Differential effect of fluorinated analogs of TRH on the cardiovascular system and prolactin release

Feuerstein, Giora; Lozovsky, David; Cohen, Louis A.; Labroo, Virender M.; Kirk, Kenneth L.; Kopin, Irwin J.; Faden, Alan I.

doi:10.1016/0143-4179(84)90004-0

Cited by 21 publications

(8 citation statements)

References 16 publications

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“…The present results confir.m the previous findings that TRH and its imidazole substituted analogs induce increments of blood pressure and heart rateandrelease prolactin (17). All the three analogs used in the present study were equipotent to TRH in eliciting cardiovascular changes.…”

Section: Discussionsupporting

confidence: 90%

“…On the other hand, the 4-nitro-TRH was far less potent than the native TRH in inducing prolactin release, while the 2-TFM-TRH and 4-TFM-TRH-analogs were significantly more potent than TRH in increasing plasma PRL. In a previous study (17) it has been reported that TRH and its 4-fluoro analog produced increases in blood pressure and heart rate and released prolactin also upon microinjections of nanomoles (28 nmol•lO ~g) of these drugs into the hypothalamic nucleus preopticus medialis (POM). The 2-TFM-TRH was significantly less potent than TRH or the 4-fluoro-TRH in inducing tachycardia, while we did not find any significant differences between the cardiovascular effects of TRH and the 2-TFM-TRH.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that 4-F-Im-TRH (4-Fluoro-TRH) and 2-TFM-TRH fail to bind to GH cells or release prolactin from them (16). On the other hand, discre~e central injection of these analogs to rats results in cardiovascular actions and PRL responses somewhat similar to those of TRH (17). In order to elaborate the effect of imidazole-ring Substitution in TRH on its biological profile, we have continued to synthetize and evaluate analogs in which the imidazole ring is modified by electron-releasing or electron-withdrawing groups in the 2-and;or 4-position.…”

Section: Introduci'ionmentioning

confidence: 99%

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

et al. 1986

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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

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introduci'ionmentioning

confidence: 99%

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

et al. 1986

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“…Although the more persistent effects of RX77368 probably reflect pharmacokinetic differences as described above, a difference in affinity between RX77368 and TRH for receptors in sites which are involved in cardiovascular control cannot be excluded [12]. Some animal data have suggested differences in cardiovascular responses between TRH and various analogues [25,26], although molecular genetic studies have only identified one human gene for TRH receptors to date [27].…”

Section: Discussionmentioning

confidence: 99%

The cardiovascular and subjective effects of thyrotropin releasing hormone (TRH) and a stable analogue, dimethyl proline‐TRH, in healthy volunteers.

Coupland

Bailey

Glue

et al. 1995

Brit J Clinical Pharma

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“…Feuerstein and coworkers [14] injected nanomolar doses of TRH or its histidyl analogs [ 16) into the nucleus preopticus medialis (POM) of conscious rats. The magnitude of the increments in mean arterial pressure and heart rate after the POM injections were, however, at the same range as the effect produced by ICV injections of the same doses of TRH [32,50].…”

Section: Sire Ofactionmentioning

confidence: 99%

Cardiovascular pharmacology of thyrotropin releasing hormone

Sirén

1988

Peptides

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SIREN A.-L. Cardiovascu/ar pharmacology of thyrotropin releasing hormone. PEPTIDES 9: Suppt. l, [69][70][71][72][73] 1988.-Thyrot;opin releasing hormone (TRH) and its receptors are present in th~ car~iovascul~ nuclei ofthe brain as ~ell as in ~he intermediolateral cell column of spinal cord. Anatomical, neurophysiological, funchonal and pharmacological stud1es suggest that TRH is a neurotransmitter/neuromodulator in the centrat nervous system. Administration of TRH to experimental animals or human subjects induces pressor and tachycardic responses and increases plasma Ievels of catecholamines. These effects are likely tobe mediated by a central nervous system activation of the sympathoadrenomedullary system with no involvement of vasopressin or renin-angiotensm system. ln the conscious rat, the TR~-induced pressor response is accompanied by an increment in cardiac output and a distinct change in organ blood flow, a hmdquarter skeletal muscle vasodilation accompanied bv renal and mesenteric vasoconstriction. The rote ofTRH in hypertension has not been studied. However, the extremely potent pressor and vasoconstrictor properties of TRH makes this tripeptide a candidate for neurotransmitters/modulators involved in the development and/or maintenance ofhypertension. The role ofTRH in the therapy of shock is at present controversial. Though preliminary experimental work raised hopes and expectations for therapeutic usage of TRH in shock and trauma, the more recent studies have shown no effect or a detrimental effect for TRH in some experimental shock states. TRHBlood pressure Organ blood flow Sympathetic nerve activity THYROTROPIN releasing hormone (TRH, 1-pyroglutamyl-1-histidyl-1-prolinamide) was the first hypothalamic releasing factor to be isolated, chemically characterized and synthesized [43]. In addition to its neuroendocrine effects (TSH, prolactin, growth hormone release), this tripeptide has centrat nervous actions which are totally unrelated to its effect on the hypothalamopituitary axis (for review see [29,38]). The presence of TRH immunoreactivity and TRH receptors in brain areas related to the cardiorespiratory control, together with the extremely potent pressor and tachycardic actions of exogenously administered TRH suggest that this peptide might have a role in modulating the brain regulation of blood pressure and respiration. This review aims to summarize the sturlies on TRH in the centrat nervous system with special emphasis on the cardiovascular pharmacology of this peptide. TRH SYSTEM IN THE DRAINTRH immunoreactivity is unevenly distributed throughout the centrat nervous system (see [42,43]). Although the highest local concentrations are found in the hypothalamus (especially in the median eminence, periventricuJar arcuate, dorsomedial and ventromedial nuclei), more than 70% of the total CNS TRH is located in extrahypothalamic areas. Outside the hypothalamus high locallevels of TRH are found in the lateral nucleus of the septum in the limbic area and in the nucleus of the solitary tract (NTS) in the...

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Differential effect of fluorinated analogs of TRH on the cardiovascular system and prolactin release

Cited by 21 publications

References 16 publications

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

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

The cardiovascular and subjective effects of thyrotropin releasing hormone (TRH) and a stable analogue, dimethyl proline‐TRH, in healthy volunteers.

Cardiovascular pharmacology of thyrotropin releasing hormone

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