Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat

Abstract

The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hor.mone (TRH), 4-nitro-imidazole TRH (4-nitro-TRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoromethyl-imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). None of the analogs were more potent than TRH in inducing cardiovascular changes. The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elici ted a 4 to 5 fold increase in PRL at the higher dose. The present results suggest that the receptors for TRH-elicited PRL release differ from TRH-receptors involved in its cardiovascular actions. INTRODUCI'IONIn addition to the thyrotropin release, thyrotropin releasing hor.mone (TRH) releases prolactin (PRL) from the pituitaLY of several mammalian species (1). Moreover, TRH has central nervous system actions which are totally unrelated to its effect on the hypothalamopituitary axis (2,3). In both experimental animals (4-7) and humans (8,9), TRH producespresser and tachycardic responses. The variety of autonomic endocrine and neural functions regulated by TRH suggests that different receptors might mediate the various effects of TRH. The existance of multiple TRH receptors is supported by both biological (10,11) and biochemdcal studies (3,12,13). Appropriate modification of the TRH molecule might, therefore, yield analogs with an action selective for either neuroendocrine or central nervaus system. 63

Differential Response of Lactotrophs and Somatotrophs to a Joint Application of Vasoactive Intestinal Peptide and Thyrotrophin‐Releasing Hormone in the Rat

“…The present results lend further support to previous findings showing that T R H stimulates only PRL (1,6,15) and TSH (16), but not G H release (2,8) in intact rats. In contrast, rats deprived of hypothalamic inputs to the pituitary exhibit a G H response to the peptide (7).…”

Thyrotropin-releasing hormone in cardiovascular pathophysiology

“…Its destruction avoids the development of different forms of hypertension, such as that produced by DOCA-salt, sinoaortic denervation or lesion of the tractus solitarius nucleus [25]. In fact, microinjections of TRH intracere-broventricularly (icv) or into the POA produce dosedependent pressor effects [26,27].…”

Imidazole-Substituted Analogues of TRH Limit Behavioral Deficits After Experimental Brain Trauma

“…In previous studies, 2,4 diiodo(Im)TRH appeared to have minimal cardiovascular actions in contrast to TRH, to pyroglutamyl-substituted analogues, and to 4(5)-N02(Im)TRH; furthermore, 4(5)-N02(Im)TRH and 2,4-diiodo(Im)TRH are markedly less potent than TRH with regard to prolactin or TSH release (Siren et al, 1986;Paakkari et al, 1990). These observations provide further support for the conclusion that the neuroprotective actions of TRH and TRH analogues are independent of the autonomie or endocrine effects of these compounds.…”

“…Different substitutions at the two and four positions of the imidazole ring have produced compounds with more selective autonomie or endocrine activity, perhaps suggesting actions at separate populations of TRH isoreceptors (Feuerstein et al, 1984a;Siren et al, 1986;Labroo et al, 1987).…”