Paakkari I, Järvinen A, Vonhof S, Männistö P T, Cohen L A, Labroo V M, Feuerstein G
Department of Neurology, Uniformed Services University of the Health Science, Bethesda, MD 20814-4799.
Peptides. 1990 Sep-Oct;11(5):939-44. doi: 10.1016/0196-9781(90)90013-u.
The biological activity of thyrotropin-releasing hormone (TRH) and its analogs 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH was assessed by means of their effects on: 1) the mean arterial pressure (MAP), 2) heart rate (HR), 3) ventilation minute volume (MV), 4) contractility of the rat duodenum, and 5) concentrations of thyrotropin (TSH) or prolactin (PRL) in serum. Also their binding to TRH-receptors in brain homogenates was studied. In urethane-anesthetized rats TRH ICV increased MAP, HR and MV. 4(5)-I-Im-TRH was equally as active as TRH on HR and MV but a significant elevation in MAP was observed only at a dose 100-fold to that of TRH. However, the maximal responses of 4(5)-I-Im-TRH and TRH did not differ. In conscious rats, TRH 1A elevated MAP and HR but 4(5)-I-Im-TRH was active on MAP only. 2,4(5)-I2-Im-TRH was devoid of cardiorespiratory activity. TRH dose-dependently inhibited the contractions of the rat duodenum while the iodinated analogs lacked such an activity. To induce a significant release of TSH several hundred times more of 4(5)-I-Im-TRH and over 1000 times more of 2,4(5)-I2-Im-TRH were needed as compared to TRH. The iodoanalogs elevated PRL levels only at doses 2000-fold higher than those of TRH. The iodoanalogs displaced [3H][3-Me-His2]TRH [( 3H]MeTRH) from its binding sites at concentrations about 1000 times higher than those of TRH. Substitutions of the histidyl moiety of TRH in 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH resulted in substantial loss of the endocrine activity. While the di-iodinated analog was practically devoid of any biological activity the monoiodinated analog exerted similar cardiorespiratory activity to that of TRH.
通过促甲状腺激素释放激素（TRH）及其类似物4(5)-I-Im-TRH和2,4(5)-I2-Im-TRH对以下方面的影响来评估其生物活性：1）平均动脉压（MAP），2）心率（HR），3）每分钟通气量（MV），4）大鼠十二指肠的收缩性，以及5）血清中促甲状腺激素（TSH）或催乳素（PRL）的浓度。此外，还研究了它们与脑匀浆中TRH受体的结合情况。在氨基甲酸乙酯麻醉的大鼠中，TRH脑室内注射可升高MAP、HR和MV。4(5)-I-Im-TRH在升高HR和MV方面与TRH活性相当，但仅在剂量比TRH高100倍时才观察到MAP有显著升高。然而，4(5)-I-Im-TRH和TRH的最大反应并无差异。在清醒大鼠中，TRH皮下注射可升高MAP和HR，但4(5)-I-Im-TRH仅对MAP有活性。2,4(5)-I2-Im-TRH无心肺活性。TRH剂量依赖性地抑制大鼠十二指肠的收缩，而碘化类似物则缺乏这种活性。与TRH相比，诱导TSH显著释放需要4(5)-I-Im-TRH的量是TRH的几百倍，2,4(5)-I2-Im-TRH的量则超过TRH的1000倍。碘化类似物仅在剂量比TRH高2000倍时才升高PRL水平。碘化类似物在浓度比TRH高约1000倍时才能从其结合位点上取代[3H][3-甲基组氨酸2]TRH [3H]MeTRH。4(5)-I-Im-TRH和2,4(5)-I2-Im-TRH中TRH组氨酸部分的取代导致内分泌活性大幅丧失。双碘化类似物几乎没有任何生物活性，而单碘化类似物具有与TRH相似的心肺活性。
