Pathogenesis of heterogeneity in human multinodular goiter. A study on growth and function of thyroid tissue transplanted onto nude mice.

Functional and morphologic heterogeneity of human multinodular goiters was investigated in 300 samples from "cold" and "hot" regions of 20 goiters transplanted onto nude mice. Transplants were labeled with [3H]thymidine and radioiodine, while the host's thyroid-stimulating hormone (TSH) secretion was either stimulated or suppressed. Proliferation and function of follicular cells were assessed in whole follicles reconstructed from autoradiographs of serial sections. Hot transplants had a higher autonomous iodine uptake than those of cold tissue in TSH-suppressed hosts. Functional autonomy widely varied among the follicles, but even more so among individual cells. Hot grafts differed from cold ones only by a comparatively larger fraction of autonomous cells. Intercellular differences of iodinating activity were not abolished by TSH. Grafts faithfully reproduced the individual growth pattern of the original tissue. Between 0.5% and 7% of all follicular cells replicated despite suppression of TSH. Up to 70% of these cells were clustered, forming scattered foci of autonomously growing tissue. Other cells only started replicating after long-term TSH stimulation. Thus, goiters contained subsets of cells with high and others with low growth response. Progenies of replicating cells remained clustered, sometimes budding outwards to form new follicles. Autonomy of growth and autonomy of function are independent traits of epithelial cells. Epithelial cells have their individual growth pattern, replication rate, and functional capacity. These traits are passed on from a mother cell to its progeny during follicle neogenesis. To this main mechanism accounting for the morphologic and functional heterogeneity of human goiters, inheritable modifications of gene expression must probably be added.     

The effect of xenotransplantation of human thyroid tissue following radioactive iodine-induced thyroid ablation on thyroid function in the nude mouse.

We have attempted to determine whether xenotransplanted human thyroid tissue into nude mice would act as a physiological substitute for the mouse thyroid gland after the mice had been rendered hypothyroid, using radioactive iodine (131I). The dosage of 0.2 millicuries of 131I was given to each mouse. The xenotransplantations of human thyroid tissue, i.e., normal, Graves' and nontoxic multinodular goitre, were carried out three weeks after radioactive ablation. The values of TSH in all mice rose to high levels (71 +/- 15.6 ng/ml, +/- SD) by three weeks after 131I administration. The TSH values in the mice declined rapidly and reached normal levels by 3-5 weeks after xenotransplantation. In addition, the serum T4 values were generally in the euthyroid range by 3-6 weeks after xenotransplantation. There were no marked differences in the changes of serum T4 and TSH when the three groups were compared. These results indicated that the xenografted human thyroid tissue permitted a return to a normal feedback system as reflected by normal serum TSH and T4 values in the animals. The Graves' thyroid tissue reverted to normal physiological function when removed from its human (abnormal) immune environment, signifying that Graves' thyrocytes are mere passive captives to immune events. This model should prove to be useful in the study of human thyroid physiology and pathophysiology.     

斑蝥素抑制胰腺癌sw1990裸鼠移植瘤细胞增殖研究

目的　探讨斑蝥素对裸鼠移植瘤胰腺癌细胞增殖的影响。方法　在培养人胰腺癌sw1990细胞的基础上建立荷瘤鼠胰腺癌模型并进行移植瘤抑制实验，实验分为空白对照组、斑蝥素用药组，观测荷瘤鼠移植瘤大小改变和免疫组化方法检测增殖相关基因PCNA蛋白的表达。结果　斑蝥素对荷瘤鼠胰腺癌移植瘤的生长有明显的抑制作用，用药组移植瘤体积增长幅度明显小于对照组；用药组移植瘤重量为(0.6421±0.2193)g，对照组为(0.9541±0.2122)g，(P<0.05)。用药组PCNA蛋白染色的细胞明显减少，表达率显著降低(P<0.05)。结论　斑蝥素可明显抑制裸鼠胰腺癌移植瘤的生长，其机制可能与斑蝥素能抑制肿瘤细胞的有关。     

Shock Wave Application Increases the Antineoplastic Effect of Molecular Iodine Supplement in Breast Cancer Xenografts

We evaluated the effect of oral molecular iodine supplementation and shock wave application under three different conditions on human MDA-MB231 cancer cell xenografts. After tumor volume reached 1 cm³, mice were randomly assigned to groups and treated for 3 weeks. The results revealed that high-dose shock wave treatment (150 shock waves at a pressure of 21.7 MPa, SW150/21.7) generated tissue lesions without decreasing tumor growth, canceled the antineoplastic action of iodine and promoted pro-tumor conditions (increased hypoxia-induced factor [HIF] and vascular endothelial growth factor [VEGF]). In contrast, moderate (SW35/21.7) and low (SW35/9.9) doses of shock waves had significant antineoplastic effects and, in combination with iodine supplement, attenuated the aggressiveness of these cells by decreasing expression of the markers of stem cells (CD44 and Sox2) and invasion (HIF and VEGF). These results allow us to propose the combination of shock waves and iodine as a possible adjuvant in breast cancer therapy.     

327例Graves病^131治疗后早发甲低的相关因素分析

【目的】探讨弥漫性甲状腺肿伴甲状腺功能亢进症（Graves病^131 I治疗后发生早发甲状腺功能减退（简称甲低）的相关因素。【方法】收集327例Graves病行…I治疗患者的临床资料,采用Logistic多元回归分析年龄、发病情况、甲状腺质地、吸碘率曲线形态及每克甲状腺组织的^131 I量、甲状腺过氧化物酶（TPO）、甲状腺球蛋白（TGA）与甲低的相关性,判别早发甲低的发生与不发生率的准确率。【结果】①单因素分析年龄、发病情况、甲状腺质地、疗程、吸碘率曲线形态、每克甲状腺组织的^131 I量、TP0、TGA8个因素与早发甲低有相关性。②多因素分析年龄、发病情况、甲状腺质地、吸碘率曲线形态、患者每克甲状腺组织的^131 II量、TPO、TGA等7个因素与早发甲低有相关性;③早发甲低的发生与不发生率的准确性分别高达79．1％、98．2％,总准确性为95．7％。【结论】由于影响Graves病^131 I治疗后发生早发甲低因素较多,且各因素间彼此相互作用,故从多角度、多因素进行综合考虑,利于个体化治疗方案的制定。     

Transforming growth factor beta regulates thyroid growth. Role in the pathogenesis of nontoxic goiter.

The production and growth regulatory activity of transforming growth factor beta were studied in human thyroid tissue. As estimated by its mRNA expression in fresh tissue samples, transforming growth factor beta was produced in normal and in diseased thyroid glands. Transforming growth factor beta mRNA was mainly produced by thyroid follicular cells and in lesser quantities by thyroid infiltrating mononuclear cells. The concentrations of transforming growth factor beta mRNA were lower in iodine-deficient nontoxic goiter than in Graves' disease and normal thyroid tissue. Transforming growth factor beta protein secretion by cultured thyroid follicular cells was also low in nontoxic goiter, but could be increased by addition of sodium iodide (10 microM) to the culture medium. Recombinant transforming growth factor beta did not affect basal tritiated thymidine incorporation in cultured thyroid follicular cells, but inhibited, at a concentration of 10 ng/ml, the growth stimulatory influence of insulin-like growth factor I, epidermal growth factor, transforming growth factor alpha, TSH, and partly that of normal human serum on cultured thyroid follicular cells. This inhibition was greater in Graves' disease than in nontoxic goiter. These results suggest that transforming growth factor beta may act as an autocrine growth inhibitor on thyroid follicular cells. Decreased transforming growth factor beta production and decreased responsiveness to transforming growth factor beta may be cofactors in the pathogenesis of iodine-deficient nontoxic goiter.     

Species variation in pulmonary endothelial aminopeptidase P activity.

Pulmonary endothelial aminopeptidase P (AmP) may be an important contributor to the inactivation of circulating bradykinin in certain species. To examine this possibility, we measured AMP activity in vivo and in vitro using Arg-Pro-Pro-[3H]benzylamide (3H-APPB) as substrate under conditions of first order enzyme kinetics. Utilizing multiple indicator dilution techniques, metabolism of 3H-APPB to Arg and Pro-Pro-[3H]benzylamide by AmP was not detectable during a single transpulmonary passage in anesthetized rabbits (n = 4), cats (n = 3) and pigs (n = 4). However, percent metabolism of 3H-APPB ranged from 54 to 63% in anesthetized rats (n = 6). In all experiments, the substrate remained within the vascular space and was thus accessible to endothelial and blood AmP only. At the same time, single-pass transpulmonary percent metabolism of [14C]benzoyl-Ala-Gly-Pro by endothelial-bound angiotensin converting enzyme was remarkably similar among rabbits, cats, rats and pigs (60-65%). In culture, Vmax/Km of AmP was 3 to 10 x 10(-4) min-1 for human basal arterial and rabbit and bovine pulmonary arterial endothelial cell monolayers (2 x 10(5) cells). AmP activity in the supernatant of lung and kidney tissue (homogenized in saline containing 1-o-n-octyl-beta-glucopyranoside) from rabbit, cat, pig and rat expressed as Vmax/Km(min-1) per (g wet tissue/ml) was 0.74, 2.25, 3.91 and 185.8 (lung), and 1.0, 3.7, 8.4 and 438.3 (kidney), respectively. Similarly, Vmax/Km values of AmP in plasmas of cat, dog, rabbit, pig, calf (serum), human and rat were 0, 0.016, 0.025, 0.068, 0.191, 0.237 and 3.53 min-1. These results suggest that 1) there are large interspecies variations in AmP activities of plasma, lung and kidney; 2) of the species studied, the rat contains the largest activities of AmP; and 3) AmP appears to be located on the luminal surface of the rat pulmonary endothelium.     

Reaccumulation of thyroglobulin and colloid in rat and mouse thyroid follicles during intense thyrotropin stimulation. A clue to the pathogenesis of colloid goiters.

Since Marine's observations some 50 years ago, it has been generally accepted that colloid goiters invariably result from colloid repletion of originally hyperplastic goiters after cessation of the goitrogenic stimulus. However, clinical observations suggest that many goiters never go through a stage of hyperplasia, but are colloid-rich from the beginning. We have injected rats and mice with thyrotropin (TSH), three times a day for 4 d, while the animals were kept on an iodine-rich diet (HID). Additional groups of animals were fed an iodine-poor diet (LID) or a diet containing 0.15% propylthiouracil (PTU) or 1% sodium perchlorate (ClO4). At intervals, thyroid weight, DNA, iodine and thyroglobulin content, thyroglobulin iodination, and intracellular droplet formation were measured. Histologic sections were also prepared and stained with periodic acid Schiff. Furthermore, thyroxine concentration was measured in the serum. Thyroglobulin content dropped by approximately 30% in HID animals but by 60% in all other groups 1 d after starting TSH. Thereafter, thyroglobulin reaccumulation occurred and droplet formation correspondingly decreased despite continuous heavy TSH stimulation. The largest amount of thyroglobulin was reaccumulated in HID animals followed by the PTU/LID groups, whereas no reaccumulation was observed in the ClO4 group. Reaccumulation of thyroglobulin only occurred if there was concomitant organification of at least some iodine. The subsequent phases of depletion and reaccumulation of thyroglobulin were mirrored by the morphology of the follicular lumina, the staining properties of the colloid and the serum T4 concentration. These observations suggest that endocytosis gradually becomes refractory to continuous TSH stimulation if a certain minimal amount of iodine is available for organic binding. Thus, primarily colloid-rich goiters may form in the presence of continuously higher than normal thyrotropin levels without a previous stage of follicular hyperplasia. The view should be revised that accumulation of colloid and intense thyrotropin stimulation are mutually exclusive events.     

黄芩苷对高致瘤HL-60细胞裸鼠移植瘤模型的体内抑瘤作用和机制探讨

本研究旨在探讨黄芩苷对高致瘤人白血病HL-60细胞裸鼠异种移植瘤的体内抑瘤作用及其作用机制。制备高致瘤HL-60细胞裸鼠异种移植瘤模型,将荷瘤裸鼠随机分为6组:阴性对照组(注射5%NaHCO3),黄芩苷25、50和100 mg/kg剂量组,联合用药组(黄芩苷50 mg/kg+VP16 2 mg/kg)和VP16 4 mg/kg阳性对照组,每组10只裸鼠。采用腹腔注射方式给药,14 d后每组处死5只裸鼠,对剥取的瘤块称重计算抑瘤率;通过电子显微镜观察瘤组织超微结构,病理组织学观察裸鼠各主要脏器结构改变,瘤块组织蛋白检测信号转导通路指标。观察裸鼠生存时间。结果表明,黄芩苷可抑制裸鼠HL-60细胞皮下移植瘤的生长,呈剂量依赖性。瘤组织病理组织学和透射电子显微镜检查结果显示,黄芩苷组和联合用药组的肿瘤坏死和细胞凋亡现象较阴性对照组多见。黄芩苷可能通过抑制Akt活性,下调p-Akt、mTOR和p-mTOR的表达来抑制裸鼠异种移植瘤的增长。联合用药组裸鼠中位生存时间明显长于阴性对照组(P<0.05)。结论:黄芩苷可抑制高致瘤HL-60细胞裸鼠异种移植瘤的生长,诱导瘤组织中HL-60细胞的凋亡,其机制之一可能与抑制Akt活性并下调PI3K/Akt/mTOR信号通路有关;黄芩苷与VP16联用可明显提高荷瘤裸鼠的中位生存期,具有协同抗高致瘤HL-60细胞裸鼠异种移植瘤的作用。     

吡柔比星联合内皮抑素对治疗人乳腺癌裸鼠移植瘤的研究

[目的]探讨内皮抑素（E S ）联合吡柔比星对人乳腺癌裸鼠移植瘤的肿瘤生长及新生血管生成的抑制作用。[方法]构建裸鼠乳腺癌模型,将裸鼠40只,随机分成4组,每组10只。对照组（A组）：肿瘤对侧背部皮下注射1＆#215;106/0．1 m L正常人成纤维细胞;ES组（B组）：肿瘤对侧背部皮下注射1＆#215;106/0．1 m L转染了ES的人成纤维细胞。吡柔比星组（C组）：尾静脉注射吡柔比星5 mg/kg ,每周1次,共4周,ES＋吡柔比星组（D组）：肿瘤对侧背部皮下注射1＆#215;106/0．1 m L转染了 ES的人成纤维细胞。尾静脉注射吡柔比星5 mg/kg ,每周1次,共4周。ELISA方法检测血清血管内皮生长因子（VEGF）,肿瘤组织病理切片观察微血管密度（M VD ）。[结果]B、C ,D三组抑瘤率分别为61．96％,27．33％和75．16％,D组抑瘤率明显高于其它两组,D组VEGF、MVD与其他各组比较明显减低,且差异有显著性（ P＜0．05）。[结论]ES联合吡柔比星能明显抑制人乳腺癌裸鼠移植瘤生长及新生血管生成,且两者联用具有协同作用。     

卡铂与顺铂对宫颈癌移植瘤胸苷磷酸化酶的调节作用

目的：探讨卡铂与顺铂对宫颈癌细胞株裸鼠移植瘤中胸苷磷酸化酶（thymi-dine phosphorylase，TP）的调节作用。方法：36只裸鼠均予皮下接种人宫颈鳞状细胞癌Siha细胞株，生成直径约为6～7mm的移植瘤。随机分为3组，每组12只，分别予腹腔内注射等量的卡铂、顺铂和生理氯化钠，给药10d后处死裸鼠，测量移植瘤体积及重量，计算抑瘤率，并以ELISA法测定移植瘤组织中TP的含量。结果：给药后顺铂组和卡铂组人宫颈癌细胞株裸鼠移植瘤体积均比给药前缩小，且均小于对照组（均为P〈0．05），3组的移植瘤重量由低到高依次为顺铂组、卡铂组、对照组（均为P〈0．05）。卡铂组和顺铂组的抑瘤率分别为1．6％和5．5％，2组的抑瘤率比较差异有统计学意义（P〈0．05）。3组移植瘤组织中TP含量由低至高依次为对照组、卡铂组和顺铂组（P〈0．05-0．01）。结论：卡铂和顺铂对宫颈癌细胞株裸鼠移植瘤中TP的表达具有上调作用，其中以顺铂对TP的上调作用较强。     

大剂量分割照射人肝癌细胞系移植瘤的实验研究

目的:研究不同大剂量分割照射模式对BALB/c-nu裸鼠移植瘤(人原发性肝细胞癌细胞系HepG2)抑制肿瘤作用的差异.方法:将原发性肝细胞癌移植瘤种鼠的肿瘤组织制备成1 mm3大小的肿瘤组织块,选择实验裸鼠右后肢外侧小腿腓肠肌处接种,建立原发性肝细胞癌细胞系移植瘤裸鼠照射模型.待肿瘤直径达1.0 cm时将40只实验裸鼠分成4个组:未照射空白对照组、5 Gy×6次分割组(5 Gy组)、10 Gy×3次分割组(10 Gy组)、15 Gy * 2次分割组(15 Gy组).各照射组均在2周内完成照射,照射完成后继续观察裸鼠肿瘤体积的变化.结果:实验过程中无出现裸鼠死亡,亦未观察到明显的裸鼠进食、活动减少,皮疹、腹泻、脱皮等不良反应.三种大剂量分割方案均对裸鼠的移植瘤有明显抑制作用.5 Gy组、10 Gy 组和15 Gy组肿瘤抑制率分别为30.2％,68.4％,73.1％.相对于5Gy和10 Gy照射组,15 Gy组对移植瘤的抑制作用更显著.结论:BALB/c-nu裸鼠移植瘤(人肝细胞癌细胞系HepG2)对大剂量分割照射模式能较好耐受.在相同总剂量情况下,剂量越高,移植瘤的生长抑制作用越强.15 Gy×2次较10 Gy×3次和5Gy×6次有更强的肿瘤生长抑制作用.     

Thymidine transport and metabolism in choroid plexus: effect of diazepam and thiopental

Choroid plexus contains an active transport (influx) and a facilitated diffusion (efflux) system for nucleosides. The ability of diazepam and thiopental to inhibit active transport or facilitated diffusion of thymidine in choroid plexus was measured in vitro under various conditions. When isolated rabbit choroid plexuses were incubated in artificial cerebrospinal fluid containing 1 microM [3H] thymidine for 10 min at 37 degrees C under 95% O2-5% CO2, diazepam (10 microM) and thiopental (500 microM) doubled the tissue-to-medium ratios of [3H] thymidine from 8 to 15 to 16. These results were not due to metabolism or intracellular binding but rather to inhibition of [3H] thymidine efflux from choroid plexus. Diazepam, unlike thiopental, inhibited [3H] thymidine efflux in a concentration-dependent manner. When isolated choroid plexuses were incubated in artificial cerebrospinal fluid containing low concentrations of [3H] thymidine (6 nM) to allow intracellular conversion of [3H] thymidine into [3H] thymidine phosphates and [3H] DNA, both diazepam (10 microM) and thiopental (500 microM) altered [3H] thymidine accumulation and metabolism consistent with inhibition of facilitated diffusion but not active transport of thymidine. These studies provide evidence that, at toxic but not therapeutic concentrations, diazepam and thiopental alter facilitated nucleoside transport in the choroid plexus.     

DADS对人宫颈癌细胞生长及VEGF蛋白表达的影响

【目的】探讨二烯丙基二硫（DADS）对人宫颈癌Hela细胞生长及血管内皮生长因子（VEGF）蛋白表达的影响。【方法】体外培养人宫颈癌Hela细胞,采用MTT比色法测定DADS对Hela细胞增殖活性的影响;裸鼠皮下注入人宫颈癌Hela细胞建立人宫颈癌裸鼠并种移植模型,观察腹腔注射DADS对宫颈癌移植瘤在Balb／c-nu裸鼠体内生长情况的影响,HE染色后进一步观察DADS对移植瘤组织形态的改变,SP免疫组织化学法观察移植瘤细胞VEGF蛋白酌表迭情况。【结果】DADS对人宫颈癌Hela细胞增殖有一定抑制作用,并呈浓度依赖性,以DADS60mg／L高剂量药物组抑制活性最强;腹腔注射DADS剂量为50mg／kg、100mg／kg和200mg／kg时,细胞增殖抑制率分别为28．1％、38．6%、55．3％,瘤重抑制率分别是35．9％,49．9％,55．4％;HE染色结果示DADS具有杀伤人宫颈癌裸鼠移植瘤细胞作用;SP免疫组织化学法示DADS下调移植瘤细胞VEGF表达。[结论]DADS具有抑制人宫颈癌细胞的生长作用,此作用可能与下调移植瘤细胞VEGF表达有关。     

Rat sodium iodide symporter allows using lower dose of 131I for cancer therapy

Efficient gene delivery is a critical obstacle for gene therapy that must be overcome. Until current limits of gene delivery technology are solved, identification of systems with bystander effects is highly desirable. As an anticancer agent, radioactive iodine (131)I has minimal toxicity. The physical characteristics of (131)I decay allow radiation penetration within a local area causing bystander killing of adjacent cells. Accumulation of (131)I mediated by the sodium iodide symporter (NIS) provides a highly effective treatment for well-differentiated thyroid carcinoma. Other types of cancer could also be treated by NIS-mediated concentration of lethal (131)I radiation in tumor cells. Our group and others previously reported that a significant antitumor effect in mice was achieved after adenoviral delivery of rat or human NIS gene following administration of 3 mCi of (131)I. We have also demonstrated 5-6-fold greater uptake of (125)I by rat NIS over human NIS in human cancer cells. Recently, we reported the capability of the rat NIS and (131)I to effectively induce growth arrest of relatively large tumors (approximately 800 mm(3)) in an animal model. In the present work tumor growth inhibition was achieved using adenoviral delivery of the rat NIS gene and 1 mCi of (131)I (one-third of the dose used in earlier reports). We also demonstrated that a higher concentration of (123)I was accumulated in the NIS-expressing tumors than in the thyroid 20 min after radioiodine administration. The highest intratumoral radioiodine concentration was observed along the needle track; however, the rat NIS-(131)I effectively induced growth arrest of tumor xenografts in mice through its radiological bystander effect. Importantly, the rat NIS allowed reducing the injected radioiodine dose by 70% with the same antitumor efficacy in pre-established tumors. These results suggest that the rat NIS gene may be advantageous compared to the human gene in its ability to enhance intratumoral (131)I uptake.     

Effects of thyroid-stimulating hormone on adenyl cyclase activity and intermediary metabolism of “cold” thyroid nodules and normal human thyroid tissue

"Cold" thyroid nodules do not concentrate (131)I before or after thyrotropin (TSH) administration. In an attempt to elucidate the reason for this TSH unresponsiveness, the effect of TSH in vitro on several metabolic parameters was studied in 11 "cold" thyroid adenomas, 2 medullary carcinomas, and in the surrounding normal thyroid tissue. Basal adenyl cyclase activity, glucose-1-(14)C oxidation, and (32)P incorporation into phospholipids were significantly greater in the adenomas than in the adjacent normal thyroid; basal cyclic 3',5'-adenosine monophosphate (cyclic AMP) concentration and adenine-(3)H incorporation into (3)H-labeled cyclic AMP were not different. In adenomas as well as normal thyroid, all parameters responded significantly to in vitro TSH stimulation. The response to TSH of adenyl cyclase activity and (32)P incorporation was enhanced in adenomas compared with that of the adjacent normal thyroid. These differences were not explained by an increased cellularity of the adenomas. Medullary carcinomas did not respond to TSH in any of the above parameters.The studies demonstrate an intact, TSH-responsive adenyl cyclase-cyclic AMP system in the adenomas and, accordingly, imply the presence of receptor sites for TSH on the cells of the adenoma. The failure of such nodules to concentrate (131)I may be owing to a subsequent impairment in the expression of cyclic AMP action on iodine metabolism.     

Antithyroid effects of lithium

Lithium has been reported to be goitrogenic when used for the treatment of manic-depressive psychosis. To investigate the effects of lithium on iodine metabolism, male Sprague-Dawley rats were placed on a low iodine (LID) or normal iodine diet (NID) containing enough Li(2)CO(3) to give serum lithium levels of 0.23-0.86 mEq/liter (human therapeutic range is 0.6-1.6 mEq/liter). The following effects were noted with lithium treatment: (a) thyroid weight increased concomitant with a slowing of thyroidal iodine release; (b) the ability to concentrate iodide was increased only after goiters were established; (c) on the LID, (131)I uptake was elevated throughout all phases of treatment, even when the release rate was normal; (d) iodine organification was unaffected but the proportion of (131)I present as iodothyronines was decreased; (e) the thyroidal (127)I content was increased; (f) despite these changes, the serum PBI remained normal as did the thyroxine turnover rate; and (g) thyrotropin (TSH) levels in serum were the same as controls except for a slight elevation early in the course of treatment; TSH levels did not correlate with goitrogenesis.When LiCl was injected in large doses into intact rats (giving serum lithium levels of 3.08-3.89 mEq/liter), the iodide concentrating mechanism, (131)I uptake, and (131)I release rates were depressed. Similar experiments in hypophysectomized rats receiving TSH demonstrated these to be local antithyroid effects not mediated through the pituitary.The discrepancy between acute and chronic responses to lithium, and the dissociation between the inhibition of iodine release and stimulatory effects is discussed.