Náray-Fejes-Tóth A, Rosenkranz B, Frölich J C, Fejes-Tóth G
Hypertension Research Division, Henry Ford Hospital, Detroit, MI 48202.
J Steroid Biochem. 1988;30(1-6):155-9. doi: 10.1016/0022-4731(88)90088-x.
Glucocorticoids have been shown in in vitro systems to inhibit the release of arachidonic acid metabolites, namely prostaglandins (PGs) and leukotrienes, apparently, via the induction of a phospholipase A2 inhibitory protein, called lipocortin. On the basis of these in vitro results, it has been suggested that inhibition of eicosanoid production is, at least partially, responsible for the well-known anti-inflammatory effect of glucocorticoids. There is, however, no firm evidence proving that glucocorticoids also inhibit prostaglandin or leukotriene synthesis in vivo. In a series of studies, we have investigated the effects of anti-inflammatory steroids on the production of six different cyclo-oxygenase products in vivo. Urinary prostaglandin (PG) E2(1), PGF2 alpha, thromboxane B2 (TxB2), 6-keto-PGF1 alpha, and the major urinary metabolites of the E and F PGs, PGE-M and PGF-M, respectively, were determined by radioimmunoassay and by GC-MS. Administration of pharmacological doses of dexamethasone to rabbits failed to inhibit urinary excretion rates of PGE2, TxB2, 6-keto-PGF1 alpha and that of PGE-M and PGF-M. In contrast, urinary PGF2 alpha was slightly reduced by dexamethasone. In further experiments the effect of dexamethasone was studied in humans. Urinary excretion rates of PGE2, PGE-M, PGF-M, 2,3-dinor TxB2 and 2,3-dinor 6-keto-PGF1 alpha were not suppressed by dexamethasone. Collagen-induced platelet TxB2 formation and platelet aggregation was also unaltered. To test one possible explanation for the apparent discrepancy between in vitro and in vivo effects of glucocorticoids on arachidonic acid metabolites we investigated the effects of dexamethasone in vivo on basal and on antidiuretic hormone-stimulated renal PG synthesis. Dexamethasone treatment failed to inhibit both basal and antidiuretic hormone-stimulated PGE2 and PGF2 alpha production. We conclude that glucocorticoids in vivo do not decrease the basal rate of total body, kidney and platelet prostanoid synthesis, and that dexamethasone does not inhibit renal PG production when it is elevated by antidiuretic hormone, a physiological stimulus. Thus, a differential effect of glucocorticoids on basal vs stimulated PG synthesis cannot account for the discrepancy between in vivo and in vitro effects.
在体外系统中已表明，糖皮质激素可通过诱导一种名为脂皮质素的磷脂酶A2抑制蛋白，来抑制花生四烯酸代谢产物（即前列腺素（PGs）和白三烯）的释放。基于这些体外实验结果，有人提出，抑制类花生酸的产生至少部分地导致了糖皮质激素众所周知的抗炎作用。然而，尚无确凿证据证明糖皮质激素在体内也能抑制前列腺素或白三烯的合成。在一系列研究中，我们调查了抗炎类固醇对体内六种不同环氧化酶产物生成的影响。通过放射免疫分析和气相色谱 - 质谱联用技术分别测定尿中前列腺素（PG）E2(1)、PGF2α、血栓素B2（TxB2）、6 - 酮 - PGF1α以及E和F前列腺素的主要尿代谢产物PGE - M和PGF - M。给兔子注射药理剂量的地塞米松未能抑制PGE2、TxB2、6 - 酮 - PGF1α以及PGE - M和PGF - M的尿排泄率。相反，地塞米松使尿中PGF2α略有降低。在进一步的实验中，研究了地塞米松对人体的影响。地塞米松并未抑制PGE2、PGE - M、PGF - M、2,3 - 二去甲TxB2和2,3 - 二去甲6 - 酮 - PGF1α的尿排泄率。胶原诱导的血小板TxB2生成和血小板聚集也未改变。为了检验糖皮质激素对花生四烯酸代谢产物的体外和体内作用之间明显差异的一种可能解释，我们研究了地塞米松在体内对基础状态以及抗利尿激素刺激的肾脏PG合成的影响。地塞米松治疗未能抑制基础状态以及抗利尿激素刺激的PGE2和PGF2α生成。我们得出结论，体内糖皮质激素不会降低全身、肾脏和血小板前列腺素合成的基础速率，并且当抗利尿激素（一种生理刺激物）使肾脏PG生成增加时，地塞米松不会抑制其生成。因此，糖皮质激素对基础状态与刺激状态下PG合成的差异作用无法解释体内和体外作用之间的差异。
