Biomedical subjects

M Mikuni

Publications and source records attributed to M Mikuni.

At least 19 recordsLinked to original sources

PubMed2006

Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients--a preliminary PET study.

OBJECTIVES: To explore neurobiological risk factors for major depressive disorder (MDD) and adjustment disorder in cancer patients by examining regional brain metabolism before psychiatric manifestation using positron emission tomography and by prospectively observing depressive and anxiety symptoms. METHOD: Cancer patients who showed no psychiatric symptoms when they underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) were followed up for one year using the Hospital Anxiety and Depression Scale (HADS). Fourteen patients who showed high HADS scores and 14 patients who showed low HADS scores were assessed by a psychiatrist 2 years after the PET scan and grouped into the deterioration group (n=10) and the no-change group (n=9). 18F-FDG PET images were analyzed to examine the difference in local brain glucose metabolism between the two groups. RESULTS: The deterioration group showed a decreased glucose metabolism in the right medial frontal gyrus (BA6) and an increased glucose metabolism in the right posterior cingulate (BA29), right anterior cingulate (BA25), left subcallosal gyrus (BA25), and left caudate compared with the no-change group. CONCLUSION: Cancer patients who later developed MDD or adjustment disorder showed regional brain metabolic changes. These regions may be associated with vulnerability to the onset of MDD or adjustment disorder in cancer patients.

Adjustment Disorders↗

PubMed2005

Plasma des-acyl and acyl ghrelin in patients with eating disorders.

A recently recognized peptide, ghrelin, increases appetite and energy retention in human. Previous reports have shown higher plasma level in eating disorder (ED) patients and correlations with body mass index (BMI). This study examined these findings by measuring active (N-RIA) and total (C-RIA) levels of plasma ghrelin. Multipurpose assessments of symptoms were conducted for 11 ED patients and 5 control females. Results revealed significant differences of C-RIA between the groups. The BMI did not correlate with ghrelin, but demonstrated reversal correlation with the ratio of N-RIA and C-RIA (NC ratio) according to the ED or control group. The NC ratio also tended to be associated with a self-rating score. The NC ratio might be related to specific characteristics of ghrelin secretion or clearance in ED patients. Further basic and clinical investigations are necessary.

Adolescent↗

PubMed2005

HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures.

OBJECTIVE: To examine the clinical effects of electroconvulsive therapy (ECT) on depressed patients with medication treatment failures, we investigated the alterations in hypothalamic-pituitary-adrenocortical (HPA) function and regional cerebral metabolism rate of glucose (rCMRGlu) after ECT in these patients. METHOD: Before and after ECT, the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test was administered to seven patients who were referred for ECT. In the same patients, (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was also assessed. RESULTS: Cortisol response in the DEX/CRH test significantly decreased after a successful ECT. A significant hypometabolism in various frontal regions and hypermetabolism in the parietal regions of these patients when compared with controls remained after ECT. CONCLUSION: Depressed patients who failed trials of antidepressant medication showed a remission with ECT that was accompanied by resolution of HPA dysregulation. However, measures of cerebral brain metabolism did not resolve.

Anti-Inflammatory Agents↗

PubMed2003

Role of the angiotensin II system in regulation of ovulation and blood flow in the rat ovary.

The aim of the present study was to examine the roles of the angiotensin II receptor subtypes, AT(1) and AT(2), in ovulation, and to evaluate the contribution of angiotensin II-mediated pathways in regulation of ovarian blood flow. The AT(1)-specific antagonist, losartan, was administered alone or in combination with the AT(2)-specific antagonist, PD123319, to preovulatory rat ovaries perfused in vitro. Losartan (100 micromol l(-1)) did not affect the number of ovulations, whereas the combination of losartan (100 micromol l(-1)) and PD123319 (10 micromol l(-1)) inhibited ovulation. The angiotensin II antagonists did not affect the ovarian production of oestradiol, progesterone, prostaglandin E(2) (PGE(2)), PGF(2 alpha) or plasminogen activator activity. Ovarian nitric oxide production was inhibited by losartan. Ovarian blood flow was measured by laser Doppler flowmetry in vivo in preovulatory rat ovaries. Intrabursal injection of angiotensin II reduced ovarian blood flow of gonadotrophin-stimulated rats. Losartan had no effect on basal ovarian blood flow but completely blocked the angiotensin II-induced reduction. In contrast, treatment with PD123319 increased basal ovarian blood flow and failed to reverse the effect of exogenously administered angiotensin II, indicating that under physiological conditions, ovarian blood flow of the rat is negatively regulated by angiotensin II mainly through the action of AT(2). Taken together, these results indicate that two different types of angiotensin II receptor facilitate ovulation by cooperative mechanisms and that they regulate ovarian blood flow in a different manner.

Angiotensin II↗

PubMed2001

A study of the relationship between metabolism using 1H-MRS and function using several neuropsychological tests in temporal lobe epilepsy.

Several investigators have reported on the relationship between metabolism, using magnetic resonance spectroscopy (MRS), and function, using neuropsychological tests in temporal lobe epilepsy (TLE) patients, but the opinions regarding the results remain in contention. The aim of this study is to examine the relationship between metabolism, using proton MRS ((1)H-MRS), and function using several neuropsychological tests in the temporal lobes of TLE patients. We studied 29 TLE patients at our hospital using(1)H-MRS and neuropsychological tests. We used a clinical 1.5 T MR unit. We conducted five neuropsychological tests to examine the function of the left or right temporal lobe. There were significant correlations between the N-acetylaspartate/creatine + phosphocreatine (NAA/Cr) ratios and the scores of almost all of the neuropsychological tests for the temporal lobe function ipsilateral to the spike focus. However, in two Wechsler Memory Scale-Revised (WMS-R) subtests we found no significant correlation in the ipsilateral side. These findings suggest that the NAA/Cr ratios, which reflect neural metabolism, are closely related to function in the temporal lobes of TLE patients. The disparity between the results in two subtests of WMS-R show that several tests may be necessary in order to assess temporal lobe function.

Adolescent↗

PubMed2001

Inhibition of ovulation in the rat by a leukotriene B(4) receptor antagonist.

The involvement of leukotriene (LT) B(4) in the ovulatory process of the rat was investigated by the use of a LTB(4)-receptor antagonist (ZK158252 = L-ANT) administered either intrabursally in vivo or to the in-vitro perfused ovary. The in-vivo experiments revealed inhibition of human chorionic gonadotrophin (HCG)-induced ovulation by 500 micromol/l L-ANT (median 5.5, 25-75% range 1.0-6.0) compared with controls (median 9.0, range 6.25-13.5). In vitro, ovulation was induced by LH (0.2 microg/ml) + 3-isobutyl-1-methylxanthine (IBMX; 0.2 mmol/l). The ovary was perfused either for 20 h, to study ovulation rate, or for 10 h to examine ovarian concentrations of the ovulatory mediators matrix metalloproteinase (MMP)-2 and MMP-9, plasminogen activator (PA), prostaglandin (PG)E(2) and PGF(2 alpha). Addition of LH+IBMX resulted in a marked stimulation of steroid release and ovulations occurred in all ovaries (median 11.0, range 10.0-14.0). The L-ANT inhibited ovulation in a dose-dependent way (median 10.0, range 8.0-13.0 at 1 micromol/l; median 6.0, range 3.5-10.0 at 10 micromol/l; median 2.0, range 0.75-5.75 at 100 micromol/l). The intra-ovarian activity of PA was increased 1.5-fold by L-ANT (100 micromol/l), but the concentrations of PGE(2) and PGF(2 alpha) remained unaltered. While no changes in MMP-9 were observed, conversion from pro-MMP-2 to active MMP-2 was inhibited by L-ANT. These results suggest that activation of the LTB(4)-receptor within the ovary is involved in the ovulatory process and that the effects of LTB(4)-receptor activation are partly mediated via MMP-2.

Animals↗

PubMed2001

Effects of genistein on the periovulatory expression of messenger ribonucleic acid for matrix metalloproteinases and tissue inhibitors of metalloproteinases in the rat ovary.

The matrix metalloproteinases (MMPs) play critical roles in the ovulatory process. Their expression and activity, together with those of the endogenous tissue inhibitors of metalloproteinases (TIMPs), are stimulated by LH. The LH surge initiates a cascade of events resulting in ovulation and formation of the corpus luteum via activation of protein kinases A and C, as well as tyrosine kinases. In vitro perfused rat ovaries were untreated, or treated with LH (0.2 microg ml(-1)) plus 0.2 mmol 3-isobutyl-1-methylxanthine l(-1) with 0, 10 or 100 micromol genistein l(-1) (an inhibitor of tyrosine kinases) to assess whether tyrosine kinases are mediators of the LH-stimulated increase in ovarian expression of the MMPs and TIMPs. After 10 h of perfusion, ovaries were collected and frozen until RNA isolation. Northern and RNase protection analyses were used to measure mRNA encoding collagenase 3, gelatinases A and B, and TIMPs-1, -2 and -3. Treatment with LH plus 3-isobutyl-1-methylxanthine resulted in a two- and fivefold increase in mRNA encoding collagenase 3 and TIMP-1, respectively (P < 0.05). Treatment with 100 micromol genistein l(-1) blocked the LH-stimulated increase in collagenase 3 (0.012 +/- 0.002 versus 0.028 +/- 0.005 relative units for 100 micromol genistein l(-1) versus LH; P < 0.05), whereas neither dose of genistein affected LH-induced TIMP-1 expression. LH alone or with genistein did not alter the expression of mRNA encoding TIMP-2 and TIMP-3, or mRNA encoding gelatinases A and B. These data indicate that tyrosine kinases play a role in the LH-induced tissue remodelling required for ovulation by mediating the LH-stimulated expression of collagenase 3.

Animals↗

PubMed2000

Human midbrain dopamine neurons express serotonin 2A receptor: an immunohistochemical demonstration.

We demonstrated intense serotonin (5-HT) 2A receptor immunoreactivity in the human ventral tegmental area (VTA) using by a recently raised antibody against 5-HT2A receptor. The substantia nigra (SN) neurons also showed 5-HT2A receptor immunoreactivity. Double immunohistochemistry of 5-HT2A receptor and tyrosine hydroxylase (TH) revealed many neurons doubly labeled by 5-HT2A receptor and TH in the VTA and SN. It is suggested that activity of human midbrain dopaminergic neurons might be strongly regulated via 5-HT2A receptors at the level of their originating nuclei.

Adult↗

PubMed2000

Evidence for the involvement of blood flow-related mechanisms in the ovulatory process of the rat.

To elucidate whether any relationship exists between ovarian blood flow and ovulation rate, the effects on these parameters were examined in equine chorionic gonadotrophin/human chorionic gonadotrophin (eCG/HCG) (15I U/15I U) primed rats after bilateral ligation and severance of either the ovarian branch of the uterine artery and vein (UL), the ovarian artery and vein (OL) or both sites (UL+OL) in comparison to sham operations. Laser Doppler flowmetry demonstrated the presence of microcirculatory vasomotion and a reduction of blood flow after UL, OL and UL+OL performed during the intervals 0-3 h (78, 66 and 19% of pretreatment values respectively) and 6-9 h (68, 57 and 20%) after HCG. Experiments utilizing radioactive microspheres also indicated decreased ovarian blood flow by UL and OL. Ovulation rate was assessed 20 h after HCG in animals where ligations had been performed at 0, 3, 6 and 9 h after HCG. No ovulations were seen after UL+OL and significantly decreased ovulation rates ( approximately 50% of sham operated animals) were seen after UL at 0 and 3 h and after OL at 0, 6 and 9 h. Progesterone concentrations in blood 20 h after HCG were reduced by OL but not UL and ovarian weights were unaffected by ligation. It is concluded that acute blood flow reduction during the ovulatory interval reduces ovulation rate in the rat.

Animals↗

PubMed2000

Time-dependent ovulation inhibition of a selective progesterone-receptor antagonist (Org 31710) and effects on ovulatory mediators in the in vitro perfused rat ovary.

Progesterone (P) is one of several local mediators in the ovulatory cascade in the rat. The precise mechanisms of action for P in ovulation and in what phase of the ovulatory process P is critical, however, need to be clarified. The present study used a selective P-receptor antagonist, Org 31710, in the in vitro perfused rat ovary model to examine the local role of P and possible effects on prostaglandin (PG) and plasminogen-activator (PA) release in ovulation. Ovaries from eCG (15 IU)-primed rats were perfused for 20 h with LH (0.2 microg/ml) and 3-isobutyl-1-methylxanthine (IBMX, 200 microM) to induce ovulation (median = 10.0, 25%-75% range = 8.5-13). Org 31710 was added at either 0, 3.5, 7, or 9 h after LH+IBMX, resulting in significant suppression of ovulation after addition at 0 and 3.5 h (1.0, 1-5.5; and 5.0, 2.5-7.75 ovulations, respectively) but no suppressive effect when added at later time points. Progesterone and estradiol levels in the perfusion media were increased after LH+IBMX but were not affected by the presence of Org 31710. Ovarian tissue levels of PGE(2), PGF(2 alpha), and PA activity were measured in ovaries that had been perfused for 10 h, a time that was 2 to 5 h before anticipated ovulation. The presence of Org 31710 significantly decreased the levels of PGE(2), PGF(2 alpha), and PA activity. These results suggest that P is essential in ovulation during the initial stages of the ovulatory process. The effect of P to facilitate ovulation seems to relate to stimulation of the PG- and PA-mediator systems.

1-Methyl-3-isobutylxanthine↗

PubMed1999

Changes in uterine size after vaginal delivery and cesarean section determined by vaginal sonography in the puerperium.

There have been few reports on postpartum changes in the uterus during the three months after delivery. The aim of this study was to evaluate uterine morphological changes in women after vaginal delivery (n=262-351) and in women after cesarean section (n=64-82) and to evaluate the relation between breast-feeding and parity, and uterine involution at 1 and 3 months postpartum measured by vaginal ultrasonography. There were no significant differences in parity between the vaginal delivery group and the cesarean section group. The length of the uterus at one month (7.93+/-1.16 cm, mean+/-SD) and, three months (7.03+/-1.19 cm) and the width of the uterus at three months (3.83+/-0.94 cm) after delivery in the cesarean section group were greater than in the transvaginal group (7.64+/-1.03 cm, 6.65+/-0.99 cm, 3.57+/-0.62 cm, respectively). Increasing maternal parity was associated slightly with larger uterine size at one month post partum. The length of the uterus of women with a breast-feeding rate of 80% or more per day was 6.35+/-0.85 cm, and shorter than in women with a rate of 20% or less 7.03+/-1.04 cm, at three months after delivery. The width of the uterine body of women with a breast-feeding rate of 80% or more per day was 3.32+/-0.45 cm, and shorter than in women with a rate of 20% or less 3.87+/-0.66 cm, at 3 months after delivery. Stepwise regression and multiple regression analysis among parity, the history of cesarean section, the breast-feeding rate at one and three months after the delivery, and the restoration of the menses at three months after the delivery showed that the uterine size at one month after the delivery was related to the cesarean section and that the uterine size at three months after delivery was mostly related to the rate of breast-feeding. These results indicated that uterine involution was related to delivery mode at one and three months postpartum, feeding mode at three months postpartum, the menses restoration, and parity. The rate of breastfeeding was mostly related to the uterine size at three months postpartum.

Adult↗

PubMed1999

Effects of a nitric oxide donor and nitric oxide synthase inhibitors on luteinizing hormone-induced ovulation in the ex-vivo perfused rat ovary.

The aim of this study was to investigate the role of nitric oxide (NO) in ovulation and ovarian steroidogenesis by the use of NO synthase (NOS) inhibitors and an NO donor administrated to the luteinizing hormone (LH)-stimulated ex-vivo perfused pre-ovulatory rat ovary. The ovaries were stimulated with LH (0.2 microgram/ml) alone or in combination with the phosphodiesterase inhibitor IBMX (200 micromol/l). The presence of both endothelial NOS (eNOS) and inducible NOS (iNOS) in the perfused rat ovary were detected by immunoblotting and a clear increase in amount of iNOS protein was seen after LH+IBMX stimulation. The addition of a non-selective NOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 300 micromol/l), to the perfusate significantly decreased ovulation numbers (median = 4. 0, range = 1-14) as compared with LH + IBMX stimulated control (12.0, 6-17). In contrast, an inhibitor with relative selectivity towards iNOS, aminoguanidine bicarbonate (AG, 300 micromol/l and 1 mmol/l), did not change the ovulation rate (11.5, 6-18 and 11.0, 7-15 respectively). In perfusions with only LH, a lower ovulation rate was seen but with similar effects (0.0, 0-8 for L-NMMA; 7.5, 3-12 for control and 7.0, 1-15 for AG 300 micromol/l). The administration of an NO donor, spermine NONOate, resulted in similar ovulation numbers as in LH-stimulated controls. The NO inhibitors did not affect steroid concentrations in the perfusion media, while 100 micromol/l NONOate increased progesterone production.

Animals↗

PubMed1999

Inhibition of ovulation by tyrosine kinase inhibitors in the in vitro perfused rat ovary.

Protein tyrosine kinase activity, leading to tyrosine phosphorylation of the intracellular domains of receptors or non-receptor proteins, is an important feature of downstream signalling after receptor binding of a variety factors, such as growth factors and cytokines. Since several members of these classes of paracrine-autocrine mediator may be involved in the intraovarian events of ovulation, the present study was designed to evaluate the effect of protein tyrosine kinase inhibition on the in vitro perfused rat ovary. Immature rats were primed with 20 iu pregnant mares' serum gonadotrophin 48 h before surgical isolation of the right ovary with connecting vasculature. The ovary was placed in a perfusion system for either 10 h, to examine ovarian concentrations of the established ovulatory mediators plasminogen activator, prostaglandins E2 and F2 alpha, or for 20 h, enabling a complete ovulatory process to occur in vitro. Ovulation was induced by ovine LH (0.2 microgram ml-1) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.2 mmol l-1) and the effects of two different protein tyrosine kinase inhibitors, genistein and tyrphostin A25, were studied. Unstimulated control ovaries did not ovulate and showed low secretion of progesterone and oestradiol. Addition of LH + 3-isobutyl-1-methylxanthine resulted in a marked stimulation of steroid release, and ovulations occurred in all ovaries (9.0 +/- 0.9; mean +/- SEM). The protein tyrosine kinase inhibitors, genistein and tyrphostin A25, significantly inhibited ovulation at the higher concentrations tested (3.0 +/- 0.3 at 100 mumol genistein l-1; 5.8 +/- 1.0 at 500 mumol tyrphostin A25 l-1) but no effect was seen at lower concentrations. The presence of genistein and tyrphostin A25 at any concentration used did not significantly decrease the LH + 3-isobutyl-1-methylxanthine-induced progesterone or oestradiol concentrations. The intraovarian concentrations of plasminogen activator activity, and prostaglandin E2 and F2 alpha were not altered by the presence genistein (100 mumol l-1). In conclusion, the results of the present study indicate that protein tyrosine kinase signalling pathways are integral parts of the mammalian ovulatory process but do not involve actions on the synthesis of steroids, plasminogen activator or prostaglandins.

Animals↗

PubMed1999

18F alpha-methyl tyrosine PET studies in patients with brain tumors.

UNLABELLED: We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. METHODS: Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. RESULTS: Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). CONCLUSION: FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.

Adolescent↗

PubMed1998

Saralasin-induced inhibition of ovulation in the in vitro perfused rat ovary is not replicated by the angiotensin II type-2 receptor antagonist PD123319.

OBJECTIVE: Our aim was to explain the effect of the nonspecific angiotensin II antagonist saralasin and the specific angiotensin II type-2 receptor antagonist PD123319 on ovulation. STUDY DESIGN: Saralasin, 1 micromol/L (n = 5), and PD123319 10 micromol/L (n = 6), were administered to in vitro perfused rat ovary. Prostaglandin (prostaglandin E2, prostaglandin F2alpha, 6-keto-prostaglandin F1alpha), hydroxy-eicosatetraenoic acid (12-hydroxy-eicosatetraenoic acid, 15-hydroxy-eicosatetraenoic acid), estradiol, and progesterone levels in the perfusate and the ovulation rate were compared (Mann-Whitney U test) with controls. RESULTS: Saralasin significantly (P < .01) inhibited the ovulation rate (3.0 +/- 1.4) versus control (13.1 +/- 1.0) and reduced prostaglandin E2 (at 3 hours P < .01 and 20 hours P < .05) and 6-keto-prostaglandin F1alpha (at 20 hours P < .05) levels. Saralasin did not alter prostaglandin F2alpha, hydroxy-eicosatetraenoic acids, or steroid levels. PD123319 decreased 15-hydroxy-eicosatetraenoic acid levels at 3 hours (P < .05) but had no effects on other eicosanoids, steroid levels, or the ovulation rate. CONCLUSION: Angiotensin II plays an important role in ovulation in the rat and is associated with ovarian prostaglandin synthesis. This effect is not selectively regulated via the angiotensin II type-2 receptor.

Angiotensin Receptor Antagonists↗

PubMed1998

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Adult↗

PubMed1998

The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary.

Eicosanoids, the active metabolites of arachidonic acid, are grouped into cyclooxygenase products (prostaglandins [PGs] and thromboxanes) and lipoxygenase products (leukotrienes [LTs] and lipoxins). Numerous studies suggest a role for the lipoxygenase system in ovulation. The aim of this study was to further characterize the effects of lipoxygenase inhibition and the interactions of the lipoxygenase and cyclooxygenase systems in the rat ovary during ovulation. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was administered in vivo and in the isolated perfused rat ovary to determine its effect on ovulation rate. The in vivo study confirmed the inhibitory effect of NDGA, and in the perfusion experiments, NDGA caused a dose-dependent reduction in the ovulation rate. To further define the interaction between the lipoxygenase and cyclooxygenase systems, a second set of perfusions was performed with NDGA (10 microM) and the combination of NDGA (10 microM) plus a nonselective cyclooxygenase inhibitor, indomethacin (10 microM). NDGA significantly reduced the number of ovulations compared to that in controls. The ovulation rate for the combination of NDGA+indomethacin was also significantly lower than in controls but not different from that in the NDGA-treated group. Steroidogenesis was decreased only in the NDGA+indomethacin perfusions. Ovarian tissue PGE2 and PGF2alpha levels in the NDGA-treated ovaries were significantly suppressed compared to those in controls. Almost a complete block of PGE2 and PGF2alpha was seen in the NDGA+indomethacin group. LTB4 levels in the 10-h-perfused ovarian tissues were significantly decreased by NDGA compared to those in control tissues. Furthermore, LTB4 (3 microg added twice) completely reversed the inhibitory effect of 0.1 microM NDGA on ovulation rate and partially reversed the effect of 10 microM NDGA in the perfusion model. These results demonstrate that the products of the lipoxygenase pathway, especially LTB4, are important in the process of ovulation in this cyclically ovulating species. The interconnected lipoxygenase and cyclooxygenase pathways may optimize ovulation and facilitate steroidogenesis.

Animals↗

PubMed1998

The selective prostaglandin endoperoxide synthase-2 inhibitor, NS-398, reduces prostaglandin production and ovulation in vivo and in vitro in the rat.

Two isoforms of prostaglandin G/H synthase, PGS-1 and PGS-2, catalyze the formation of prostaglandins (PG). Nonselective PGS inhibitors, e.g., indomethacin, reduce the number of ovulations and PG levels in many animal models. This study evaluated the effects of the selective PGS-2 inhibitor NS-398, compared to indomethacin, on ovulation number and on PG and steroid production both in vivo and in vitro in the rat. NS-398 reduced the synthesis of PGE2 in isolated, LH-stimulated preovulatory follicles incubated in vitro. The inhibition by NS-398 was similar to that of indomethacin. Maximal inhibition was noted from 0.1 microM. Neither progesterone nor cAMP production was affected by NS-398 or indomethacin. The effect of in vivo administration of NS-398 (1, 3, or 10 mg/kg BW, s. c.) to proestrous rats 1 h after the injection of an ovulatory dose of hCG was monitored in follicles extirpated 10 h after hCG. These follicles were incubated in vitro, and NS-398 dose-dependently reduced PGE2 production. The synthesis of cAMP and progesterone was not altered. In separate experiments, the same doses of NS-398 were injected to determine their effect on ovulation in vivo. The number of ovulations was decreased by the highest dose of NS-398. In the in vitro ovarian perfusion model, NS-398 (10 microM) reduced the number of ovulations initiated by LH and isobutylmethylxanthine. Lower doses of NS-398 (0.1 and 1 microM) were less effective. The production of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was reduced in a dose-dependent manner by NS-398. The secretion of steroids was not affected. This study demonstrates that selective inhibition of PGS-2 by NS-398 reduces LH/hCG-stimulated production of prostanoids and the number of ovulations both in vivo and in vitro. These results provide direct evidence to strengthen the role of the inducible, granulosa cell-expressed PGS-2 as one of the key regulators in the ovulatory process and also document that the elevated and perhaps sustained levels of PG are obligatory for ovulation.

1-Methyl-3-isobutylxanthine↗