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SUMMARY
The effect of a single injection of dexamethasone on adrenocortical cell proliferation was studied in prepubertal male rats using tritiated thymidine. After a short latent period, all zones of the adrenal cortex showed a rapid decrease in both labelling and mitotic indices. After a prolonged period when very low indices were apparent, there was a rapid rise in both proliferative indices with most zones showing a considerable increase above control values.
A more detailed study of the initial depression showed that after a latent period of about 5 h the labelling index fell approximately 8 h before the mitotic index. This differential response in the labelling and mitotic indices was consistent with a block in the cell cycle late in the pre-DNA synthetic interval of the cell cycle (G1), with cells being prevented from entering DNA synthesis. This hypothesis was also supported by an experiment involving continuous labelling of control and dexamethasone-treated animals; again after a latent period of 5–6 h, the rate of increase of the continuous labelling index fell as cells became blocked in late G1.
By analogy with other tissues, results are interpreted in terms of a direct action of dexamethasone on adrenocortical cells; this steroid-sensitive step in the cell cycle may be important in the control of growth in the adrenal cortex.
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Although it is now established that deprivation of vitamin E may lead to disturbances of structure and function of many tissues other than those primarily concerned in the reproductive cycle, it is not surprising, when the striking nature of the testicular degeneration and the curious character of the typical resorption in the female are borne in mind, that there has been a tendency to concentrate attention on the question whether the vitamin plays an essential part in the reproductive cycle.
The most direct approach has been made by investigating whether the vitamin itself exerts a gonadotrophic action. Up to the present the evidence has been inconclusive. The most striking claim is that of Szarka [1929], who stated that oral or parenteral administration of vitamin E concentrates produces oestrus in immature female rats. Later, Verzár [1931] recorded that injection of similar materials produced hypertrophy of the uterus in similar animals, but
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SUMMARY
Recently, cell loss by necrosis has been demonstrated in the zona reticularis of the adrenal cortex; such loss is a prerequisite of the centripetal migration theory of adrenocortical cell renewal. Consequently a method has been evolved for the estimation of the rate of cell loss from the z. glomerulosa in prepubertal male rats aged 14 days.
The method depends upon measurement of the doubling time for the z. glomerulosa by weighing and serially sectioning adrenal glands at ages from 3 to 120 days, combined with point-counting. The doubling time for the z. glomerulosa at 14 days of age was 120 h.
A continuous labelling technique was used to estimate the growth fraction and the cell cycle time. In the z. glomerulosa these were 0·80 and 87 h respectively. These values gave an estimate of the cell production or birth rate of 0·00676 cells/cell/h, or 0·676 cells/100 cells/h, and consequently the potential doubling time (assuming no cell loss) was 102 h. Since the actual doubling time exceeds the potential doubling time, cells must be lost from the z. glomerulosa. This cell loss was found to be taking place at a rate of 0·0010 cells/cell/h, or 0·10 cells/100 cells/h, and the cell loss factor (ϕ) was 0·15.
Since necrosis has only been demonstrated in the z. reticularis, and evidently does not occur in the z. glomerulosa, this cell loss rate can be considered to represent the rate at which cells migrate from the z. glomerulosa. It is proposed, therefore, that in the prepubertal animal at least, centripetal cell migration does occur.
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SUMMARY
The action of testosterone on the cell kinetics of the small bowel was studied in the castrated male mouse. The parameters of the cell cycle were measured using the labelled mitoses method. No difference was found between cell cycle parameters in testosterone-treated castrated animals compared with castrated controls.
Crypt cell kinetics were studied by measuring the distribution of labelled and mitotic nuclei using a computer programme. The labelling and mitotic indices were significantly raised in the testosterone-treated animals. There was also a significant upward displacement of the cut-off position in the testosterone-treated group, indicating an increase in the size of the proliferative compartment, and thus an increase in growth fraction. This change in growth fraction was confirmed by calculation from the labelled mitoses results, and is considered to be the mechanism by which testosterone stimulates cell proliferation in the small bowel of the castrated mouse. The action of testosterone on the growth fraction may constitute an important component of the general mitogenic effect of the hormone on both target and non-target tissues.
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SUMMARY
The proliferative response of the coagulating gland of the castrated male mouse has been examined during continuous treatment with testosterone propionate. Fourteen days after castration, s.c. daily injections of testosterone propionate were begun. Mitotic (I m) and labelling (I L) index values were obtained at 3 h intervals for up to 100 h after the initial injection. These showed a biphasic response, in which I L reached a maximum at 30 and 70 h, and I m at approximately 45 and 75 h. Fraction-labelled mitoses (FLM) curves were begun 24, 48, and 72 h after the first androgen injection. In each curve the first wave of labelled mitoses rose to 100% and showed a square form indicating little spread in the durations of the G2 and S phases. Values of 7·5, 1·3 and 0·7 h, were obtained for the durations of DNA synthesis (t s), the post-synthetic period (t G2) and of mitosis (t m) respectively. In none of the FLM curves was it possible to demonstrate a second wave of labelled mitoses and direct measurement of the cell cycle time (T c) was not obtained. Continuous tritiated thymidine labelling indices revealed that after a latent period of 25 h, DNA synthesis began and labelling rose rapidly to 80% by 45 h and then more slowly to 95% by 97 h. Cell population changes during androgen stimulation estimated from measurements of total glandular DNA indicated that the number of cells present in the glands remained constant during the first 30 h after stimulation and thereafter increased to approximately 2·3 times the original value.
The data are compared with a mathematical model which assumes that the cell population of castrated mice when stimulated passes from a G0 compartment through successive waves of DNA synthesis and mitosis. After each cell division the cells may leave or remain in the proliferative cycle. This model has been subjected to computer simulation using the cell cycle parameters obtained in the kinetic experiments. There was good agreement between the simulation and experimental results in the I m and I L curves, continuous labelling, and total cell number experiments. The simulation of FLM curves was less successful. Although the first wave of labelled mitoses was clearly seen the model predicts a distinct second wave of labelled mitoses. It is concluded that this does not appear because of variation in the duration of G1.
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ABSTRACT
Infusion of bovine parathyroid hormone (bPTH) preparations into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep increases salivary phosphate concentration and gland blood flow rate with rapid onset and offset of action. These responses have been used as a bioassay for PTH and PTH analogues and for assessing the properties of an in-vitro inhibitory analogue [Nle-8, Nle-18, Tyr-34]bPTH-(3–34)amide. [Nle-8, Nle-18, Tyr-34]bPTH-(1–34)amide at 10− 9 to 10 −8 mol/l was four to five times more potent than bPTH(1–34) on both salivary phosphate and blood flow assays. Human PTH(1–34) was not significantly more potent than bPTH(1–34). The [Nle-8, Nle-18, Tyr-34]bPTH-(3–34)amide analogue had very slight agonist activity at 3 × 10−7 mol/l and at a 100:1 ratio of analogue to PTH it completely inhibited the action of bPTH(1–34) on phosphate secretion and gland blood flow. It caused partial inhibition at 10:1 and had no evident effect at 1:1. These results differ from previous in-vitro results and indicate that the preparation may be valuable for evaluation of agonist and antagonist analogues of PTH. The vascularly isolated parotid gland of the sheep permits repeated random testing of analogues in a control–test–control sequence and the results indicate high sensitivity to PTH in a rapidly reactive invivo system with two responding parameters.
J. Endocr. (1984) 102, 375–379
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Administration of bovine parathyroid hormone (PTH) preparations increased the phosphate concentration in the parotid saliva of sheep. Data on the site of action of PTH (1–84) were obtained by (a) equimolar infusions of PTH (1–84) and (1–34) directly into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep, (b) intravenous infusion of PTH (1–84) at a similar rate and (c) intra-arterial infusion of PTH (1–84) with complete drainage of the venous effluent from the gland during the infusion. Results showed substantial time– and dose–response identity of the two peptides, at 10−9 to 4 × 10−9 mol/l in arterial blood, in raising salivary phosphate concentration. The effect of PTH (1–84) was not due to recirculated fragments because the response was obtained when recirculation was prevented by complete venous drainage and little or no response occurred when the same infusion was given i.v.
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SUMMARY
From the left adrenal of ten sheep foetuses and four lambs aged from 110 days after conception to 14 days after birth, adrenal venous blood was collected and assayed for cortisol, corticosterone and aldosterone. These steroids were secreted at all ages but the rate of secretion was greatly increased toward term and after birth. The increase coincided with morphological changes in the adrenal gland. At no stage was the rate significantly increased by corticotrophin, and in two young foetuses it was not decreased by dexamethasone. In two foetuses and one lamb, angiotensin II did not increase the rate of secretion of any of the three steroids significantly, and the blood pressure was raised only in the lamb. It is probable that the secretion of the steroids was maximal under the conditions of the experiments.
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Comparisons of aldosterone responses to [des-Asp1]-angiotensin II and angiotensin II, often at single dose levels, have shown a wide range of potency ratios. Therefore four-point dose–response comparisons were performed in sodium-replete sheep, using i.v. infusion rates of angiotension II and angiotensin II amide that reproduced the physiological range of blood concentration of angiotensin II for sheep. Angiotensin III was infused i.v. at the same rates. Effects on arterial blood pressure, cortisol secretion rate, adrenal blood flow and plasma levels of Na+ and K+ were also compared. The potency ratio, angiotensin III: angiotensin II amide, was 0·87 for actual aldosterone secretion rate and 0·90 for the calculated increase in aldosterone secretion. For angiotensin III: angiotensin II the ratios were 0·80 and 0·91 respectively. These ratios were not significantly different from 1·00 but the tendency for angiotensin II to be slightly more potent was probably due to a contribution from derived angiotensin III during infusion of angiotensin II. Angiotensin II or angiotensin II amide was ∼ four times as potent as angiotensin III in raising arterial blood pressure. Cortisol secretion rate was slightly but significantly increased by all peptides at the higher infusion rates. Infusions had no effect on adrenal blood flow or plasma levels of Na + but raised plasma levels of K + slightly. These results confirm the conclusion from adrenal arterial infusion experiments that angiotensin II and III are almost equipotent in stimulating aldosterone secretion in sheep.
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Animal Reproduction and Biotechnology Laboratory, Department of Pediatrics, Department of Biomedical Sciences, Colorado State University, ARBL-Foothills Campus, Campus Delivery 1683, Fort Collins, Colorado 80-523-1683, USA
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Ovine GH (oGH) is synthesized in placental tissue during maximal placental growth and development. Our objectives were to localize oGH mRNA in the placenta, and study the impact of exogenous GH on twin pregnancies during the normal window (35–55 days of gestational age; dGA) of placental expression. In situ hybridization localized oGH mRNA in uterine luminal epithelium but not in tissues of fetal origin. While maternal GH and IGF-I concentrations were increased (P<0.001) approximately tenfold, uterine, uterine fluid, placental, and fetal weights were unaffected by treatment at either 55 or 135 dGA. Fetal length, liver weight, and liver weight per kg of body weight were unaffected by maternal GH treatment. However, in the cotyledon, IGF-binding protein (BP)-1 and IGFBP-4 mRNA concentrations were increased (P<0.05), while IGFBP-2 mRNA was decreased (P<0.05). The concentration of mRNA for IGFBP-3 was unaffected by treatment. Within the caruncle, IGFBP-1 mRNA was decreased (P<0.05), while IGFBP-3 and IGFBP-4 mRNA were increased (P<0.05), and IGFBP-2 mRNA was unchanged due to GH treatment. While our data indicate that elevated maternal GH and IGF-I concentrations during early and mid-gestation do not enhance placental and fetal growth in twin pregnancies, localization of GH mRNA in uterine luminal epithelium could explain GHs transitory expression from 35 to 55 dGA, since by the end of this period the majority of the uterine luminal epithelium has fused with chorionic binucleate cells forming the placental syncytium.
