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H. Abe, Y. Minokoshi and T. Shimazu


The effects of the β3-agonist, BRL35135A, on glucose uptake in the peripheral tissues of the rat, including skeletal muscle, were studied using the 2-[3H]deoxyglucose method in anaesthetized adult animals. Intravenous infusion of the β3-agonist dose-dependently increased the rate constant of glucose uptake in three types of skeletal muscle, brown adipose tissue, white adipose tissue, heart and diaphragm, but not in the brain, spleen or lung. Although infusion of the β3-agonist did not change the plasma concentration of glucose appreciably, it caused an increase in the plasma concentration of insulin when given at more than 25 μg/kg per h. To ascertain whether the effect of the β3-agonist on glucose uptake in skeletal muscle is mediated by insulin, glucose uptake into soleus muscle isolated from young rats was also measured in vitro using different concentrations of the β3-agonist. The β3-agonist BRL37344 (an active metabolite of BRL35135A) significantly increased glucose transport in a dose-dependent manner, with maximum stimulation at 100 pmol/l. These results demonstrate that glucose uptake in skeletal muscle can be enhanced independently of the action of insulin, probably through the mediation of β3-adrenoceptors present in the tissue.

Journal of Endocrinology (1993) 139, 479–486

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J. W. M. Chow, J. M. Lean, T. Abe and T. J. Chambers


We have previously demonstrated that administration of oestrogen, at doses sufficient to raise serum concentrations to those seen in late pregnancy, increases trabecular bone formation in the metaphysis of adult rats. To determine whether prostaglandins (PGs), which have been shown to induce osteogenesis in vivo, play a role in the induction of bone formation by oestrogen, 13-week-old female rats were given daily doses of 4 mg 17β-oestradiol (OE2)/kg for 17 days, alone or with indomethacin (1 mg/kg). The rats were also given double fluorochrome labels and at the end of the experiment tibias were subjected to histomorphometric assessment. Treatment with OE2 suppressed longitudinal bone growth and increased uterine wet weight, as expected, and neither response was affected by indomethacin. Oestrogen also induced a threefold increase in trabecular bone formation in the proximal tibial metaphysis, which resulted in a substantial increase in trabecular bone volume. As previously observed, the increase in bone formation was predominantly due to an increase in osteoblast recruitment (as judged by an increase in the percentage of bone surface showing double fluorochrome labels), with only a minor increase in the activity of mature osteoblasts (as judged by the mineral apposition rate). Indomethacin abolished the increase in osteoblastic recruitment, but the activity of mature osteoblastic cells remained high. The bone formation rate and bone volume remained similar to controls. The results suggest that PG production may be necessary for the increased osteoblastic recruitment induced by oestrogen, but not to mediate the effects of oestrogen on the activity of mature osteoblasts.

Journal of Endocrinology (1992) 133, 189–195

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A Mori-Abe, S Tsutsumi, K Takahashi, M Toya, M Yoshida, B Du, J Kawagoe, K Nakahara, T Takahashi, M Ohmichi and H Kurachi

Proliferation of vascular smooth muscle cells (VSMC) plays a major role as an initiating event of atherosclerosis. Although estrogen directly inhibits the proliferation of VSMC, the mechanism has not been firmly established. In addition, the effect of raloxifene on VSMC remains unknown. 17Beta-estradiol (E(2)) and raloxifene significantly inhibited the growth of VSMC under growth-stimulated conditions. Since mitogen-activated protein (MAP) kinases have been implicated in VSMC proliferation, the role of MAP kinases in both the E(2)- and raloxifene-induced growth inhibition of VSMC was studied. Both E(2) and raloxifene caused rapid, transient phosphorylation and activation of p38 that was not affected by actinomycin D and was blocked by ICI 182,780. In contrast with p38 phosphorylation, extracellular signal-regulated protein kinase (ERK) phosphorylation was significantly inhibited and c-Jun N-terminal kinase (JNK) phosphorylation was not changed by E(2). Because VSMC expressed both estrogen receptor (ER) alpha and ERbeta, it is not known which of them mediates the E(2)-induced phosphorylation of p38. Although E(2) did not affect the p38 phosphorylation in A10 smooth muscle cells, which express ERbeta but not ERalpha, transfection of ERalpha expression vector into A10 cells rendered them susceptible to induction of p38 phosphorylation by E(2). We then examined whether E(2) and raloxifene induce apoptosis through a p38 cascade. Both E(2) and raloxifene induced apoptosis under growth-stimulated conditions. The p38 inhibitor SB 203580 completely blocked the E(2)-induced apoptosis. Our findings suggest that both E(2)- and raloxifene-induced inhibition of VSMC growth is due to induction of apoptosis through a p38 cascade whose activation is mediated by ERalpha via a nongenomic mechanism.