Raff Hershel, Lee Julie J, Widmaier Eric P, Oaks Martin K, Engeland William C
Endocrine and Transplant Research Laboratories, St. Luke's Medical Center, Milwaukee, Wisconsin 53215, USA.
Endocrinology. 2004 Jan;145(1):79-86. doi: 10.1210/en.2003-1130. Epub 2003 Oct 2.
We previously demonstrated that 7-d-old rat pups exposed to hypoxia from birth exhibit ACTH-independent increases in corticosterone associated with an increase in steroidogenic acute regulatory (StAR) and peripheral-type benzodiazepine receptor (PBR) proteins. The purpose of the present study was to determine whether this increase in corticosterone could be attenuated by chemical sympathectomy induced with guanethidine treatment. Rat pups were exposed to normoxia or hypoxia from birth and treated with vehicle or guanethidine and studied at 7 d of age. Hypoxia per se resulted in an increase in plasma corticosterone without a change in plasma ACTH. Guanethidine treatment attenuated the increase in basal corticosterone in hypoxic pups but did not attenuate ACTH-stimulated corticosterone production. This effect was specific as basal and ACTH-stimulated aldosterone was not affected. Guanethidine also attenuated the increase in StAR protein induced by hypoxia. Neither the effect of hypoxia nor that of guanethidine could be explained by changes in the levels of adrenal tyrosine hydroxylase, StAR, or P450scc mRNA, adrenal tyrosine hydroxylase immunohistochemistry, or adrenal catecholamine content. We conclude that chemical sympathectomy normalizes basal corticosterone levels but has no effect on ACTH-stimulated corticosterone levels in 7-d-old rats exposed to hypoxia from birth. The mechanism of the effect of guanethidine to normalize hypoxia-stimulated basal corticosterone remains to be identified, although StAR protein may be an important mediator. This ACTH-independent increase in corticosterone may be a mechanism by which the neonate can increase circulating glucocorticoids necessary for survival while bypassing the hyporesponsiveness of the neonatal hypothalamic-pituitary-adrenal axis.
我们之前证明，从出生起就暴露于低氧环境的7日龄大鼠幼崽，其皮质酮水平在不依赖促肾上腺皮质激素（ACTH）的情况下升高，这与类固醇生成急性调节蛋白（StAR）和外周型苯二氮䓬受体（PBR）蛋白的增加有关。本研究的目的是确定用胍乙啶治疗诱导的化学性交感神经切除术是否能减弱这种皮质酮的增加。大鼠幼崽从出生起就暴露于常氧或低氧环境，并接受载体或胍乙啶治疗，在7日龄时进行研究。低氧本身导致血浆皮质酮增加，而血浆ACTH没有变化。胍乙啶治疗减弱了低氧幼崽基础皮质酮的增加，但没有减弱ACTH刺激的皮质酮生成。这种作用是特异性的，因为基础和ACTH刺激的醛固酮不受影响。胍乙啶还减弱了低氧诱导的StAR蛋白的增加。低氧或胍乙啶的作用都不能通过肾上腺酪氨酸羟化酶、StAR或细胞色素P450侧链裂解酶（P450scc）mRNA水平的变化、肾上腺酪氨酸羟化酶免疫组织化学或肾上腺儿茶酚胺含量来解释。我们得出结论，化学性交感神经切除术可使基础皮质酮水平正常化，但对从出生起就暴露于低氧环境的7日龄大鼠的ACTH刺激的皮质酮水平没有影响。胍乙啶使低氧刺激的基础皮质酮正常化的作用机制尚待确定，尽管StAR蛋白可能是一个重要的介质。这种不依赖ACTH的皮质酮增加可能是新生儿在绕过新生儿下丘脑 - 垂体 - 肾上腺轴反应低下的情况下增加生存所需循环糖皮质激素的一种机制。
