Relationship between membrane potential, delayed rectifier K+ currents and hypoxia in rat pulmonary arterial myocytes

Turner, JL; Kozlowski, Roland Z.

doi:10.1113/expphysiol.1997.sp004052

Cited by 36 publications

(39 citation statements)

References 38 publications

(54 reference statements)

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“…A lack of the role of extracellular Ca 2þ removal in H 2 O 2 -induced contraction in pulmonary arteries also was observed by other investigators (63,80). Further studies are needed to resolve the reported inconsistent findings and to demonstrate further the role of K V channel inhibition in ROS-dependent, hypoxic Ca 2þ and contractile responses in PASMCs (78,86,90,100).…”

Section: Ros-dependent Hypoxic Increases In [Camentioning

confidence: 81%

ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

Wang

Zheng

2010

Antioxidants & Redox Signaling

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Hypoxic exposure causes pulmonary vasoconstriction, which serves as a critical physiologic process that ensures regional alveolar ventilation and pulmonary perfusion in the lungs, but may become an essential pathologic factor leading to pulmonary hypertension. Although the molecular mechanisms underlying hypoxic pulmonary vasoconstriction and associated pulmonary hypertension are uncertain, increasing evidence indicates that hypoxia can result in a significant increase in intracellular reactive oxygen species concentration ([ROS] i ) through the mitochondrial electron-transport chain in pulmonary artery smooth muscle cells (PASMCs). The increased mitochondrial ROS subsequently activate protein kinase C-e (PKCe) and NADPH oxidase (Nox), providing positive mechanisms that further increase [ROS]

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Section: Ros-dependent Hypoxic Increases In [Camentioning

confidence: 81%

ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

Wang

Zheng

2010

Antioxidants & Redox Signaling

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“…Previous studies reported that whole cell I (K(V) appears as a rapidly activating and slowly decaying delayed rectifier with no transient component in freshly isolated rat PASMCs (35,43,45,50). The current is only slightly attenuated by 3-10 mM TEA (35,43,45) but markedly blocked by 4-AP (18,43,45,58).…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of voltage-gated K⁺ channels in mouse pulmonary artery smooth muscle cells

Ko¹,

Burg²,

Platoshyn³

et al. 2007

American Journal of Physiology-Cell Physiology

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June 20, 2007; doi:10.1152/ajpcell.00101.2007.-Mice are useful animal models to study pathogenic mechanisms involved in pulmonary vascular disease. Altered expression and function of voltage-gated K ϩ (KV) channels in pulmonary artery smooth muscle cells (PASMCs) have been implicated in the development of pulmonary arterial hypertension. KV currents (IK(V)) in mouse PASMCs have not been comprehensively characterized. The main focus of this study was to determine the biophysical and pharmacological properties of IK(V) in freshly dissociated mouse PASMCs with the patch-clamp technique. Three distinct whole cell IK(V) were identified based on the kinetics of activation and inactivation: rapidly activating and noninactivating currents (in 58% of the cells tested), rapidly activating and slowly inactivating currents (23%), and slowly activating and noninactivating currents (17%). Of the cells that demonstrated the rapidly activating noninactivating current, 69% showed IK(V) inhibition with 4-aminopyridine (4-AP), while 31% were unaffected. Whole cell IK(V) were very sensitive to tetraethylammonium (TEA), as 1 mM TEA decreased the current amplitude by 32% while it took 10 mM 4-AP to decrease I K(V) by a similar amount (37%). Contribution of Ca 2ϩ -activated K ϩ (KCa) channels to whole cell IK(V) was minimal, as neither pharmacological inhibition with charybdotoxin or iberiotoxin nor perfusion with Ca 2ϩ -free solution had an effect on the whole cell I K(V). Steady-state activation and inactivation curves revealed a window K ϩ current between Ϫ40 and Ϫ10 mV with a peak at Ϫ31.5 mV. Single-channel recordings revealed large-, intermediate-, and smallamplitude currents, with an averaged slope conductance of 119.4 Ϯ 2.7, 79.8 Ϯ 2.8, 46.0 Ϯ 2.2, and 23.6 Ϯ 0.6 pS, respectively. These studies provide detailed electrophysiological and pharmacological profiles of the native K V currents in mouse PASMCs.

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“…Currently, the most widely held hypothesis is that this Ca 2ϩ entry is mediated via voltage-dependent L-type channels, as a result of hypoxia-induced inhibition of K ϩ channels and consequent depolarization (1,23,46). The evidence underlying this hypothesis is convincing, as many studies have reported that L-type channel blockers suppress HPV and/or the rise in [Ca 2ϩ ] i (7,17,19,32,37,39), and hypoxia has been shown to inhibit K ϩ channels and cause depolarization in both pulmonary artery and PASM cells (2,14,(23)(24)(25)49).However, the K ϩ channel hypothesis is not unassailable, as some reports have shown either no or only partial block of HPV with L-type channel blockers (8,9,30,31), and others have suggested that hypoxia causes insufficient depolarization to activate L-type channels in the absence of some form of priming stimulus (24,33,38). In particular, Robertson et al (30) showed that both the elevation in [Ca 2ϩ ] i and HPV in small intrapulmonary arteries (IPA) were unaffected by simultaneous L-type channel blockade and depolarization with 80 mM K ϩ and suggested that hypoxia activates a voltage-independent Ca 2ϩ entry pathway through unidentified nonselective cation channels (NSCC) (30).…”

mentioning

confidence: 93%

Capacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?

Ward¹,

Robertson²,

Aaronson³

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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IT IS KNOWN THAT hypoxic pulmonary vasoconstriction (HPV) requires an elevation in cytosolic [Ca 2ϩ ] ([Ca 2ϩ ] i ) of pulmonary arterial smooth muscle (PASM), and numerous studies in both isolated PASM cells and arteries have shown that physiological hypoxia elicits a sustained increase in [Ca 2ϩ ] i , sometimes preceded by a transient rise (2, 6, 28 -30, 32, 39, 47). There is strong evidence that this involves Ca 2ϩ entry across the cell membrane, as removal of extracellular Ca 2ϩ or blockade of Ca 2ϩ entry tends to abolish HPV and at least the sustained elevation in [Ca 2ϩ ] i (6,17,19,30,32,39). Currently, the most widely held hypothesis is that this Ca 2ϩ entry is mediated via voltage-dependent L-type channels, as a result of hypoxia-induced inhibition of K ϩ channels and consequent depolarization (1,23,46). The evidence underlying this hypothesis is convincing, as many studies have reported that L-type channel blockers suppress HPV and/or the rise in [Ca 2ϩ ] i (7,17,19,32,37,39), and hypoxia has been shown to inhibit K ϩ channels and cause depolarization in both pulmonary artery and PASM cells (2,14,(23)(24)(25)49).However, the K ϩ channel hypothesis is not unassailable, as some reports have shown either no or only partial block of HPV with L-type channel blockers (8,9,30,31), and others have suggested that hypoxia causes insufficient depolarization to activate L-type channels in the absence of some form of priming stimulus (24,33,38). In particular, Robertson et al. (30) showed that both the elevation in [Ca 2ϩ ] i and HPV in small intrapulmonary arteries (IPA) were unaffected by simultaneous L-type channel blockade and depolarization with 80 mM K ϩ and suggested that hypoxia activates a voltage-independent Ca 2ϩ entry pathway through unidentified nonselective cation channels (NSCC) (30).There is now a significant body of work suggesting that hypoxia-induced Ca 2ϩ release from intracellular stores is an early and essential requirement for HPV (11,16,20,32,47). Store release activates store-operated channels (SOC) and capacitative Ca 2ϩ entry (CCE) in many cell types (27), including PASM (18,30,34,40,48). Interestingly, CCE seems to have an unusually prominent role in distal IPA, since activation of CCE elicits vasoconstriction in distal IPA, but not in small systemic arteries (34). These factors all support the suggestion that CCE might contribute to the elevation in PASM [Ca 2ϩ ] i during hypoxia (30, 43), and indeed in two recent papers hypoxia has been shown to activate CCE as a consequence of store release and thus elevate [Ca 2ϩ ] i in freshly isolated (22) and cultured PASM cells (41). Nevertheless, changes in [Ca 2ϩ ] i are not necessarily associated with vasoconstriction (e.g., Ref. 34), and these reports on their own cannot conclusively prove a physiological role for CCE in HPV. The decisive study by Weigand et al., the current article in focus (Ref. 45, see p. L5 in this issue), extends their previous work (41) to examine the role of CCE and NSCC in HPV of isolated perfused lungs of rats. The...

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Relationship between membrane potential, delayed rectifier K+ currents and hypoxia in rat pulmonary arterial myocytes

Cited by 36 publications

References 38 publications

ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

Functional characterization of voltage-gated K⁺ channels in mouse pulmonary artery smooth muscle cells

Capacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?

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Relationship between membrane potential, delayed rectifier K+ currents and hypoxia in rat pulmonary arterial myocytes

Cited by 36 publications

References 38 publications

ROS-Dependent Signaling Mechanisms for Hypoxic Ca2+Responses in Pulmonary Artery Myocytes

ROS-Dependent Signaling Mechanisms for Hypoxic Ca2+Responses in Pulmonary Artery Myocytes

Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells

Capacitative calcium entry: a central role in hypoxic pulmonary vasoconstriction?

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ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

ROS-Dependent Signaling Mechanisms for Hypoxic Ca²⁺Responses in Pulmonary Artery Myocytes

Functional characterization of voltage-gated K⁺ channels in mouse pulmonary artery smooth muscle cells