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Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta

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2021
Authors
Gajić Bojić, Milica
Todorović, Lidija
Santrač, Anja
Mian, Md Yeunus
Sharmin, Dishary
Cook, James M.
Savić, Miroslav
Article (Published version)
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Abstract
Different subtypes of GABAA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABAA receptors are expressed on blood vessels, through which positive allosteric modulators of GABAA receptors exhibit vasodilatory effects. This study involved two parts: one to determine the presence of α1-6 subunit GABAA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABAA receptor modulators: zolpidem (α1-selective), XHe–III–074 (α4-selective), MP–III–022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective). Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue ba...th assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe–III–074, MP–III–022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10−7 M and 3 × 10−7 M). The present work suggests that the observed vasoactivity is due to modulation of “vascular” GABAA receptors, which after further detailed research may provide a therapeutic target.

Keywords:
Positive allosteric modulators (PAMs) / Rat thoracic aorta / Vascular” GABAA receptors / Vasoactivity
Source:
European Journal of Pharmacology, 2021, 899
Publisher:
  • Elsevier B.V.
Funding / projects:
  • Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs (RS-175076)
  • NIH for generous financial support (DA-043204, R01NS076517)
  • National Science Foundation, Division of Chemistry [CHE-1625735]

DOI: 10.1016/j.ejphar.2021.174023

ISSN: 0014-2999

WoS: 000641378500010

Scopus: 2-s2.0-85103314450
[ Google Scholar ]
2
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3812
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Gajić Bojić, Milica
AU  - Todorović, Lidija
AU  - Santrač, Anja
AU  - Mian, Md Yeunus
AU  - Sharmin, Dishary
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3812
AB  - Different subtypes of GABAA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABAA receptors are expressed on blood vessels, through which positive allosteric modulators of GABAA receptors exhibit vasodilatory effects.  This study involved two parts: one to determine the presence of α1-6 subunit GABAA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABAA receptor modulators: zolpidem (α1-selective), XHe–III–074 (α4-selective), MP–III–022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective).  Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue bath assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe–III–074, MP–III–022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10−7 M and 3 × 10−7 M).  The present work suggests that the observed vasoactivity is due to modulation of “vascular” GABAA receptors, which after further detailed research may provide a therapeutic target.
PB  - Elsevier B.V.
T2  - European Journal of Pharmacology
T1  - Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta
VL  - 899
DO  - 10.1016/j.ejphar.2021.174023
ER  - 
@article{
author = "Gajić Bojić, Milica and Todorović, Lidija and Santrač, Anja and Mian, Md Yeunus and Sharmin, Dishary and Cook, James M. and Savić, Miroslav",
year = "2021",
abstract = "Different subtypes of GABAA (gamma-aminobutyric acid A) receptors, through their specific regional and cellular localization, are involved in the manifestation of various functions, both at the central and peripheral levels. We hypothesized that various non-neuronal GABAA receptors are expressed on blood vessels, through which positive allosteric modulators of GABAA receptors exhibit vasodilatory effects.  This study involved two parts: one to determine the presence of α1-6 subunit GABAA receptor mRNAs in the rat thoracic aorta, and the other to determine the vasoactivity of the various selective and non-selective positive GABAA receptor modulators: zolpidem (α1-selective), XHe–III–074 (α4-selective), MP–III–022 (α5-selective), DK-I-56-1 (α6-selective), SH-I-048A and diazepam (non-selective).  Reverse transcription-polymerase chain reaction (RT-PCR) analysis data demonstrated for the first time the expression of α1, α2, α3, α4 and α5 subunits in the rat thoracic aorta tissue. Tissue bath assays on isolated rat aortic rings revealed significant vasodilatory effects of diazepam, SH-I-048A, XHe–III–074, MP–III–022 and DK-I-56-1, all in terms of achieved relaxations (over 50% of relative tension decrease), as well as in terms of preventive effects on phenylephrine (PE) contraction. Diazepam was the most efficient ligand in the present study, while zolpidem showed the weakest vascular effects. In addition, diazepam-induced relaxations in the presence of antagonists PK11195 or bicuculline were significantly reduced (P < 0.001 and P < 0.05, respectively) at lower concentrations of diazepam (10−7 M and 3 × 10−7 M).  The present work suggests that the observed vasoactivity is due to modulation of “vascular” GABAA receptors, which after further detailed research may provide a therapeutic target.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmacology",
title = "Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta",
volume = "899",
doi = "10.1016/j.ejphar.2021.174023"
}
Gajić Bojić, M., Todorović, L., Santrač, A., Mian, M. Y., Sharmin, D., Cook, J. M.,& Savić, M.. (2021). Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta. in European Journal of Pharmacology
Elsevier B.V.., 899.
https://doi.org/10.1016/j.ejphar.2021.174023
Gajić Bojić M, Todorović L, Santrač A, Mian MY, Sharmin D, Cook JM, Savić M. Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta. in European Journal of Pharmacology. 2021;899.
doi:10.1016/j.ejphar.2021.174023 .
Gajić Bojić, Milica, Todorović, Lidija, Santrač, Anja, Mian, Md Yeunus, Sharmin, Dishary, Cook, James M., Savić, Miroslav, "Vasodilatory effects of a variety of positive allosteric modulators of GABAA receptors on rat thoracic aorta" in European Journal of Pharmacology, 899 (2021),
https://doi.org/10.1016/j.ejphar.2021.174023 . .

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