Selective cardiorespiratory activity of an iodinated analog of thyrotropin-releasing hormone (TRH)

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.