Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

1992 ◽  
Vol 262 (4) ◽  
pp. C882-C890 ◽  
Author(s):  
J. M. Post ◽  
J. R. Hume ◽  
S. L. Archer ◽  
E. K. Weir
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
K Channel ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
K Currents

Cellular mechanisms responsible for hypoxic pulmonary vasoconstriction were investigated in pulmonary arterial cells, isolated perfused lung, and pulmonary artery rings. Three K+ channel antagonists, Leiurus quinquestriatus venom, tetraethylammonium, and 4-aminopyridine, mimicked the effects of hypoxia in isolated lung and arterial rings by increasing pulmonary artery pressure and tension and also inhibited whole cell K+ currents in isolated pulmonary arterial cells. Reduction of oxygen tension from normoxic to hypoxic levels directly inhibited K+ currents and caused membrane depolarization in isolated canine pulmonary arterial smooth muscle cells but not in canine renal arterial smooth muscle cells. Nisoldipine or high buffering of intracellular Ca2+ concentration with [1,2-bis(2)aminophenoxy] ethane-N,N,N',N'-tetraacetic acid prevented hypoxic inhibition of K+ current, suggesting that a Ca(2+)-sensitive K+ channel may be responsible for the hypoxic response. These results indicate that K+ channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by causing membrane depolarization and subsequent Ca2+ entry.

Abstract 13027: Periostin Cre-mediated Hypoxia-inducible Transfroming Growth Factor-β Receptor Deletion in Pulmonary Artery Attenuates the Progression of Pulmonary Arterial Hypertension in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mitsuru Seki ◽  
Norimichi Koitabashi ◽  
Hirokazu Arakawa ◽  
Masahiko Kurabayashi
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Right Ventricular ◽  
Muscle Cells ◽  
Wild Type ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle ◽  
Β Receptor

Introduction: Mutations in the bone morphogenetic protein type II receptor, transforming growth factor-β (TGF-β) receptor superfamily member, are responsible for heritable pulmonary arterial hypertension (PAH). Although this mutation is associated with TGF-β signal activation, the precise role of TGF-β signaling still remains uncertain in pathogenesis of PAH. Under hypoxic condition, Periostin(Pn) which usually expresses in fibroblasts protein has been shown to express on vascular smooth muscle cell. Therefore, Pn-Cre-loxP system may work as conditional inhibition in hypoxic pulmonary arterial smooth muscle cells. Methods: We established TGF-β type I receptor knockout mice specifically in periostin expressing cell (PnCre/Alk5flox model mice). A mouse model of hypoxia-induced PAH was used for this study. We evaluated right ventricular systolic pressure, function, hypertrophy, and vascular remodeling of pulmonary artery after 3 weeks of exposure to 10% of oxygen. Results: Those mice were induced proliferation of pulmonary arterial smooth muscle cells and perivascular fibrotic change, causing pulmonary hypertension. Right ventricular pressure measured by pressure catheter was significantly decreased in PnCreAlk5flox model mice compared with wild-type mice (44.8±7.8 vs 55.0±9.7mmHg, p<0.05). Right ventricular function and right ventricular weight showed no significant difference between both mice. Histological analysis revealed inhibition of medial thickening of pulmonary artery and perivascular fibrotic change in PnCreAlk5flox model mice compared with wild-type mice (% muscularization of pulmonary artery ; 52.0±14.3 vs 78.4±11.5%, p<0.05). Conclusions: These results indicate that TGF-β signaling in fibroblasts and smooth muscle cells has a critical role on pathogenesis of PAH, suggesting the usefulness of therapy by targeting TGF-β signaling.

Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 292 (6) ◽  
pp. C2297-C2305 ◽  
Author(s):  
Shen Zhang ◽  
Hui Dong ◽  
Lewis J. Rubin ◽  
Jason X.-J. Yuan
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Reverse Mode ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a trigger for pulmonary vasoconstriction and a stimulus for PASMC proliferation and migration. Multiple mechanisms are involved in regulating [Ca2+]cyt in human PASMC. The resting [Ca2+]cyt and Ca2+ entry are both increased in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH), which is believed to be a critical mechanism for sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in these patients. Here we report that protein expression of NCX1, an NCX family member of Na+/Ca2+ exchanger proteins is upregulated in PASMC from IPAH patients compared with PASMC from normal subjects and patients with other cardiopulmonary diseases. The Na+/Ca2+ exchanger operates in a forward (Ca2+ exit) and reverse (Ca2+ entry) mode. By activating the reverse mode of Na+/Ca2+ exchange, removal of extracellular Na+ caused a rapid increase in [Ca2+]cyt, which was significantly enhanced in IPAH PASMC compared with normal PASMC. Furthermore, passive depletion of intracellular Ca2+ stores using cyclopiazonic acid (10 μM) not only caused a rise in [Ca2+]cyt due to Ca2+ influx through store-operated Ca2+ channels but also mediated a rise in [Ca2+]cyt via the reverse mode of Na+/Ca2+ exchange. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange, but did not accelerate Ca2+ extrusion via the forward mode of Na+/Ca2+ exchange. These observations indicate that the upregulated NCX1 and enhanced Ca2+ entry via the reverse mode of Na+/Ca2+ exchange are an additional mechanism responsible for the elevated [Ca2+]cyt in PASMC from IPAH patients.

K+ channel inhibition, calcium signaling, and vasomotor tone in canine pulmonary artery smooth muscle

2000 ◽  
Vol 279 (2) ◽  
pp. L242-L251 ◽  
Author(s):  
Shouzaburoh Doi ◽  
Derek S. Damron ◽  
Koji Ogawa ◽  
Satoru Tanaka ◽  
Mayumi Horibe ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
K Channel ◽  
Voltage Gated ◽  
Channel Inhibition ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

We investigated the role of K+ channels in the regulation of baseline intracellular free Ca2+ concentration ([Ca2+]i), α-adrenoreceptor-mediated Ca2+ signaling, and capacitative Ca2+ entry in pulmonary artery smooth muscle cells (PASMCs). Inhibition of voltage-gated K+ channels with 4-aminopyridine (4-AP) increased the membrane potential and the resting [Ca2+]i but attenuated the amplitude and frequency of the [Ca2+]i oscillations induced by the α-agonist phenylephrine (PE). Inhibition of Ca2+-activated K+ channels (with charybdotoxin) and inhibition (with glibenclamide) or activation of ATP-sensitive K+ channels (with lemakalim) had no effect on resting [Ca2+]i or PE-induced [Ca2+]i oscillations. Thapsigargin was used to deplete sarcoplasmic reticulum Ca2+ stores in the absence of extracellular Ca2+. Under these conditions, 4-AP attenuated the peak and sustained components of capacitative Ca2+ entry, which was observed when extracellular Ca2+ was restored. Capacitative Ca2+ entry was unaffected by charybdotoxin, glibenclamide, or lemakalim. In isolated pulmonary arterial rings, 4-AP increased resting tension and caused a leftward shift in the KCl dose-response curve. In contrast, 4-AP decreased PE-induced contraction, causing a rightward shift in the PE dose-response curve. These results indicate that voltage-gated K+ channel inhibition increases resting [Ca2+]i and tone in PASMCs but attenuates the response to PE, likely via inhibition of capacitative Ca2+entry.

PDGF/MEK/ERK axis represses Ca2+ clearance via decreasing the abundance of plasma membrane Ca2+ pump PMCA4 in pulmonary arterial smooth muscle cells

2021 ◽  
Vol 320 (1) ◽  
pp. C66-C79
Author(s):  
Liyu Deng ◽  
Jidong Chen ◽  
Ting Wang ◽  
Bin Chen ◽  
Lei Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by vascular remodeling and vasoconstriction, which is associated with increased intracellular calcium ion concentration ([Ca2+]i). Platelet-derived growth factor-BB (PDGF-BB) is the most potent mitogen for pulmonary arterial smooth muscle cells (PASMCs) and is involved in vascular remodeling during PAH development. PDGF signaling has been proved to participate in maintaining Ca2+ homeostasis of PASMCs; however, the mechanism needs to be further elucidated. Here, we illuminate that the expression of plasma membrane calcium-transporting ATPase 4 (PMCA4) was downregulated in PASMCs after PDGF-BB stimulation, which could be abolished by restraining the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK). Functionally, suppression of PMCA4 attenuated the [Ca2+]i clearance in PASMCs after Ca2+ entry, promoting cell proliferation and elevating cell locomotion through mediating formation of focal adhesion. Additionally, the expression of PMCA4 was decreased in the pulmonary artery of monocrotaline (MCT)- or hypoxia-induced PAH rats. Moreover, knockdown of PMCA4 could increase the right ventricular systolic pressure (RVSP) and wall thickness (WT) of pulmonary artery in rats raised under normal conditions. Taken together, our findings demonstrate the importance of the PDGF/MEK/ERK/PMCA4 axis in intracellular Ca2+ homeostasis in PASMCs, indicating a functional role of PMCA4 in pulmonary arterial remodeling and PAH development.

scholarly journals Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells

1998 ◽  
Vol 275 (3) ◽  
pp. H887-H899 ◽  
Author(s):  
A. M. Evans ◽  
O. N. Osipenko ◽  
S. G. Haworth ◽  
A. M. Gurney
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Delayed Rectifier ◽  
Membrane Excitability ◽  
Delayed Rectifier Current ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Pulmonary Artery Smooth Muscle ◽  
Low K

The pulmonary circulation changes rapidly at birth to adapt to extrauterine life. The neonate is at high risk of developing pulmonary hypertension, a common cause being perinatal hypoxia. Smooth muscle K+ channels have been implicated in hypoxic pulmonary vasoconstriction in adults and O2-induced vasodilation in the fetus, channel inhibition being thought to promote Ca2+ influx and contraction. We investigated the K+ currents and membrane potentials of pulmonary artery myocytes during development, in normal pigs and pigs exposed for 3 days to hypoxia, either from birth or from 3 days after birth. The main finding is that cells were depolarized at birth and hyperpolarized to the adult level of −40 mV within 3 days. Hypoxia prevented the hyperpolarization when present from birth and reversed it when present from the third postnatal day. The mechanism of hyperpolarization is unclear but may involve a noninactivating, voltage-gated K+channel. It is not caused by increased Ca2+-activated or delayed rectifier current. These currents were small at birth compared with adults, declined further over the next 2 wk, and were suppressed by exposure to hypoxia from birth. Hyperpolarization could contribute to the fall in pulmonary vascular resistance at birth, whereas the low K+-current density, by enhancing membrane excitability, would contribute to the hyperreactivity of neonatal vessels. Hypoxia may hinder pulmonary artery adaptation by preventing hyperpolarization and suppressing K+ current.

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