Sharp B M, Matta S G
Endocrine-Neuroscience Research Laboratory, Minneapolis Medical Research Foundation, Minnesota 55404.
Endocrinology. 1993 Jan;132(1):269-74. doi: 10.1210/endo.132.1.8380377.
To determine whether prostaglandins (PGs) mediate the ACTH response to tumor necrosis factor-alpha (TNF alpha), indomethacin (Indo; 0.1-1.0 mg/kg, iv) was administered before TNF alpha (1 microgram, iv) in freely moving, alert rats. While Indo alone did not affect plasma ACTH levels, it dose-dependently blocked the ACTH response to TNF alpha. The highest dose of Indo abolished the ACTH response to TNF alpha [peak plasma ACTH values (mean +/- SEM): buffer/buffer, 137 +/- 34 pg/ml; Indo/buffer, 115 +/- 31; buffer/TNF alpha, 469 +/- 77; Indo/TNF alpha, 120 +/- 27] without modifying the ACTH response to CRF 1 microgram/kg, iv, demonstrating that pituitary responsiveness was unaffected. Since it has been reported that Indo elevates plasma corticosterone (B) levels, the effect of Indo could reflect rapid negative feedback by B, rather than the involvement of PGs. However, inhibition of ACTH secretion was shown to be dependent on the dose of Indo, whereas plasma B levels were elevated to the same degree, independent of the Indo dose. In addition, Indo failed to block the ACTH response to an unrelated ACTH stimulus, insulin-induced hypoglycemia (area under response curve: insulin alone, 31,131 +/- 2,794 pg/min.ml; Indo/insulin, 32,919 +/- 3,582 pg/min.ml). Finally, in adrenalectomized B-replaced rats, TNF alpha elevated ACTH to levels similar to those seen in sham animals, and Indo inhibited these ACTH responses to the same extent in both groups. Thus, Indo inhibited the ACTH response to TNF alpha by a mechanism independent of B feedback. These results indicate that acute systemic administration of TNF alpha stimulates ACTH secretion through a PG-dependent mechanism.
为了确定前列腺素（PGs）是否介导促肾上腺皮质激素（ACTH）对肿瘤坏死因子-α（TNFα）的反应，在自由活动、清醒的大鼠静脉注射TNFα（1微克）之前，先静脉注射吲哚美辛（Indo；0.1 - 1.0毫克/千克）。虽然单独使用Indo不影响血浆ACTH水平，但它能剂量依赖性地阻断ACTH对TNFα的反应。Indo的最高剂量消除了ACTH对TNFα的反应[血浆ACTH峰值（均值±标准误）：缓冲液/缓冲液组，137±34皮克/毫升；Indo/缓冲液组，115±31；缓冲液/TNFα组，469±77；Indo/TNFα组，120±27]，且不改变ACTH对静脉注射1微克/千克促肾上腺皮质激素释放因子（CRF）的反应，表明垂体反应性未受影响。由于有报道称Indo会升高血浆皮质酮（B）水平，Indo的作用可能反映了B的快速负反馈，而非PGs的参与。然而，ACTH分泌的抑制显示依赖于Indo的剂量，而血浆B水平升高到相同程度，与Indo剂量无关。此外，Indo未能阻断ACTH对无关ACTH刺激（胰岛素诱导的低血糖）的反应（反应曲线下面积：单独胰岛素组，31,131±2,794皮克/分钟·毫升；Indo/胰岛素组，32,919±3,582皮克/分钟·毫升）。最后，在肾上腺切除并补充B的大鼠中，TNFα使ACTH升高至与假手术动物相似的水平，且Indo在两组中对这些ACTH反应的抑制程度相同。因此，Indo通过独立于B反馈的机制抑制了ACTH对TNFα的反应。这些结果表明，急性全身给予TNFα通过一种依赖PG的机制刺激ACTH分泌。
