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NO synthase inhibition attenuates EDHF-mediated relaxation induced by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery: Role of TxA2

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Abstract

Background

The aim of the present study was to observe the concomitant activation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery and explore the mechanism by which NO synthase inhibition attenuates EDHF-mediated relaxation in endothelium-intact rat pulmonary artery.

Methods

Tension experiments were conducted on the pulmonary artery from male Wistar rats.

Results

TRPV4 channel agonist GSK1016790A (GSK) caused concentration-dependent relaxation (Emax 86.9 ± 4.6%; pD2 8.7 ± 0.24) of the endothelium-intact rat pulmonary artery. Combined presence of apamin and TRAM-34 significantly attenuated the relaxation (Emax 61.1 ± 6.0%) to GSK. l-NAME (100 μM) significantly attenuated (8.2 ± 2.9%) the relaxation response to GSK that was resistant to apamin plus TRAM-34. However, presence of ICI192605 or furegrelate alongwith l-NAME revealed the GSK-mediated EDHF-response (Emax of 28.5 ± 5.2%; Emax 24.5 ± 4.3%) in this vessel, respectively. Further, these two TxA2 modulators (ICI/furegrelate) alongwith l-NAME had no effect on SNP-induced endothelium-independent relaxation in comparison to l-NAME alone. This EDHF-mediated relaxation was sensitive to inhibition by K+ channel blockers apamin and TRAM-34 or 60 mM K+ depolarizing solution. Further, combined presence of apamin and TRAM-34 in U46619 pre-contracted pulmonary arterial rings significantly reduced the maximal relaxation (Emax 71.6 ± 6.9%) elicited by GSK, but had no effect on the pD2 (8.1 ± 0.03) of the TRPV4 channel agonist in comparison to controls (Emax, 92.4 ± 4.3% and pD2, 8.3 ± 0.06).

Conclusion

The present study suggests that NO and EDHF are released concomitantly and NO synthase inhibition attenuates GSK-induced EDHF response through thromboxane pathway in the rat pulmonary artery.

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Abbreviations

ACh:

acetylcholine

ANOVA:

analysis of variance

EDHF:

endothelium-derived hyperpolarizing factor

GSK:

GSK1016790A

ICI192605:

[4-(Z)-6-(2-0-chlrophenyl-4-Ohydroxyphenyl-1,3-dioxan-cis5-yl) hexenoic acid]

IKCa (KCa 3.1):

intermediate conductance potassium channel

l-NAME:

NG-nitro-l-arginine methyl ester

MKHS:

modified Krebs-Henseleit solution

NO:

nitric oxide

NOS:

nitric oxide synthase

PE:

phenylephrine

PKG:

protein kinase G

SKCa (KCa 2.3):

small conductance potassium channel

SNP:

sodium nitroprusside

TRAM-34:

1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole

TRPV4:

transient receptor potential vanilloid 4

TP:

thromboxane/prostanoid receptor

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Authors and Affiliations

  1. Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, India

    M. Pule Addison, Thakur Uttam Singh, Subhashree Parida, Soumen Choudhury, Jaya Kiran Kasa, Susanth V. Sukumaran, Sajad Ahmad Darzi, Kannan Kandasamy, Vishakha Singh, Dinesh Kumar & Santosh Kumar Mishra

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  1. M. Pule Addison
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  2. Thakur Uttam Singh
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  3. Subhashree Parida
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Correspondence to Thakur Uttam Singh.

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Addison, M.P., Singh, T.U., Parida, S. et al. NO synthase inhibition attenuates EDHF-mediated relaxation induced by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery: Role of TxA2. Pharmacol. Rep 68, 620–626 (2016). https://doi.org/10.1016/j.pharep.2016.01.003

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  • DOI: https://doi.org/10.1016/j.pharep.2016.01.003

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