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M. B. Kerr, K. Marshall and J. Senior

ABSTRACT

The uterotrophic response in the normotensive (CD) and the hypertensive (SHR) rat was compared in intact cyclic rats and in ovariectomized rats given oestradiol. The parameters measured were blood flow, and uterine wet and dry weights. In the cyclic animals blood flow to the oestogen target tissue varied throughout the oestrous cycle, peak flows being achieved at pro-oestrus; in the SHR rat, however, the pro-oestrous maximum was significantly attenuated compared with the CD rat. Uterine wet and dry weights were similar.

The temporal response to oestradiol in ovariectomized rats showed that in the CD rat the hyperaemic response peaked earlier than in the SHR rat, significant changes in terms of increased water imbibition also occurred more quickly in the CD strain. In both strains, uterine dry weight was the last parameter to be significantly increased, the maximum weight being attained more quickly in the SHR rat.

The results of this study indicated that it is the blood flow to the oestrogen target tissues of the uterus and vagina that is most susceptible to change with strain of rat.

Journal of Endocrinology (1992) 135, 263–269

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M. B. Kerr, K. Marshall and J. Senior

ABSTRACT

The role of thromboxane in the gravid normotensive (CD) and hypertensive (SHR) rat was investigated (by utilizing two thromboxane receptor-blocking drugs, EP092 and AH23848) both at mid-gestation and at term. The parameters examined were uterine blood flow (blood flows were measured by the microsphere technique) and uterine weight and placental blood flow at term, fetal mass and number.

At mid-gestation EP092 significantly (P< 0·005) increased uterine blood flow in both strains whilst the increases seen with AH23848 were not statistically significant. At term (day 22 in the CD and day 23 in the SHR rat) the antagonists increased uterine blood flow in the CD rats alone. However, at this time the antagonists caused an increase in placental blood flow in both strains.

Thromboxane appears to be involved in the regulation of uteroplacental blood flow. The observation that the antagonists were able to potentiate blood flow by mid-gestation may provide a clinical indication with respect to potential prophylactic use of this class of compounds in cases of pregnancy-induced hypertension in women.

Journal of Endocrinology (1992) 135, 257–261

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N Duckworth, K Marshall and JK Clayton

The aim of this study was to compare the effect of two known spasmogens, oxytocin and the stable thromboxane receptor mimetic, U46619, on human myometrium treated with the prostaglandin E receptor (EP2) agonist, butaprost (selective for the EP2 receptor). Strips of myometrium from pregnant and non-pregnant donors were set up in a superfusion apparatus. Butaprost was administered as a bolus dose and via infusion. During the infusion of 10(-6) M butaprost, spasmogens were administered as bolus doses. Butaprost caused dose-related inhibition of myometrial activity when administered as a bolus dose (3-100 nmol) and concentration-dependent inhibition during infusion studies (10(-8)-10(-5 )M). Butaprost (10(-6 )M) attenuated the response to U46619 (0.l-10 nmol) in pregnant myometrium, but this difference was not statistically significant. Responses of pregnant myometrium to oxytocin (0.01-0.1 nmol) were significantly attenuated (P<0.05) in the presence of butaprost (10(-6)M). Butaprost physiologically antagonised the oxytocin response, possibly by increasing intracellular cAMP levels. This antagonism was much more marked than that seen with butaprost and U46619. It is unclear why these two types of antagonism differ and this effect is currently being investigated further using other prostanoid and non-prostanoid agents.

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S. M. Marshall, A. Flyvbjerg, K. D. Jørgensen, J. Weeke and H. Ørskov

ABSTRACT

The effects of treatment for 11 days with human growth hormone (hGH; 140 μg/day), thyroxine (T4; 3 μg/day) and hGH + T4 on renal growth and content of insulin-like growth factor-I (IGF-I) in hypophysectomized rats have been compared with saline-treated hypophysectomized animals and intact control animals. Right kidney weight and kidney weight/body weight ratio remained low in the saline-treated group (313±9 vs 694±28 mg in controls on day 11, P<0·001 and 3·4±0·12 × 10−3 vs 4·2±0·10× 10−3, P< 0·005 respectively). In T4- and hGH-treated animals, kidney weight gain was similar (to 420 ± 14 and 450±22 mg on day 11 respectively, P>0·05), whilst the increase was greater in the group given hGH + T4 (to 572 ±34 mg, P< 0·001 compared with hGH- and T4-treated groups). The kidney weight/body weight ratio became normal in the T4- and hGH + T4-treated animals but remained low in the hGH-treated group. The renal content of IGF-I was low in the salinetreated animals throughout the study (92±10 ng/g on day 11 vs 219±8 ng/g in control animals, P< 0·001), but increased to a maximum of 88% above baseline on day 1 in the group given T4. In the hGH-and hGH + T4-treated groups, renal IGF-I concentration rose to a peak of 317% above baseline on days 2 to 4, then fell to the values seen in control animals on day 11 (hGH: 242±18 ng/g; hGH + T4: 320 ± 41 ng/g; controls: 219 ± 8 ng/g; P> 0·05 for all comparisons). Thus treatment with hGH or T4 results in similar kidney weight gain, despite a greater rise in the renal concentration of IGF-I in the hGH-treated animals. Treatment with both hGH + T4 leads to an increase in the renal concentration of IGF-I similar to that seen with hGH treatment alone, but a larger increase in kidney weight, suggesting that T4 does not stimulate renal growth via the IGF-I pathway and that growth promotion by hGH and T4 is additive.

Journal of Endocrinology (1993) 136, 399–406

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M. J. Evans, A. G. Marshall, N. E. Kitson, K. Summers and R. A. Donald

ABSTRACT

The multifactorial control of ACTH is well established. We wished to establish and characterize an in-vitro perifusion system, using equine anterior pituitary cells and physiological concentrations of secretagogues, to investigate factors which affect the dynamics of ACTH secretion. Anterior pituitary tissue was divided for dispersion into cells with collagenase, trypsin or dispase, or by mechanical dispersion. After dispersal followed by 18-h incubation, cells were perifused and the ACTH response to 10-min pulses of arginine vasopressin (AVP; 100 nmol/l), corticotrophin-releasing hormone (CRH; 0·01 nmol/l), and AVP (100 nmol/l) plus CRH (0·01 nmol/l) determined. ACTH responses to these secretagogues were lower (P <0·05) in cells prepared using the enzymes dispase and trypsin than with the enzyme collagenase. Cells prepared by mechanical methods were not responsive. Collagenase-prepared cells were used in subsequent experiments.

In dose-response studies (10-min pulse length), a steep CRH–ACTH dose-response curve was obtained with the minimum effective concentration of CRH between 0·001 and 0·01 nmol/l, and a maximum effective concentration of 1·0 nmol/l. A less steep AVP–ACTH dose-response curve was obtained with a minimum effective concentration of AVP between 0·5 and 5 nmol/l, and no plateau in response up to 5000 nmol AVP/l. Increasing the incubation time between cell preparation and stimulation with AVP from 18 h to 90 h significantly (P <0·01) increased the ACTH response. Repeated stimulation by AVP (100 nmol/l) or CRH (0·01 nmol/l) (5-min pulses every 30 min for 23 pulses) produced ACTH responses which decreased in an approximately exponential curve with time.

When AVP and CRH were given at physiological concentrations, pulse lengths and pulse frequency, the ACTH response to repeated 1-min pulses of AVP, measured as height above basal secretion, was potentiated by the addition of CRH (1, 2·5, 5, 10 and 20 pmol/l) as a constant perifusion at all AVP concentrations tested (1 nmol AVP/l, P < 0·02; 10 nmol AVP/l, P <0·0005; 25 nmol AVP/l, P <0·0005). During the 1-min AVP pulse, the AVP concentration at the level of the cells was 30% of the expected concentration. Potentiation was increased both by increasing AVP concentration (P <0·00005) and by increasing CRH concentration (P <0·00005) up to 5 pmol CRH/l. The ACTH height response to repeated AVP stimulation significantly (P = 0·0034) decreased with time, independent of CRH and AVP concentration. There was a significant (P = 0·014) decrease in ACTH response to CRH infusion with time, independent of CRH concentration.

We conclude that the responsiveness of pituitary cells is markedly influenced by the preparative techniques. The collagenase-dispersed cells, in the in-vitro perifusion system developed, responded to secretagogues which were given at physiological concentrations, pulse lengths and periods. The system thus fulfills our requirements of in-vitro responses reflecting those observed in vivo, and can therefore be used to investigate the multifactorial control of ACTH secretion further.

Journal of Endocrinology (1993) 137, 391–401

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A L Griffiths, K M Marshall, J Senior, C Fleming and D F Woodward

Previous studies in this laboratory have suggested that the isolated uterus from non-pregnant mice has a prostaglandin F and a thromboxane receptor population similar to that found in human myometrium. The aim of this study was to investigate any regional variation in myogenic activity ) and the and responsiveness to prostaglandin F (PGF thromboxane mimetic U46619 in the mouse uterus taken during different stages of the oestrous cycle and during pregnancy. Uterine samples from BKW mice were taken from different anatomical segments along the length of each uterine horn and set up for superfusion at 2 ml/min with Krebs solution (containing 1 μM indometacin) at 37 °C, and gassed with 95%O2/5%CO2. Responses (area under the curve) are expressed as a percentage of the final contraction induced by hypotonic shock. Data are expressed as the means ± s.e.m. of n=5–12 and were analysed using Student’s paired t-test or two-way ANOVA with a Bonferroni post hoc test. Regional variation in myogenic activity was observed in all tissues studied except those taken during labour. These tissues displayed significantly greater myogenic activity than tissues taken at late gestation and at all stages of the oestrous cycle. Tissues from pregnant animals were generally more responsive to U46619 and PGF than tissues taken from non-pregnant animals. Tissues taken from the upper segment of the uterine horn were more responsive to both agonists during the oestrous cycle. The findings demonstrated that the hormonal milieu and site of excision are important for myogenic activity and responsiveness.