination, not conversion only, events. An RN was generally found at pachytene in homologously synapsed inverted regions.

Crossing Over, Genetic↗
PubMed1993

Evidence from a maize desynaptic mutant points to a probable role of synaptonemal complex central region components in provision for subsequent chiasma maintenance.

Homozygotes for the dsy1 desynaptic mutant of maize show massive failure of chiasma maintenance during diplotene and diakinesis. Although some chiasmata persist until anaphase I in most microsporocytes expressing this mutant, homozygotes are completely or nearly completely sterile, owing apparently to disjunctive irregularities. Pachytene synaptic errors and some synaptic failure also are found, but recombination nodules are common in homologously synapsed regions, and equational separation of a heterozygous knob into univalents or open arms at diakinesis clearly demonstrates that chiasma failure occurs following crossing-over. A wider than normal synaptonemal complex central region and uniform apparent weakness of central region cross connections to spreading procedures strongly suggest the presence of a genetic lesion in a synaptonemal complex central region component. The dsy1 mutant may provide an especially important source of material for molecular studies on the nature of chiasma maintenance mechanism.

Chromosomes↗
PubMed1992

Inhibition kinetics and selectivity of the tyrosine kinase inhibitor erbstatin and a pyridone-based analogue.

The inhibition mechanisms of the epidermal growth factor (EGF) receptor tyrosine kinase and the cAMP-dependent kinase activities by erbstatin and its analogue, RG 14921, were studied by kinetic analysis. Both compounds were slow-binding inhibitors of the EGF receptor kinase. Erbstatin inhibited the EGF receptor kinase as a partial competitive inhibitor with respect to both ATP and the peptide substrate, suggesting that it binds at a site distinct from the ATP and peptide binding sites of the enzyme, and thus lowers the binding affinities of the enzyme for both substrates. In contrast, the analogue RG 14921 inhibited EGF receptor kinase activity as a non-competitive inhibitor with respect to both ATP and the peptide substrate. The distinct modes of inhibition by structurally related compounds suggest a dynamic and possibly extended structure of the catalytic center of the kinase domain of the receptor. Erbstatin and RG 14921 exerted similar effects on cAMP-dependent protein kinase activity. In this system, both compounds displayed potent inhibition and acted by a mode of competitive inhibition with respect to ATP and non-competitive with the peptide substrate.

Adenosine Triphosphate↗
PubMed1992

The evolution of meiosis.

Meiosis is too complex to have arisen at once full blown and a stepwise scheme is proposed for its evolution, where each step is believed to have provided an immediate selective advantage: (1) The first step in this tentative sequence is the development of a haploidization process by means of a rapid series of mitotic non-disjunctions, turned on under conditions where haploidy is favored. The non-disjunctions may have resulted from a conditional mutation which caused sister centromere cohesiveness in the past mitotic metaphase. (2) Next probably came the formation of rudimentary synaptonemal complex type structures, first at Holliday-type configurations and later extending from these along chromosome pairs. These structures between homologues, though costly to produce and maintain, may have directly served the disjunctive function by setting the stage for the production of haploidy in one division, under conditions where it was advantageous. (3) Then secondarily acquired functions of the synaptonemal complex or structures associated with it may have promoted greatly increased crossover frequency, in part at least by increasing the frequency of the isomerization-type reaction. The resulting recombination of linked genes could have been advantageous under some conditions. (4) Finally, it is proposed that the capability was acquired for enhanced association of sister chromatids during the period between pachytene and anaphase I to give rise to chiasma-mediated disjunction, so that the relatively costly synaptonemal complex maintenance until anaphase I could be abandoned without losing disjunctive capability. It is implied that the modern synaptonemal complex is a structure which embodies a number of separately encoded proteins and that secondary structures and functions are associated with close homologue pairing. This scheme is based upon observable cytological and molecular characteristics of modern organisms.

Animals↗
PubMed1991

Synaptonemal complex behavior in asynaptic maize.

Synatonemal complexes were studied in silver-stained spread preparations of microsporocyte complements of asynaptic maize. Complexes were found predominantly in terminal regions of chromosome pairs. These tend to be aggregated in a common portion of the nucleus and to have polar orientation. As many as 19 of the 20 ends were found to be involved in relatively short paired segments. Intercalary regions of cores were not strongly organized and aligned, but some contained completed synaptonemal complex segments. The defect in asynaptic appears to represent stalling of the synaptic process at an early stage of synaptic progression.

Microscopy, Electron↗
PubMed1991

The desynaptic mutant of maize as a combined defect of synaptonemal complex and chiasma maintenance.

The phenotype of the desynaptic (dy) mutant of maize in microsporocytes at meiotic prophase was compared with normal microsporocytes of a closely related strain and with microsporocytes of a maize inbred line (KYS) assumed to be normal. Strikingly more univalents and open arms of bivalents were found in the mutant cells than in normal cells at diakinesis, and where there was heterozygosity for a distal knob (heterochromatic region), separation was usually equational, indicating the occurrence of normal crossing-over followed by failure of chiasma maintenance in the mutant. Differences found in the mutant by electron microscopy were a statistically significant wider dimension of the synaptonemal complex central region and also less twisting of synapsed configurations at pachytene. It is suggested that these are side-effect symptoms of a defect in the synaptonemal complex (or associated substance), which is expressed later as sporadic loss of chiasma maintenance.

Microscopy, Electron↗