The effects of an acute load of thyroxine on the transport and peripheral metabolism of triiodothyronine in man

In order to examine the question of whether thyroxine-binding globulin (TBG) influences significantly the peripheral metabolism of 3,3',5-triiodo-L-thyronine (T(3)) in vivo, paired studies of the effects of a large intravenous load of L-thyroxine (T(4)) on the kinetics of (131)I-labeled T(3) metabolism were carried out in five normal subjects. After the T(4) load, both the early distributive loss of labeled T(3) from serum and the volume of T(3) distribution, observed after distribution equilibrium had been attained, were greatly increased. These alterations were consistent with those to be expected from displacement of T(3) from its extracellular binding sites. After the T(4) load, however, the fractional rate of T(3) turnover was decreased. This finding is ascribed either to competition between T(3) and T(4) for common intracellular pathways of degradation or excretion or to displacement of T(3) from sites of more rapid to sites of less rapid metabolism. These effects of alterations in the binding activity of TBG on the peripheral metabolism of T(3), together with those previously reported by others, are consistent with the interpretation that T(3) is significantly bound by TBG in vivo. However, it is suggested that the effects of alterations in the T(3)-TBG binding interaction on the metabolism of T(3) are obscured by alterations in the extracellular-cellular partitioning of T(4) that would result from concurrent alterations in T(4)-binding by TBG.     

温肾方药对甲状腺功能减退症大鼠甲状腺素代谢和性激素水平的调节

目的：观察温肾方药对甲状腺功能减退症大鼠甲状腺功能及血清性激素水平的影响，并分析该影响是否有剂量依赖性，该方药与西药甲状腺片合用是否效果更好。 方法：实验于2005—04／05在上海中医药大学附属龙华医院科技实验中心完成。①选用清洁级健康成年Wistar大鼠60只，雌雄各半。②取10只为正常对照组正常饲养。给予其余50只大鼠每天灌胃0．4g／L他巴唑混悬液1．35mL（2．7mg/kg），持续45d。第46天。将造模后大鼠50只随机分为5组：模型组、甲状腺片组、温肾方小剂量组、温肾方大剂量组、温肾方合甲状腺片组，每组10只。③模型组：灌胃9．0mL／kg生理盐水；甲状腺片组：灌胃9．0mL／kg甲状腺片混悬液（上海市实业联合集团长城药业有限公司生产，批号20051001，40mg／片；用生理盐水配成0．4g／L混悬液）；温肾方小剂量组：灌胃9．0mL／kg半硫丸悬液（半硫丸，主要成分为硫磺；将硫磺和豆腐以1：1．5的比例进行炮制；由上海中医药大学附属龙华医院药剂科制为胶囊，用生理盐水配成30g／L混悬液）；温肾方大剂量组：18．0mL／kg半硫丸胶囊混悬液；温肾方＋甲状腺片组：灌胃9．0mL／kg甲状腺片混悬液和9．0mL／kg半硫丸悬液，1次／d，共15d。④15d后取大鼠颈部血液，采用放射免疫法测定血清游离三碘甲状腺原氨酸、游离甲状腺素、促甲状腺激素、促卵泡激素、促黄体生成素、雌二醇、孕酮水平。⑤各组计量结果差异比较采用方差分析和q检验。 结果：大鼠60只均进入结果分析。①温肾方对甲状腺功能减退症大鼠甲状腺功能的影响：各治疗组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于模型组（P〈0．05-0．01），血清促甲状腺激素水平明显低于模型组（P〈0．05～0．011）。温肾方大剂量组、甲状腺片组、温肾方＋甲状腺片组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于温肾方小剂量组（P〈0．01），血清促甲状腺激素水平明显低于温肾方小剂量组（P〈0．05—0．01）。温肾方＋甲状腺片组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于其他治疗组及模型组（P〈0．01），血清促甲状腺激素水平明显低于其他治疗组及模型组（P〈0．05—0.01）。②温肾方对甲状腺功能减退症大鼠血清性激素水平的影响：除温肾方小剂量组对雄性大鼠促黄体生成素、雌性大鼠促卵泡激素外，各治疗组大鼠血清性激素水平明显高于模型组（P〈0．01）；除温肾方大剂量组雌性大鼠促黄体生成素、孕酮外，温肾方大剂量组、甲状腺片组、温肾方＋甲状腺片组大鼠血清促卵泡激素、促黄体生成素、雌二醇、孕酮水平均明显高于温肾方小剂量组（P〈0．05-0．01）；其中温肾方＋甲状腺片组与其他治疗组比较，均差异明显（P〈0．05～0.01）。 结论：温肾方可调节甲状腺功能减退症血清性激素水平，改善甲状腺功能，且该作用存在剂量依赖性，温肾方与甲状腺片合用效果更好。     

温肾方药对甲状腺功能减退症大鼠甲状腺素代谢和性激素水平的调节

目的:观察温肾方药对甲状腺功能减退症大鼠甲状腺功能及血清性激素水平的影响,并分析该影响是否有剂量依赖性,该方药与西药甲状腺片合用是否效果更好。方法:实验于2005-04/05在上海中医药大学附属龙华医院科技实验中心完成。①选用清洁级健康成年Wistar大鼠60只,雌雄各半。②取10只为正常对照组:正常饲养。给予其余50只大鼠每天灌胃0.4g/L他巴唑混悬液1.35mL(2.7mg/kg),持续45d。第46天,将造模后大鼠50只随机分为5组:模型组、甲状腺片组、温肾方小剂量组、温肾方大剂量组、温肾方合甲状腺片组,每组10只。③模型组:灌胃9.0mL/kg生理盐水;甲状腺片组:灌胃9.0mL/kg甲状腺片混悬液穴上海市实业联合集团长城药业有限公司生产,批号20051001,40mg/片;用生理盐水配成0.4g/L混悬液雪;温肾方小剂量组:灌胃9.0mL/kg半硫丸悬液(半硫丸,主要成分为硫磺;将硫磺和豆腐以1∶1.5的比例进行炮制;由上海中医药大学附属龙华医院药剂科制为胶囊,用生理盐水配成30g/L混悬液);温肾方大剂量组:18.0mL/kg半硫丸胶囊混悬液;温肾方 甲状腺片组:灌胃9.0mL/kg甲状腺片混悬液和9.0mL/kg半硫丸悬液,1次/d,共15d。④15d后取大鼠颈部血液,采用放射免疫法测定血清游离三碘甲状腺原氨酸、游离甲状腺素、促甲状腺激素、促卵泡激素、促黄体生成素、雌二醇、孕酮水平。⑤各组计量结果差异比较采用方差分析和q检验。结果:大鼠60只均进入结果分析。①温肾方对甲状腺功能减退症大鼠甲状腺功能的影响:各治疗组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于模型组(P<0.05～0.01),血清促甲状腺激素水平明显低于模型组(P<0.05～0.01)。温肾方大剂量组、甲状腺片组、温肾方 甲状腺片组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于温肾方小剂量组(P<0.01),血清促甲状腺激素水平明显低于温肾方小剂量组(P<0.05～0.01)。温肾方 甲状腺片组血清游离三碘甲状腺原氨酸、游离甲状腺素水平明显高于其他治疗组及模型组(P<0.01),血清促甲状腺激素水平明显低于其他治疗组及模型组(P<0.05～0.01)。②温肾方对甲状腺功能减退症大鼠血清性激素水平的影响:除温肾方小剂量组对雄性大鼠促黄体生成素、雌性大鼠促卵泡激素外,各治疗组大鼠血清性激素水平明显高于模型组(P<0.01);除温肾方大剂量组雌性大鼠促黄体生成素、孕酮外,温肾方大剂量组、甲状腺片组、温肾方 甲状腺片组大鼠血清促卵泡激素、促黄体生成素、雌二醇、孕酮水平均明显高于温肾方小剂量组(P<0.05～0.01);其中温肾方 甲状腺片组与其他治疗组比较,均差异明显(P<0.05～0.01)。结论:温肾方可调节甲状腺功能减退症血清性激素水平,改善甲状腺功能,且该作用存在剂量依赖性,温肾方与甲状腺片合用效果更好。     

Alterations in thyroid iodine release and the peripheral metabolism of thyroxine during acute falciparum malaria in man

Previous studies of thyroid function during various infections have yielded conflicting results, but most have suggested an acceleration of peripheral thyroxine (T₄) turnover during the acute infectious illness. In the present studies, thyroid function was examined by a method allowing simultaneous analysis of both endogenous thyroidal release and peripheral T₄ disposal in normal volunteers after induction of acute falciparum malaria. Subjects received iodide-¹²⁵I, followed in 5-7 days by ¹³¹I-T₄ intravenously. 4 days later, infection was induced by the injection of parasitized red blood cells. Bidaily measurements of serum protein-bound ¹²⁵I and protein-bound ¹³¹I, and urinary ¹²⁵I and ¹³¹I, together with frequent estimates of serum ¹²⁷I-T₄ (Murphy-Pattee) and free T₄ (FT₄), were made during a control period, during acute illness, and during convalescence. Alterations in the peripheral metabolism of ¹³¹I-T₄ during infection included significant decreases in the fractional disappearance rate for T₄ [(k)], and in the clearance and daily disposal of T₄, all of which returned to control values during convalescence. Total serum ¹²⁷I-T₄ increased late in the infected period to become greater during convalescence than either before or during infection, while FT₄ did not increase significantly until convalescence. An analysis of serum ¹³¹I-T₄/¹²⁷I-T₄ and ¹³¹I-T₄/PB¹²⁵I ratios confirmed these observations. The slope with time of ratios for urinary ¹²⁵I/¹³¹I, a reflection of thyroidal iodine release, was decreased during infection, but rebounded to control values during the convalescent period. The observed increments in serum ¹²⁷I-T₄ concentration in the convalescent phase may reflect in part the slowing of (k), but together with the rising ratios of urine ¹²⁵I/¹³¹I suggests enhanced thyroidal T₄ secretion immediately after the acute illness. Thus, with malarial infection, there appears to be an initial depression followed by a rebound in rates of thyroidal iodine release. In contradistinction to other infections, fractional turnover and daily disposal of hormone is decreased in malaria, perhaps due to hepatic dysfunction and the consequent impairment in cellular deiodinative processes.     

The effect of diphenylhydantoin on thyroxine metabolism in man

The effect of 5,5'-diphenylhydantoin on thyroxine metabolism was examined in five normal volunteers. Intravenous injection of radiothyroxine was followed by a 10-12 day control and subsequent 9-14 day treatment periods. During oral administration of diphenylhydantoin, plasma thyroxine concentration decreased to about 80% of its pretreatment level and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. These changes were a result of increases in both urinary and fecal excretion of radioisotope.A minimum plasma thyroxine was apparent after 10-12 days of diphenylhydantoin administration. In two of the subjects, treatment was sufficiently prolonged to achieve this new steady state. In these subjects, the decrease in total body thyroxine was balanced by the increase in the fractional turnover rate. As a result, absolute thyroxine degradation during diphenylhydantoin administration was unchanged from the pretreatment values.Plasma ultrafiltration was used to estimate the free thyroxine fraction at regular intervals during the control and treatment periods. During diphenylhydantoin treatment, there was little or no change in this fraction and therefore, absolute free thyroxine decreased. Thyroxine-binding globulin and thyroxine-binding prealbumin capacities remained constant.These results indicate that thyroxine degradation can proceed at a normal rate in subjects receiving diphenylhydantoin despite decreases in plasma free thyroxine concentration. If free thyroxine is the only portion of the hormone available for cellular utilization, then free thyroxine clearance must be increased in these subjects. This increase in clearance could represent either a direct stimulation of peripheral thyroxine metabolism by diphenylhydantoin, or it could reflect the response of intrinsic regulatory systems to a diphenylhydantoin-mediated displacement of thyroxine from thyroxine-binding globulin. Whatever the mechanism for this effect, a decreased free thyroxine value in patients receiving diphenylhydantoin may not imply hypothyroidism.     

Effect of thyroid-suppressive doses of triiodothyronine on thyroxine turnover and on the free thyroxine fraction

The relationship between free thyroxine concentration and thyroxine turnover was studied during thyroid suppression with triiodothyronine. Although there was some increase in the proportion of serum thyroxine bound to thyroxine-binding globulin, the ratio of ultrafilterable to protein-bound hormone was not significantly affected. The fractional disappearance rate of thyroxine increased from an average control value of 11.47%/day to 14.72%/day. Because of contraction of the thyroxine distribution space the clearance of thyroxine was less markedly affected, increasing from 1.37 to 1.56 liters/day. Since the ratio of thyroxine turnover to free thyroxine concentration, i.e., the free thyroxine clearance, increased proportionately (4.79-5.55 liters x 10(3)/day) we conclude that triiodothyronine stimulates thyroxine clearance by a mechanism that is independent of effects on free thyroxine concentration.     

Studies of peripheral thyroxine distribution in thyrotoxicosis and hypothyroidism

Compartmental analysis of the peripheral distribution of labeled thyroxine was applied to various groups of subjects with thyrotoxicosis and hypothyroidism. It was observed that the hepatic incorporation of thyroxine was augmented in subjects with Graves' disease when compared to non-Graves' disease control groups at all levels of thyroid function. Decreased values of hepatic incorporation occurred in primary hypothyroid subjects. These lowered values were not acutely corrected by elevation of the serum thyroxine level, but were observed to be rectified after several months' therapy with exogenous thyroid hormone. These alterations of the hepatic thyroxine-(131)I incorporation were independently verified by direct quantitative liver scintiscan determinations.Employing a dual thyroxine tracer system, we were able to demonstrate that during the early phases of equilibration of a tracer dose of thyroxine, alterations in the rate of deiodination were observed to be present in the various thyroid disease states. Increased deiodination rates were found in subjects with Graves' disease and the reverse was noted in patients with primary hypothyroidism. Kinetic analysis of thyroxine compartmental distribution during this early phase of equilibration of a labeled thyroxine tracer indicated that the primary tissue uptake occurred in the liver. These findings supported the contention that the amount of labeled thyroxine incorporated in the liver may be directly related to the deiodination rate of thyroxine by that organ. The pathogenetic basis of these alterations is presently unknown.     

The integrity of the ether linkage during thyroxine metabolism in man

The structures of thyroxine metabolites after total deiodination bear on the mode of thyroxine (T(4)) action in vivo. The present study was undertaken to determine the integrity of the ether linkage during thyroxine metabolism in man. Normal volunteers were given simultaneous intravenous injections of two thyroxines labeled with either (14)C or (3)H on the opposite sides of the ether linkage, D,L-[alpha,beta-(3)H]T(4) and D,L-[phenolic ring-(14)C]T(4). The ratio of alanine side chain to phenolic ring which was measured as (3)H:(14)C ratio was found to remain constant in the serum, urine, and feces during the subsequent 3 wk. The disappearance rates of the (3)H and (14)C radioactivity from blood were similar. The values of half-life were in the ranges of 4.2-6.7 days. 51-63% of the (3)H and 50-57% of the (14)C doses were recovered from urine and 13-20% of the (3)H and 15-20% of the (14)C doses were recovered from feces. Chromatography of the urinary metabolites confirmed that the phenolic ring and the nonphenolic ring including at least part of the side chain remained linked together.     

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with 125I either at the 5'-position of the outer-ring (125I-beta-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-beta-T4 in an atmosphere of O2, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of 125I-labeled iodide (125I-I-) and chromatographically immobile origin material (125I-OM), but only a minute proportion of 125I-labeled 3,5,3'-triiodothyronine (125I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 125I-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 125I-labeled 3,5-diiodotyrosine (125I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under O2, but not N2, aminotriazole consistently elicited the formation of large proportions of 125I-DIT, indicating that the ether link of T4 was being cleaved by an O2-dependent process. Formation of 125I-DIT in the presence of aminotriazole and O2 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole. Activation of the in vitro formation of 125I-DIT from 125I-U-T4 was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of 125I-DIT from 125I-U-T4 was increased by the addition of the inhibitor of iodotyrosine dehalogenase, 3,5-dinitrotyrosine. However, as judged from studies conducted in parallel with radioiodine-labeled DIT and 125I-U-T4 as substrates, none of the factors that altered the proportion of 125I-DIT found after incubations with 125I-U-T4 did so by altering the degradation of the 125I-DIT formed. The factors that influenced DIT formation from T4 in rat liver had opposite effects on T3 neogenesis. Thus, aminotriazole, endotoxin, NEM, and an aerobic atmosphere, all of which enhanced DIT formation, were inhibitory to T3 neogenesis. In contrast, anaerobiosis and GSH inhibited ether-link cleavage of T4, but facilitated T3 neogenesis. The foregoing results suggest that a pathway for the ether-link cleavage of T4 to yield DIT is present in rat liver. Activity of this pathway, which appears to be peroxidase mediated, is inversely related to activity of the pathway for the T3 neogenesis. It is further suggested that this reciprocity reflects a reciprocal relationship between hepatic GSH and H2O2, the former increasing T3 formation and inhibiting DIT formation, and the latter producing opposite effects.     

Effect of epinephrine on defibrillation in ischemic ventricular fibrillation

Epinephrine is thought to improve the success of defibrillation with countershock therapy. However, a recent study failed to show any effect of epinephrine in dogs with normal coronary arteries undergoing electrically-induced ventricular fibrillation (VF). In the current study, the effects of epinephrine were examined in dogs with coronary occlusion undergoing both spontaneous and electrically-induced fibrillation. Forty pentobarbital-anesthetized dogs were prepared by placing snares around the circumflex and left anterior descending coronary arteries. Fibrillation and subsequent resuscitation were carried out with one coronary artery occluded. Dogs were randomly allocated so that half of the animals underwent spontaneous fibrillation and half were electrically fibrillated. In addition, half received epinephrine (1 mg) during resuscitation and half received normal saline solution (1 ml). After 3 minutes of cardiac arrest, cardiopulmonary resuscitation (CPR) was begun, and 30 seconds later epinephrine or saline were injected. One minute later defibrillation was attempted using successive stored energy doses of 1, 2, 4, 8, 16, and 32 J/kg. Delivered energy and transthoracic impedance were measured for each countershock. Successful defibrillation was defined as conversion to any rhythm other than VF or ventricular tachycardia that degenerated in VF within 10 seconds. No other drugs were given during resuscitation. Neither the type of fibrillation (electrically-induced versus spontaneous) or drug therapy (epinephrine versus placebo) had a significant effect on the incidence of defibrillation or the energy necessary for successful defibrillation. Epinephrine did significantly increase the incidence of resuscitation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of dopamine and epinephrine on hemodynamics and oxygen metabolism in hypoxic anesthetized piglets

Background  

The most appropriate inotropic agent for use in the newborn is uncertain. Dopamine and epinephrine are commonly used, but have unknown effects during hypoxia and pulmonary hypertension; the effects on the splanchnic circulation, in particular, are unclear.     

血管加压素与肾上腺素对心肺复苏大鼠心肌损伤的影响

目的：比较血管加压素与肾上腺素对心肺复苏大鼠心肌损伤的程度。方法：60只雄性SD大鼠随机分为模型组、阴性对照组、血管加压素组及肾上腺素组,每组15只。模型组仅行窒息前准备,不实施窒息处理,其他3组成功建立心搏骤停模型后分别经尾静脉注射生理盐水、血管加压素0.4 u/kg和肾上腺素0.04 mg/kg。记录大鼠自主循环恢复后30 min内血压、心率及存活时间;采用免疫组织化学方法检测白细胞介素-6与肿瘤坏死因子-α水平,分光光度计检测丙二醛、超氧化物歧化酶水平。结果：血管加压素组复苏成功率与肾上腺素组比较差异无统计学意义(P＞0.05);在自主循环恢复的30 min内血管加压素组平均动脉压高于肾上腺素组(P＜0.05)。自主循环恢复30 min时,模型组丙二醛、超氧化物歧化酶、白细胞介素-6、肿瘤坏死因子-α水平与血管加压素组、肾上腺素组比较差异有统计学意义(P＜0.05),血管加压素组丙二醛、超氧化物歧化酶水平与肾上腺素组比较差异无统计学意义(P＞0.05);血管加压素组白细胞介素-6和肿瘤坏死因子-α水平低于肾上腺素组(P＜0.05)。结论：血管加压素与肾上腺素在大鼠心肺复苏过程中复苏成功率相近,但血管加压素能维持复苏后平均动脉压在较高水平,对心肌细胞的损伤相对较轻。     

Effect of insulin induced hypoglycaemia on thyroid function and thyroxine turnover

Abstract. The effect of long-term hypoglycemia induced by insulin on thyroid metabolism has been investigated in 13 normal subjects. No modification of the uptake or release of radioactive iodine by the thyroid has been observed. A significant increase of circulating thyroxine was found for as long as 8 h after insulin injection. Turnover studies with radioactive thyroxine indicate that during the period of insulin administration, there is a slower disappearance rate of labelled thyroxine from the plasma which occurs simultaneously with a significant drop of the hepatic radioactivity. It seems likely that the enhanced concentration of serum thyroxine is related to the release of thyroxine molecules stored in the liver.