Article

The Role of Ion Channels in Hypoxic Pulmonary Vasoconstriction

VA Medical Center, 1 Veterans Drive, 111C, Minneapolis, MN, 55417, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.83). 01/2010; 661:3-14. DOI: 10.1007/978-1-60761-500-2_1
Source: PubMed

ABSTRACT Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which localized flow of blood in small resistance pulmonary arteries is matched to alveolar ventilation. This chapter discusses the role of several potassium and calcium channels in HPV, both in enhancing calcium influx into smooth muscle cells (SMCs) and in stimulating the release of calcium from the sarcoplasmic reticulum, thus increasing cytosolic calcium. The increase in calcium sensitivity caused by hypoxia is reviewed in Chapter 19. Particular attention is paid to the activity of the L-type calcium channels which increase calcium influx as a result of membrane depolarization and also increase calcium influx at any given membrane potential in response to hypoxia. In addition, activation of the L-type calcium channel may, in the absence of any calcium influx, cause calcium release from the sarcoplasmic reticulum. Many of these mechanisms have been reported to be involved in both HPV and in normoxic contraction of the ductus arteriosus.

0 Followers
 · 
90 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21 % FiO(2)) or chronic hypoxia (10 % FiO(2)) for three weeks. 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). 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. 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.
    Beiträge zur Klinik der Tuberkulose 08/2014; 192(5). DOI:10.1007/s00408-014-9633-2 · 2.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, profound structural remodeling of vasculatures and alterations in Ca(2+) homeostasis in arterial smooth muscle cells (SMCs), while the underlying mechanisms are still elusive. By regulating the expression of proteins, microRNAs (miRNAs) are known to play an important role in cell fates including differentiation, apoptosis and proliferation, and may be involved in the development of PAH. Based on our previous study, hypoxia produced a significant increase of the miR-190 level in the pulmonary artery (PA), here, we used synthetic miR-190 to mimic the increase in hypoxic conditions and showed evidence for the effects of miR-190 on pulmonary arterial vasoconstriction and Ca(2+) influx in arterial SMCs. Synthetic miR-190 remarkably enhanced the vasoconstriction responses to phenylephrine (PE) and KCl. The voltage-gated K(+) channel subfamily member, Kcnq5, mRNA was shown to be a target for miR-190. Meanwhile, miR-190 antisense oligos can partially reverse the effects of miR-190 on PASMCs and PAs. Therefore, these results suggest that miR-190 appears to be a positive regulator of Ca(2+) influx, and play an important role in hypoxic pulmonary vascular constriction. J. Cell. Biochem. 9999: XX-XX, 2014. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 06/2014; 115(6). DOI:10.1002/jcb.24771 · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Significance: An acute lack of oxygen in the lung causes hypoxic pulmonary vasoconstriction, which optimizes gas exchange. In contrast, chronic hypoxia triggers a pathological vascular remodeling causing pulmonary hypertension, and ischemia can cause vascular damage culminating in lung edema. Recent advances: Regulation of ion channel expression and gating by cellular redox state is a widely accepted mechanism; however, it remains a matter of debate whether an increase or a decrease in reactive oxygen species (ROS) occurs under hypoxic conditions. Ion channel redox regulation has been described in detail for some ion channels, such as Kv channels or TRPC6. However, in general information on ion channel redox regulation remains scant. Critical issues and future directions: In addition to the debate of increased vs. decreased ROS production during hypoxia, we aim here to describe and decipher why different oxidants, under different conditions can cause both, activation and inhibition of channel activity. While the upstream pathways affecting channel gating are often well described, we need a better understanding of redox protein modifications in order to be able to determine the complexity of ion channel redox regulation. Against this background we summarize the current knowledge on hypoxia-induced ROS-mediated ion channel signaling in the pulmonary circulation.
    Antioxidants and Redox Signaling 12/2014; DOI:10.1089/ars.2014.6234 · 7.67 Impact Factor

Preview

Download
0 Downloads
Available from