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

Paakkari, Ilari; Järvinen, Asko; Vonhof, Stefan; Männistö, Pekka T.; Cohen, Louis A.; Labroo, Virender M.; Feuerstein, Giora

doi:10.1016/0196-9781(90)90013-u

Cited by 8 publications

(5 citation statements)

References 24 publications

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“…In accordance with our previous reports, TRH dose-dependently inhibited the contractions of transmurally stimulated rat duodenum (Paakkari et al 1990; Jarvinen & Paakkari 1991a). The contractions evoked by transmural stimulation were caused by direct stimulation of the smooth muscle since they were not abolished by the muscarinic blocking agent atropine, the ganglion blocking agent pentolinium or tetrodotoxin, which blocks the neuronal sodium channels (Narahashi 1972 ; Barchi 1987).…”

Section: Discussionsupporting

confidence: 93%

“…1979;Furukawa et al 1980). We observed that TRH inhibits the contractions of transmurally stimulated rat duodenum but does not alter the tone of the preparation (Paakkari et al 1990). Specific mode of action of TRH is suggested by the findings that the potency of various analogues of TRH in duodenal smooth muscle corresponded well to their endocrine activity and that the tachyphylaxis in the duodenum was specific for TRH (Paakkari el al.…”

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confidence: 70%

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Atipamezole, Benzodiazepines, Bicucullin and Tifluadom Antagonize the Effect of TRH on Rat Duodenum and Displace it from Brain and Anterior Pituitary Receptors

Järvinen

1991

Pharmacology & Toxicology

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The mechanism of action of the TRH induced inhibition of contractions of the transmurally stimulated rat duodenum has been studied. The effect of TRH was not antagonized by atropine, pentolinium, phenoxybenzamine, sotalol, methysergide, domperidone, diphenhydramine, cimetidine, aminophylline, antazolin, indomethacin, morphine, naloxone or tetrodotoxin. In contrast, the adrenergic alpha 2-antagonist atipamezole, the benzodiazepines chlordiaxepoxide and midazolam or GABA-A-antagonist bicucullin but not picrotoxin or SR-95531 attenuated the response to TRH. An opioid-kappa-receptor agonist having benzodiazepine structure, tifluadom, but not MR 2034 also diminished the response to TRH. However, these actions were not modified by the alpha 2-agonist medetomidine, benzodiazepine antagonist flumazenil, GABA-agonists muscimol or baclofen or naloxone, respectively. While the binding of [3H][3-Me-His2]TRH to the rat anterior pituitary, hypothalamus, cortex and brainstem homogenates was saturable and of high affinity, no saturable binding was observed in the duodenal smooth muscle. Agents that were effective in the duodenal preparation displaced [3H][3-Me-His2]TRH from its binding sites in brain homogenates and the inhibitory constants (Ki) were (in microM): 0.038-0.107 (TRH), 0.19-5.8 (chlordiazepoxide), 0.021-8.9 (midazolam), 1.5-17 (tifluadom), 60-210 (bicucullin) and 150-530 (atipamezole). Atipamezole, bicucullin and chlordiazepoxide caused competitive displacement indicated by the increased KD of the labelled ligand but no change in the Bmax while tifluadom increased KD and decreased Bmax. It is concluded that the inhibitory effect of TRH on the contractions of the duodenal smooth muscle is mediated directly by the smooth muscle and it is apparently specific for TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 93%

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confidence: 70%

Atipamezole, Benzodiazepines, Bicucullin and Tifluadom Antagonize the Effect of TRH on Rat Duodenum and Displace it from Brain and Anterior Pituitary Receptors

Järvinen

1991

Pharmacology & Toxicology

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“…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.…”

Section: Discussionmentioning

confidence: 96%

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

Faden

Labroo²,

Cohen³

1993

Journal of Neurotrauma

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Treatment with thyrotropin releasing hormone (TRH) or TRH analogues improves outcome after experimental brain or spinal cord trauma. TRH analogues with modifications at the N-terminal position of the tripeptide are effective, whereas analogues with modifications of the C-terminal residue are not. Imidazole-substituted TRH analogues, which modify the middle amino acid (histidine) of the tripeptide, have more recently been developed but have not been evaluated in models of central nervous system (CNS) trauma. In the present studies two imidazole-substituted analogues--4(5)-NO2(Im)TRH and 2,4 diiodo(Im)TRH--are shown to improve behavioral recovery following fluid percussion-induced traumatic brain injury (TBI) in rats. Because 4(5)-NO2(Im)TRH has little endocrine activity and 2,4 diiodo(Im)TRH has minimal cardiovascular effects, these experiments support the hypothesis that the neuroprotective actions of TRH analogues are independent of their endocrine or autonomic actions.

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“…12,24 Jain et al have reported the synthesis of TRH analogs in which both pGlu and central histidine residue was simultaneously modified. 25,26 Gershengorn and Jain et al 27,28 have showed for the first time that certain TRH analogs were more efficacious agonists at TRH-R1 and TRH-R2 than TRH itself. They found that decrease in the affinities caused by TRH analogs correlate inversely with the analog ability to activate TRH-Rs.…”

Section: Introductionmentioning

confidence: 97%

Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice

Meena

Thakur

Nandekar

et al. 2015

Bioorganic & Medicinal Chemistry

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

Cited by 8 publications

References 24 publications

Atipamezole, Benzodiazepines, Bicucullin and Tifluadom Antagonize the Effect of TRH on Rat Duodenum and Displace it from Brain and Anterior Pituitary Receptors

Atipamezole, Benzodiazepines, Bicucullin and Tifluadom Antagonize the Effect of TRH on Rat Duodenum and Displace it from Brain and Anterior Pituitary Receptors

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

Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice

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