Biomedical subjects

C M Milne

Publications and source records attributed to C M Milne.

4 recordsLinked to original sources

PubMed1987

Reduced estradiol production by a substituted triazole results in delayed ovulation in rats.

Ovulation in the rat is delayed by a single administration of the substituted triazole R151885 (1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol). This delay results from a 24-hr shift in the preovulatory luteinizing hormone (LH) surge since administration of chorionic gonadotrophin on proestrus restores ovulation. Plasma levels of estradiol are markedly reduced (42-45%) 6-12 hr after administration of R151885. The restoration of ovulation in R151885-pretreated rats, by administration of exogenous estradiol benzoate, indicates that the reduced estradiol levels play a pivotal role in the delay of ovulation. Granulosa cells isolated from rat ovaries produce estradiol and progesterone in vitro in the presence of both follicle-stimulating hormone and testosterone. The addition of R151885 to such cultures results in a dose-dependent inhibition of estradiol production (69% by 1 microM) without a significant effect on progesterone production. This inhibition occurs at concentrations of R151885 similar to those measured in vivo. R151885 is a competitive inhibitor of human placental aromatase (apparent Ki with androstenedione substrate of 410 nM) and produces a type II spectral perturbation of cytochrome P-450 from placental microsomes. Pituitaries isolated from R151885-treated rats have reduced LH output in response to gonadotrophin-releasing hormone stimulation compared with those of controls. It is proposed that R151885 competitively inhibits aromatase activity in developing ovarian follicles. The resultant temporary reduction of plasma estradiol levels at a critical time in the estrous cycle, and consequent inadequate pituitary sensitization, produces a 24-hr delay in the preovulatory LH surge and hence ovulation is delayed by 24 hr.

Animals↗

PubMed1987

Altered renal function in chronically hyperprolactinaemic rats.

1. Standard renal clearance techniques were used to investigate the effects of chronic hyperprolactinaemia on kidney function in male, female and ovariectomized female rats. 2. All hyperprolactinaemic rats showed a significantly increased glomerular filtration rate (G.F.R.) compared to controls. Values were (microliter min-1) 2738 +/- 146 vs. 2299 +/- 99 for males (P less than 0.05), 2236 +/- 79 vs. 1865 +/- 74 for females (P less than 0.01) and 2200 +/- 76 vs. 1941 +/- 62 for ovariectomized females (P less than 0.05). 3. Hyperprolactinaemic rats in all groups also showed a significant increase in absolute tubular reabsorption of water, sodium and chloride compared to their respective controls. Increases here averaged 19%. 4. There was a significantly greater fractional tubular reabsorption of fluid and solutes in hyperprolactinaemic male rats compared to controls. Values were (%) 92.9 +/- 0.6 vs. 90.3 +/- 0.7 for water, 93.0 +/- 0.4 vs. 91.0 +/- 0.6 for sodium and 89.9 +/- 0.7 vs. 86.5 +/- 0.9 for chloride. In each case P less than 0.05. 5. These results imply an osmoregulatory role for prolactin which is not specific to pregnancy or related female reproductive states.

Absorption↗

PubMed1987

Hormone profiles for progesterone, oestradiol, prolactin, plasma renin activity, aldosterone and corticosterone during pregnancy and pseudopregnancy in two strains of rat: correlation with renal studies.

Plasma samples were obtained throughout pregnancy and pseudopregnancy from Sprague-Dawley (SD) rats and during pregnancy from rats of the Munich Wistar (MW) strain. The concentrations of progesterone, oestradiol, prolactin, plasma renin activity (PRA), aldosterone and corticosterone were measured by radioimmunoassay to establish hormonal profiles in the two strains of rat. Circulating progesterone concentrations in both strains of rat were significantly higher during pregnancy than in virgin controls, except at term in the SD group. The hormonal pattern for pseudopregnancy was similar to that of the first half of pregnancy. Oestradiol concentrations were similar to, or lower than, those in virgin controls throughout pseudopregnancy and for the first 2 weeks of pregnancy in both strains of rat. Increased concentrations of steroid were seen only in the pregnant groups towards term. In SD rats, highest prolactin concentrations were apparent during the first half of pregnancy and pseudopregnancy, and at term in the pregnant group. Pregnant MW rats showed a different profile for this hormone, with low levels throughout pregnancy except at term. In all groups PRA rose to a peak at day 9 and decreased to day 16. Pregnant SD rats also showed a significant increase at term. Aldosterone concentrations were significantly increased at several stages of pregnancy in both strains of rat, particularly during the second half of gestation. Pseudopregnant animals showed a different hormone profile, with no significant changes until day 16 when lower concentrations were recorded. There was little variation in the circulating corticosterone concentration except in pregnant rats at term when levels fell. These findings are discussed in relation to the known renal changes of pregnancy and pseudopregnancy.

Aldosterone↗

PubMed1986

Ovulation in rats is delayed by a substituted triazole.

When a single oral dose of 5 or 25 mg/kg of the substituted triazole R151885 [1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol] was administered at midday on diestrus-2 to rats with regular 4-day estrous cycles, the subsequent ovulation was delayed by 24 or 48 hr, respectively. There was no evidence of toxicity at the doses used. The only morphological changes detected in the reproductive tract were a delay in accumulation of uterine fluid and prolonged but normal follicular maturation prior to the delayed ovulation. The delayed follicles were slightly larger than normal follicles at the time of ovulation. The preovulatory peak plasma concentrations of progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were delayed by 24 hr in rats treated with 5 mg/kg of R151885 on diestrus-2. Although there was a normal preovulatory peak plasma concentration of estradiol, values were reduced by between 30 to 50% late on diestrus-2 and early on proestrus. Additionally, in ovariectomized rats, 3 daily doses of 25 mg/kg of R151885 antagonized the action of estradiol on the uterus by 45%. We suggest that the reductions in plasma estradiol concentrations during diestrus-2 and proestrus, combined with some antagonism of estradiol's action, may prevent adequate priming of the pituitary thereby suppressing the preovulatory LH surge required for ovulation. The suppression of this LH surge is of a temporary nature indicating a reversible effect of R151885 on the hormonal control system.

Administration, Oral↗