Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

Post, Joseph; Hume, Joseph R.; Archer, Stephen L.; Weir, Ε. Kenneth

doi:10.1152/ajpcell.1992.262.4.c882

Cited by 437 publications

(323 citation statements)

References 25 publications

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“…An increase in cytosolic calcium concentration appears to be a key event in HPV (2,9,21,31). Calcium accumulation occurs by release from intracellular stores such as the sarcoplasmic reticulum or influx through voltage-dependent channels.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Tsai¹,

Wang²,

Pitcher³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C. Am J Physiol Lung Cell Mol Physiol 287: L1215-L1219, 2004. First published August 20, 2004 doi:10.1152/ ajplung.00179.2004.-Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-␣ and IL-1␤ via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-␣ and IL-1␤ mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-␣ and IL-1␤ mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application. hypoxia; pulmonary hypertension; inflammation; tumor necrosis factor HYPOXIA FREQUENTLY OCCURS in conjunction with inflammatory conditions such as the acute respiratory distress syndrome or severe pulmonary infection. In the absence of infection, an inflammatory response may occur following acute injuries such as ischemia-reperfusion and hypoxia (4, 17). Although much data exist regarding the systemic release of proinflammatory cytokines following acute injury, little is known about the local tissue production of inflammatory cytokines. It is now known that cardiomyocytes generate an intense inflammatory response following acute ischemia-reperfusion injury (14), and these inflammatory mediators contribute to myocardial dysfunction. Therefore, it is possible that hypoxia may stimulate inflammatory cytokine expression from the pulmonary artery (PA) tissue itself.The signaling pathways involved in generating an acute inflammatory response involve mediators such as protein kinase C (PKC). PKC is a regulatory enzyme activated by numerous effectors, growth factors, hormones, and ne...

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Section: Discussionmentioning

confidence: 99%

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Tsai¹,

Wang²,

Pitcher³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The accessory β-subunits are members of the aldose reductase superfamily of NADPH oxidoreductases, providing a surface interaction with several proteins, including protein kinases and phosphatases. Like α-subunits, each β-subunit has splice variants, contributing to tissue heterogeneity [10].…”

Section: Potassium Channels In Regulation Of Cell Proliferation and Cmentioning

confidence: 99%

Potassium channels in pulmonary arterial hypertension

et al. 2015

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Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with various origins. All forms of PAH share a common pulmonary arteriopathy characterised by vasoconstriction, remodelling of the pre-capillary pulmonary vessel wall, and in situ thrombosis. Although the pathogenesis of PAH is recognised as a complex and multifactorial process, there is growing evidence that potassium channels dysfunction in pulmonary artery smooth muscle cells is a hallmark of PAH. Besides regulating many physiological functions, reduced potassium channels expression and/or activity have significant effects on PAH establishment and progression. This review describes the molecular mechanisms and physiological consequences of potassium channel modulation. Special emphasis is placed on KCNA5 (Kv1.5) and KCNK3 (TASK1), which are considered to play a central role in determining pulmonary vascular tone and may represent attractive therapeutic targets in the treatment of PAH. @ERSpublications Comprehensive overview of the roles of potassium channels in the pathogenesis of pulmonary arterial hypertension

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“…In both cell types the hypoxic transduction cascade involves inhibition of O 2 -sensitive K + channels, activation of voltage operated Ca 2+ channels, and generation of Ca 2+ -dependent responses (López-Barneo et al, 1988;Post et al, 1992;Gonzalez et al, 2002). In CB chemoreceptor cells, final output of the hypoxic transduction cascade is the Ca 2+ -dependent release of neurotransmitters, and the magnitude of neurotransmitter release response is proportional to the intensity of hypoxia Montoro et al, 1996;Vicario et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

Gomez-Niño

Agapito

Obeso

et al. 2009

Respiratory Physiology & Neurobiology

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a b s t r a c tLow oxygen sensing in chemoreceptor cells involves the inhibition of specific plasma membrane K + channels, suggesting that mitochondria-derived reactive oxygen species (ROS) link hypoxia to K + channel inhibition, subsequent cell depolarization and activation of neurotransmitter release. We have used several mitochondrial poisons, alone and in combination with the antioxidant N-acetylcysteine (NAC), and quantify their capacity to alter GSH/GSSG levels and glutathione redox potential (E GSH ) in rat diaphragm. Selected concentrations of mitochondrial poisons with or without NAC were tested for their capacity to activate neurotransmitter release in chemoreceptor cells and to alter ATP levels in intact rat carotid body (CB). We found that rotenone (1 M), antimycin A (0.2 g/ml) and sodium azide (5 mM) decreased E GSH ; NAC restored E GSH to control values. At those concentrations mitochondrial poisons activated neurotransmitter release from CB chemoreceptor cells and decreased CB ATP levels, NAC being ineffective to modify these responses. Additional experiments with 3-nitroprionate (5 mM), lower concentrations of rotenone and dinitrophenol revealed variable relationships between E GSH and chemoreceptor cell neurotransmitter release responses and ATP levels. These findings indicate a lack of correlation between mitochondrialgenerated modifications of E GSH and chemoreceptor cells activity. This lack of correlation renders unlikely that alteration of mitochondrial production of ROS is the physiological pathway chemoreceptor cells use to signal hypoxia.

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Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

Cited by 437 publications

References 25 publications

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Potassium channels in pulmonary arterial hypertension

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

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