Malendowicz Ludwik K, Spinazzi Raffaella, Majchrzak Mariola, Nowak Magdalena, Nussdorfer Gastone G, Ziolkowska Agnieszka, Macchi Carlo, Trejter Marcin
Department of Histology and Embryology, School of Medicine, Karol Marcinkowski University of Medical Sciences, PL-60781 Poznan, Poland.
Int J Mol Med. 2003 Dec;12(6):903-9.
Many lines of evidence indicate that cholecystokinin (CCK) and its receptors, named CCK1-R and CCK2-R, are expressed in the hypothalamo-pituitary-adrenal (HPA) axis, the function of which they acutely stimulate. However, the role of endogenous CCK system in the regulation of HPA axis is still unknown. To address this issue we investigated the effect of the prolonged (6-day) administration of CCK, CCK-R antagonists (CCK-RAs) and pentagastrin (PG), a CCK2-R agonist, on adult rat HPA axis. Semiquantitative reverse transcription-polymerase chain reaction showed that CCK treatment lowered the expression of CCK1-R and CCK2-R mRNAs in the pituitary, but not adrenal gland. ACTH plasma concentration was not affected by any treatment. Neither CCK nor PG administration induced significant changes in the blood levels of aldosterone and corticosterone. CCK1-RA, although being per se ineffective, in the presence of CCK raised plasma levels of aldosterone and corticosterone; conversely, CCK2-RA, either alone or in the presence of agonists, lowered the blood concentrations of the two hormones. CCK, but not PG, treatment decreased relative adrenal weight, and morphometry showed that CCK-induced adrenal atrophy was coupled to decreases in the volume of adrenocortical zones, which in turn mainly depended on the lowering in the volume and number of adrenocortical cells. PG administration raised and CCK2-RA per se decreased the volume and number of adrenocortical cells. Taken together, these findings allow us to draw the following main conclusions: i) the prolonged exposure to elevated CCK concentrations down-regulates CCK-R expression in the pituitary gland, which accounts for the lack of effect of CCK on ACTH secretion; ii) adrenal CCK1-Rs and CCK2-Rs inhibit and stimulate, respectively, corticosteroid secretion; and iii) endogenous CCK system plays a minor role in the physiological regulation of rat HPA axis, its main effect being the CCK2-R-mediated maintenance of adrenocortical-cell number.
多条证据表明，胆囊收缩素（CCK）及其受体，即CCK1-R和CCK2-R，在下丘脑-垂体-肾上腺（HPA）轴中表达，并且它们能急性刺激该轴的功能。然而，内源性CCK系统在HPA轴调节中的作用仍不清楚。为解决这一问题，我们研究了CCK、CCK受体拮抗剂（CCK-RAs）和五肽胃泌素（PG，一种CCK2-R激动剂）长期（6天）给药对成年大鼠HPA轴的影响。半定量逆转录-聚合酶链反应表明，CCK处理降低了垂体中CCK1-R和CCK2-R mRNA的表达，但对肾上腺无影响。促肾上腺皮质激素（ACTH）血浆浓度不受任何处理的影响。给予CCK和PG均未引起醛固酮和皮质酮血水平的显著变化。CCK1-RA本身无效，但在存在CCK的情况下会提高醛固酮和皮质酮的血浆水平；相反，CCK2-RA单独使用或与激动剂同时使用时，会降低这两种激素的血浓度。CCK处理可降低相对肾上腺重量，但PG处理则不然，形态学测量表明，CCK诱导的肾上腺萎缩与肾上腺皮质区体积减小有关，而这又主要取决于肾上腺皮质细胞体积和数量的减少。给予PG会增加肾上腺皮质细胞的体积和数量，而CCK2-RA本身则会使其减少。综上所述，这些发现使我们得出以下主要结论：i）长期暴露于升高的CCK浓度会下调垂体中CCK-R的表达，这解释了CCK对ACTH分泌缺乏影响的原因；ii）肾上腺CCK1-R和CCK2-R分别抑制和刺激皮质类固醇分泌；iii）内源性CCK系统在大鼠HPA轴的生理调节中起次要作用，其主要作用是通过CCK2-R介导维持肾上腺皮质细胞数量。
