Prokocimer P G, Maze M, Vickery R G, Hoffman B B
Department of Anesthesia, Stanford University, California 94305.
Endocrinology. 1988 Jul;123(1):528-33. doi: 10.1210/endo-123-1-528.
Prolonged stimulation of beta-adrenergic receptors with catecholamines leads to desensitization of their ability to activate cAMP accumulation. However, little is known about the relationship between these changes and possible alterations in physiological responses. We have used isolated adipocytes prepared from NEDH rats harboring pheochromocytomas, a norepinephrine-secreting tumor, to address this question. As expected, there was a decrease in the ability of isoproterenol to maximally activate cAMP accumulation in adipocytes from rat harboring pheochromocytoma [323 +/- 107 vs. 707 +/- 145 pmol/10(5) cells.min (mean +/- SD) in controls]. This change was associated with an increase in the EC50 of isoproterenol for activation of cAMP-dependent protein kinase (5.8 X 10(-8) vs. 2.4 X 10(-8) M in controls) and a decrease in maximal activation of the kinase (38 +/- 16% vs. 77 +/- 14% in controls). For lipolysis there was a loss in sensitivity to isoproterenol but no change in maximal lipolytic rate in the adipocytes from rats harboring pheochromocytoma. For both groups there was a similar relationship between kinase activation and lipolysis; maximal lipolysis had already occurred for protein kinase-A activity ratios less than 30%. Therefore, the blunted cAMP response in adipocytes from rats harboring pheochromocytoma did not impair the maximal lipolytic rate. These results demonstrate that adipocytes can efficiently maintain maximal lipolysis in a desensitized state because of considerable reserve in the biochemical cascade leading to the lipolytic response. In addition, our findings demonstrate that there are no regulatory changes induced by prolonged exposure to catecholamines that are distal to cAMP accumulation.
儿茶酚胺对β-肾上腺素能受体的长期刺激会导致其激活环磷酸腺苷（cAMP）积累能力的脱敏。然而，关于这些变化与生理反应可能改变之间的关系，我们知之甚少。我们使用从患有嗜铬细胞瘤（一种分泌去甲肾上腺素的肿瘤）的NEDH大鼠制备的分离脂肪细胞来解决这个问题。正如预期的那样，异丙肾上腺素在患有嗜铬细胞瘤大鼠的脂肪细胞中最大程度激活cAMP积累的能力下降了[对照组为707±145 pmol/10(5)细胞·分钟，患有嗜铬细胞瘤的大鼠为323±107 pmol/10(5)细胞·分钟（平均值±标准差）]。这种变化与异丙肾上腺素激活cAMP依赖性蛋白激酶的半数有效浓度（EC50）增加（对照组为2.4×10(-8) M，患有嗜铬细胞瘤的大鼠为5.8×10(-8) M）以及激酶最大激活程度降低（对照组为77±14%，患有嗜铬细胞瘤的大鼠为38±16%）有关。对于脂肪分解，患有嗜铬细胞瘤大鼠的脂肪细胞对异丙肾上腺素的敏感性丧失，但最大脂肪分解速率没有变化。两组中激酶激活与脂肪分解之间存在相似的关系；当蛋白激酶 - A活性比小于30%时，最大脂肪分解已经发生。因此，患有嗜铬细胞瘤大鼠的脂肪细胞中cAMP反应减弱并不损害最大脂肪分解速率。这些结果表明，由于导致脂肪分解反应的生化级联中有相当大的储备，脂肪细胞能够在脱敏状态下有效地维持最大脂肪分解。此外，我们的研究结果表明，长期暴露于儿茶酚胺不会在cAMP积累的下游诱导调节变化。
