Hemmings Susan J, Wilson Thomas R
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Mol Cell Biochem. 2003 Aug;250(1-2):167-77. doi: 10.1023/a:1024973908194.
A highly malignant transplantable rat lymphosarcoma was studied to determine the involvement of hepatic adrenergic receptors in the development of the hypoglycemia of cancer cachexia. Following inoculation of Fischer 344 rats with lymphosarcoma cells, rats were examined at 2 and 4 weeks, at the pre-cachexic stage; 6 weeks, at the transitional stage; and 7 weeks, at the cachexic hypoglycemic stage of lymphosarcoma progression. Death occurred by the 8th week. Blood glucose levels in lymphosarcoma-bearing rats relative to control rats were: unaffected at week 2; significantly reduced 8% at weeks 4 and 6; and reduced 24% at week 7. Alpha1 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 114, 89, 67 and 30% of control at weeks 2, 4, 6, and 7, respectively. Kinetic analysis indicated that the lymphosarcoma-induced decrease at week 7 was due to a decrease in numbers of receptors with no change in affinity: B(max)(control): 1411.1 fmol/mg: Kd(control): 0.44 nm; B(max)(lympho): 345.5 fmol/mg; Kd(lympho): 0.50 nm. Alpha2 adrenergic receptor binding to plasma membranes isolated from the livers of lymphosarcoma-bearing rats was: 130, 137, 243 and 212% of control at weeks 2,4, 6, and 7, respectively. The pattern of changes in hepatic alpha1, alpha2 and beta adrenergic receptors at week 6 was comparable to that of 17 day fetal liver: a decrease in alpha1 and beta and an increase in alpha2. Hepatic adrenergic receptor changes occurred in the absence of liver damage and were not due to contamination of the liver plasma membrane fractions with lymphosarcoma cells. Plasma insulin levels displayed modest (10-15%), but not statistically significant, increases post-inoculation after week 4. Plasma glucagon levels fluctuated post-inoculation until week 7 where they were significantly increased: 202% of control. Plasma T3 and T4 levels displayed an early and steady decline after lymphosarcoma inoculation: T3: unchanged at week 2 and significantly decreased 14, 44 and 50% at weeks 4, 6 and 7, respectively. T4 increased 20% at week 1; decreased 9% at week 4 and significantly decreased thereafter: 55 and 49% at weeks 6 and 7, respectively. We propose that the development of the hypoglycemia of cancer cachexia in this lymphosarcoma model is due primarily to an early and progressive thyroid hormone dependent decrease in the number of hepatic alpha1 adrenergic receptors, compounded by an increase and decrease, respectively, in the hepatic beta and alpha2 adrenergic receptors.
研究了一种高度恶性的可移植大鼠淋巴肉瘤，以确定肝脏肾上腺素能受体在癌症恶病质低血糖症发展过程中的作用。给Fischer 344大鼠接种淋巴肉瘤细胞后，在2周和4周（恶病质前期）、6周（过渡期）以及7周（淋巴肉瘤进展的恶病质低血糖期）对大鼠进行检查。大鼠在第8周死亡。与对照大鼠相比，荷淋巴肉瘤大鼠的血糖水平在第2周未受影响；在第4周和第6周显著降低8%；在第7周降低24%。从荷淋巴肉瘤大鼠肝脏分离的质膜上，α1肾上腺素能受体结合率在第2、4、6和7周分别为对照的114%、89%、67%和30%。动力学分析表明，第7周时淋巴肉瘤诱导的降低是由于受体数量减少，亲和力无变化：B(max)(对照)：1411.1 fmol/mg；Kd(对照)：0.44 nm；B(max)(淋巴肉瘤)：345.5 fmol/mg；Kd(淋巴肉瘤)：0.50 nm。从荷淋巴肉瘤大鼠肝脏分离的质膜上，α2肾上腺素能受体结合率在第2、4、6和7周分别为对照的130%、137%、243%和212%。第6周时肝脏α1、α2和β肾上腺素能受体的变化模式与17天胎肝的变化模式相似：α1和β受体减少，α2受体增加。肝脏肾上腺素能受体的变化发生在无肝损伤的情况下，并非由于肝质膜部分被淋巴肉瘤细胞污染。接种后第4周血浆胰岛素水平有适度（10 - 15%）但无统计学意义的升高。接种后血浆胰高血糖素水平波动，直到第7周显著升高：为对照的202%。接种淋巴肉瘤后血浆T3和T4水平早期即开始稳定下降：T3在第2周无变化，在第4、6和7周分别显著下降14%、44%和50%。T4在第1周升高20%；在第4周下降9%，此后显著下降：在第6周和第7周分别为55%和49%。我们认为，在这个淋巴肉瘤模型中，癌症恶病质低血糖症的发展主要是由于肝脏α1肾上腺素能受体数量早期逐渐减少，这种减少依赖于甲状腺激素，同时肝脏β和α2肾上腺素能受体分别增加和减少。
