Role of a Novel K<sub>Ca</sub> Opener in Regulating K<sup>+</sup> Channels of Hypoxic Human Pulmonary Vascular Cells

Peng, Wei; Hoidal, John R.; Farrukh, I. S.

doi:10.1165/ajrcmb.20.4.3390

Cited by 50 publications

(35 citation statements)

References 17 publications

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“…In contrast, it has been shown that acute hypoxia could inhibit canine and fetal ovine PASMC K Ca channels (11,36). In addition, chronic hypoxia decreased CTX-sensitive K Ca channels in human PASMC (32). In our murine model, perinatal exposure to hypoxia results in increased BK Ca channel activity and protein content in adults.…”

Section: Discussionmentioning

confidence: 56%

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Marino¹,

Bény²,

Peyter³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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August 24, 2007; doi:10.1152/ajplung.00126.2007.-Adverse events during the perinatal period, like hypoxia, have been associated with adult diseases. In pulmonary vessels, K ϩ channels play an important role in the regulation of vascular tone. In the fetus, Ca 2ϩ -activated K ϩ channels (K Ca) are predominant, whereas from birth voltage-gated K ϩ channels (K V) prevail in the adult. We postulated that perinatal hypoxia could alter this maturational shift and influence regulation of pulmonary vascular tone in relation to K ϩ channels in adulthood. We evaluated the effects of perinatal hypoxia on KV and KCa channels in the adult main pulmonary artery (PA) using a murine model. Electrophysiological measurements showed a greater outward current in PA smooth muscle cells of mice born in hypoxia than in controls. In controls, only KV channels contributed to this current, whereas in mice born in hypoxia both KV and KCa channels were implicated. KV channel activity was even higher in mice born in hypoxia than in controls. Therefore, perinatal hypoxia results in increased KCa and KV channel activity in adult PA. Moreover, PA of adults born in hypoxia displayed higher large-conductance KCa ␣-subunit and KV1.5 ␣-subunit protein expression than controls. Interestingly, relaxation induced by nitric oxide (NO) donors [S-nitroso-N-acetyl-D,L-penicillamine, 2-(N,N-diethylamino)-diazenolate-2-oxide] in isolated PA of control mice was not mediated by KCa channels and only slightly by KV channels, whereas following perinatal hypoxia both KCa and KV channels contributed to this relaxation. Thus perinatal hypoxia results in altered expression and activity of different K ϩ channels in the adult main PA, which could contribute to modifications of pulmonary vasoreactivity.mouse; potassium ion channel activity; potassium ion channel blockers; nitric oxide donors ADVERSE EVENTS IN THE PERINATAL period may predispose to pathological responses later in life. In utero growth restriction and perinatal hypoxia have been involved in the development of adult diseases such as coronary artery disease, systemic hypertension, stroke, and non-insulin-dependent diabetes mellitus (4,5,12).Several lines of evidence indicate that chronic pulmonary vascular diseases and altered pulmonary vascular reactivity in adulthood may be associated with a perinatal hypoxic insult (13,15,20,31,42,44). Human and animal studies showed that individuals having suffered from a transient hypoxic insult in utero and/or soon after birth displayed exaggerated pulmonary vasoconstrictive responses when reexposed to hypoxia later in life (9, 14 -18, 42, 45). The mechanisms underlying the exaggerated pulmonary vasoconstrictor responsiveness and the resulting altered lung circulation in adulthood following a perinatal hypoxic event have not been elucidated so far.

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Section: Discussionmentioning

confidence: 56%

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Marino¹,

Bény²,

Peyter³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This leads to a deep change in the PA properties, and PA from CH rats do not respond to further acute hypoxic stress. DHEA has been characterized by Peng et al (13) as a BK Ca channel opener at 100 M. IPA rings from CH-DHEA animal develop higher reactivity to IbTx, which blocks K Ca as compared with CH rats, suggesting an involvement of the BK Ca in the control of IPA basal tone from CH-DHEA rats. Furthermore, in smooth muscle cells from CH-PHT rats, acute exposure to DHEA induced a decrease of the resting [Ca 2ϩ ] i that is blocked by IbTx.…”

Section: Discussionmentioning

confidence: 99%

“…We sought to enhance expression and function of BK Ca by using DHEA, a BK Ca opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BK Ca and Kv activation and thus repolarization of the PASMCs membrane potential and its effects on the [Ca 2ϩ ] i. In vivo PA pressure (PAP) as well as right ventricular (RV) wall thickness were measured in closed-chest rats undergoing CH.…”

mentioning

confidence: 99%

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Bonnet

Roque

Bégueret

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

127

121

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Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg͞kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca 2؉ -activated potassium channel (BK Ca)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.hypoxia ͉ potassium channels E xposure of animals to chronic hypoxia leads to the development of chronic hypoxic-pulmonary hypertension (CH-PHT). In human beings CH-PHT is frequently associated with severe pulmonary diseases. CH-PHT involve pulmonary arterial vasoconstriction and remodeling (1). Although the endothelium is involved in the pathogenesis of CH-PHT, the role of vascular smooth muscle cells (SMCs) is increasingly recognized (2).Both the contractile status and the proliferative status of SMCs are regulated by the levels of intracellular Ca 2ϩ ([Ca 2ϩ ] i ). The [Ca 2ϩ ] i levels are determined in part by the influx of Ca 2ϩ through the voltage-gated, L-type Ca 2ϩ channels. In pulmonary artery (PA) SMCs, the membrane potential is regulated by large conductance Ca 2ϩ -activated channels (BK Ca ) (3) and voltagegated K ϩ channels (Kv), including shaker family Kv (4, 5). K channel (BK Ca and Kv) function and expression are downregulated with development and maintenance of CH-PHT (6, 7). CH reduces K current density in PASMCs, resulting in a state of depolarization (8, 9), followed by elevation of [Ca 2ϩ ] i , which induces contraction and proliferation (10).The mechanism for K channel down-regulation is unclear, but recent work suggests that it is related to the altered redox state induced by CH (8). Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K ϩ channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxiainducible factor (HIF) (12).We sought to enhance expression and function of BK Ca by using DHEA, a BK Ca opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BK Ca and Kv activatio...

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“…(Figure 1), DHEA was hypothesized to have vasodilating properties. DHEA was found to efficiently inhibit hypoxic pulmonary vasoconstriction, at least in part by opening BK Ca channels in pulmonary VSMCs [60][61][62]. Western Blot analysis of arterial pulmonary extract showed that the BK Casubunit expression is upregulated after DHEA treatment compared to chronic hypoxia rats [63].…”

Section: Dhea Vasodilating Propertiesmentioning

confidence: 99%

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Paulin¹

2013

J Steroids Horm Sci

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Role of a Novel K_Ca Opener in Regulating K⁺ Channels of Hypoxic Human Pulmonary Vascular Cells

Cited by 50 publications

References 17 publications

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

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Role of a Novel KCa Opener in Regulating K+ Channels of Hypoxic Human Pulmonary Vascular Cells

Cited by 50 publications

References 17 publications

Perinatal hypoxia triggers alterations in K+channels of adult pulmonary artery smooth muscle cells

Perinatal hypoxia triggers alterations in K+channels of adult pulmonary artery smooth muscle cells

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

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Role of a Novel K_Ca Opener in Regulating K⁺ Channels of Hypoxic Human Pulmonary Vascular Cells

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells

Perinatal hypoxia triggers alterations in K⁺channels of adult pulmonary artery smooth muscle cells