Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle.

Abstract

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCβ1 expression, BAY 60-2770 did increase sGCβ1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.

• Authors: Rodney D Britt Jr, Michael A Thompson, Ine Kuipers, Alecia Stewart, Elizabeth R Vogel, James Thu, Richard J Martin, Christina M Pabelick, Y S Prakash
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 309 Issue 6 Pg. L537-42 (Sep 15 2015) ISSN: 1522-1504 [Electronic] United States
• PMID: 26254425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
• 4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
• Benzoates
• Biphenyl Compounds
• Hydrocarbons, Fluorinated
• Pyrazoles
• Pyridines
• Receptors, Cytoplasmic and Nuclear
• Guanylate Cyclase
• Soluble Guanylyl Cyclase
• Cyclic GMP
• Oxygen

Topics

• Benzoates (pharmacology)
• Biphenyl Compounds (pharmacology)
• Bronchi (pathology)
• Calcium Signaling
• Cells, Cultured
• Cyclic GMP (metabolism)
• Drug Evaluation, Preclinical
• Guanylate Cyclase (antagonists & inhibitors, metabolism)
• Humans
• Hydrocarbons, Fluorinated (pharmacology)
• Hyperoxia (drug therapy, enzymology)
• Muscle, Smooth (drug effects, embryology, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Oxygen (physiology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• Soluble Guanylyl Cyclase
• Trachea (pathology)