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GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries. / Abramavicius, Silvijus; Petersen, Asbjørn G.; Renaltan, Nirthika S.; Prat-Duran, Judit; Torregrossa, Roberta; Stankevicius, Edgaras; Whiteman, Matthew; Simonsen, Ulf.

In: Frontiers in Pharmacology, Vol. 12, 613989, 03.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Abramavicius, S, Petersen, AG, Renaltan, NS, Prat-Duran, J, Torregrossa, R, Stankevicius, E, Whiteman, M & Simonsen, U 2021, 'GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries', Frontiers in Pharmacology, vol. 12, 613989. https://doi.org/10.3389/fphar.2021.613989

APA

Abramavicius, S., Petersen, A. G., Renaltan, N. S., Prat-Duran, J., Torregrossa, R., Stankevicius, E., Whiteman, M., & Simonsen, U. (2021). GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries. Frontiers in Pharmacology, 12, [613989]. https://doi.org/10.3389/fphar.2021.613989

CBE

Abramavicius S, Petersen AG, Renaltan NS, Prat-Duran J, Torregrossa R, Stankevicius E, Whiteman M, Simonsen U. 2021. GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries. Frontiers in Pharmacology. 12:Article 613989. https://doi.org/10.3389/fphar.2021.613989

MLA

Vancouver

Abramavicius S, Petersen AG, Renaltan NS, Prat-Duran J, Torregrossa R, Stankevicius E et al. GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries. Frontiers in Pharmacology. 2021 Mar;12. 613989. https://doi.org/10.3389/fphar.2021.613989

Author

Abramavicius, Silvijus ; Petersen, Asbjørn G. ; Renaltan, Nirthika S. ; Prat-Duran, Judit ; Torregrossa, Roberta ; Stankevicius, Edgaras ; Whiteman, Matthew ; Simonsen, Ulf. / GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries. In: Frontiers in Pharmacology. 2021 ; Vol. 12.

Bibtex

@article{169a3dc5b2b449e1969f7eaebb37526f,
title = "GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries",
abstract = "Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.",
keywords = "GYY4137, hydrogen sulfide, potassium channels, small mesenteric arteries, sodium sulfide",
author = "Silvijus Abramavicius and Petersen, {Asbj{\o}rn G.} and Renaltan, {Nirthika S.} and Judit Prat-Duran and Roberta Torregrossa and Edgaras Stankevicius and Matthew Whiteman and Ulf Simonsen",
note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Abramavicius, Petersen, Renaltan, Prat-Duran, Torregrossa, Stankevicius, Whiteman and Simonsen. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = mar,
doi = "10.3389/fphar.2021.613989",
language = "English",
volume = "12",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Research Foundation",

}

RIS

TY - JOUR

T1 - GYY4137 and Sodium Hydrogen Sulfide Relaxations Are Inhibited by L-Cysteine and KV7 Channel Blockers in Rat Small Mesenteric Arteries

AU - Abramavicius, Silvijus

AU - Petersen, Asbjørn G.

AU - Renaltan, Nirthika S.

AU - Prat-Duran, Judit

AU - Torregrossa, Roberta

AU - Stankevicius, Edgaras

AU - Whiteman, Matthew

AU - Simonsen, Ulf

N1 - Publisher Copyright: © Copyright © 2021 Abramavicius, Petersen, Renaltan, Prat-Duran, Torregrossa, Stankevicius, Whiteman and Simonsen. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.

AB - Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.

KW - GYY4137

KW - hydrogen sulfide

KW - potassium channels

KW - small mesenteric arteries

KW - sodium sulfide

UR - http://www.scopus.com/inward/record.url?scp=85103903141&partnerID=8YFLogxK

U2 - 10.3389/fphar.2021.613989

DO - 10.3389/fphar.2021.613989

M3 - Journal article

C2 - 33841145

AN - SCOPUS:85103903141

VL - 12

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 613989

ER -