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NS1619-Induced Vasodilation is Enhanced and Differentially Mediated in Chronically Hypoxic Lungs

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Abstract

Purpose

To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21 % FiO2) or chronic hypoxia (10 % FiO2) for three weeks.

Methods

Isolated perfused lungs were preconstricted (U46619), and dose-dependent vasodilation to NS1619 was assessed. To elucidate the mechanisms responsible, NS1619 vasodilatory responses were assessed following inhibition of large-conductance Ca2+-activated (BKCa; iberiotoxin and paxilline), L-type Ca2+ (nifedipine), K+ (tetraethylammonium), Cl− (niflumic acid), and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME).

Results

Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia; however, NO-dependent vasodilation and BKCa-mediated vasodilation, in response to NS1619, were similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-type Ca2+ and non-BKCa K+ channel was involved in the NS1619-induced vasodilation only in hypoxic lungs.

Conclusions

NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways, including stimulation of NO production, activation of BKCa channels, other TEA-sensitive K+ channels, and L-type Ca2+ channels, and could be considered as a therapeutic agent in hypoxic PH.

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Acknowledgments

This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development: Biomedical Laboratory Research and Development Service (MERIT Review Award to GC, IBX000711A). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

Conflict of interest

None.

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Authors and Affiliations

  1. Vascular Research Laboratory, Providence VA Medical Center, 830 Chalkstone Avenue, Providence, RI, 02908, USA

    Danielle J. McCullough, Alexander Vang & Gaurav Choudhary

  2. Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Danielle J. McCullough & Gaurav Choudhary

Authors
  1. Danielle J. McCullough
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  2. Alexander Vang
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  3. Gaurav Choudhary
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Correspondence to Gaurav Choudhary.

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McCullough, D.J., Vang, A. & Choudhary, G. NS1619-Induced Vasodilation is Enhanced and Differentially Mediated in Chronically Hypoxic Lungs. Lung 192, 811–817 (2014). https://doi.org/10.1007/s00408-014-9633-2

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  • DOI: https://doi.org/10.1007/s00408-014-9633-2

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