Role of phosphoinositide metabolism in mediation of the inhibitory effect of alpha1-adrenergic agonist on mouse thyroid.

在小鼠甲状腺，去甲肾上腺素（NE）通过作用于α-肾上腺素能受体，抑制促甲状腺素诱导的甲状腺素释放，增加磷脂酰肌醇的代谢，提示α_1-肾上腺素能受体激动剂对甲状腺素释放的抑制作用是通过降解多磷酸肌醇介导的。1.为了验证这种可能性，我们研究了在体外用（^3H）肌醇预孵育3小时的小鼠甲状腺中，腺苷能激动剂对（^3H）肌醇磷酸产生的影响。去甲肾上腺素（10 μ <-5>M）可促进小鼠甲状腺（^3H）肌醇向单磷酸肌醇、二磷酸肌醇和三磷酸肌醇（IP_3）的积累。去甲肾上腺素的作用可被去甲肾上腺素所模拟，但不能被可乐定或异丙肾上腺素所模拟;去甲肾上腺素的作用可被哌唑嗪所拮抗，但不能被育亨宾或心得安所拮抗。这些结果提示NE诱导的小鼠甲状腺肌醇磷酸的产生是由α_1肾上腺素受体介导的。2.在用（^3H）甘油预孵育的甲状腺中，1，2二酰甘油（DG）早在加入NE后30秒就积累。NE诱导的DG生成增加可能是通过α，β-肾上腺素能受体介导的，因为哌唑嗪有减少NE诱导的DG蓄积的趋势。3. NE诱导（^ Pi）标记甲状腺中4，8-二磷酸磷脂酰肌醇（TPI）相当缓慢的分解<32>：与NE孵育5-10 min后，TPI组分的放射性显著降低。4.这些结果表明，α_1-肾上腺素能激动剂抑制小鼠甲状腺激素的释放，最可能是通过诱导IP 3的产生，这反过来又提高了细胞内游离钙水平。NE可促进TPI合成DG，DG可能通过激活蛋白激酶C介导α_1抑制作用。

In mouse thyroids, norepinephrine (NE) inhibited the thyrotropin-induced release of thyroxine and increased phosphatidylinositol turnovel through acting on the alpha -adrenoceptors, suggesting that the inhibiroty effect of alpha_1 -Adrenergic agonists on thyroxine release in mediated by the degradation of polyphosphoinostitides. 1. To examine this possibility, we inverstigated the effects of adtenergic agonists on the production of (^3H)inositol phosphates in the mouse thyroid preincubated with (^3H)inositol for 3 h in vitro. NE (10^<-5> M) inctreased (^3H) inositol accumulation into inositol monophosphate, inositol bidphosphate, inositol trisphosphate (IP_3) of mouse thyrois linearly up to 30 min in the presence of lithium. The effect of NE was mimicked by phynylephrime but not by clonidine or isoproterenol, and was antagonized by prazosin but not by yohimbine or propranolo. These reults suggest that NE-induced production if inositol phosphates in mouse thyrois is mediated by alpha_1 -adtenoceptors. 2. 1,2 Diacylglycerol (DG) accumulated as early as 30 sec after addition of NE in thyroids preinucubated with (^3H) glycerol. NE-induced rise in DG production may probably be mediated through alpha,-adrenoceptors, because prazosin showed a tendency to dectease the NE-induced DG accumulation. 3. NEinduced a rather slow breakdown of phosphatidulinositol 4,8-bisphosphate (TPI) in (^<32>Pi)-labeled thyroids: a significant dectease in radioactivity of TPI fraction was seen after 5-10 min incubation with NE. 4. These results suggest that alpha_1 -adrenergic agonist inhibits the release of thyroid hormone from mouse thyroids most probably by inducing IP3 production, which in turn elevates the free cytosolic calcium levels. However, NE inctrases the production of DG from TPI, at least partly, therefore, DG may play some role in mediating the inhibitory alpha_1 effect in mouse thyroids through activation of protein kinase C.