Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BK channels

Dubuis, Eric; Potier, Marie Claude; Wang, Rui; Vandier, Christophe

doi:10.1016/j.cardiores.2004.11.007

Cited by 65 publications

(42 citation statements)

References 58 publications

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“…BK Ca channels, with seven transmembrane domains and a calcium-binding region (bowl), are somewhat structurally unique, even within the K Ca family [17,18] . They are expressed widely in smooth muscle cells and play an important role in regulating vascular tone, which is activated by both membrane depolarization and intracellular calcium [19][20][21] .…”

Section: Discussionmentioning

confidence: 99%

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

et al. 2015

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altitude diseases that are associated with significant morbidity and mortality, such as high-altitude pulmonary edema and heart diseases [3] . Echinacoside (ECH) (Figure 1) is a phenylethanoid glycoside found in a variety of Chinese herbs such as the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa [4,5] . Lagotis brevituba Maxim is a species of Lagotis spp belonging to the Scrophulariaceae and grows widely at an altitude over 3000 meter in the Qinghai-Tibet Plateau. ECH has various desirable pharmacological characteristics, such as antioxidative, anti-inflammatory, neuroprotective, hepatoprotective, and nitric oxide (NO) radical-scavenging properties [6] . It can also elicit endothelium-dependent relaxation in rat thoracic aortic rings and cure cardiovascular diseases [7] . HowEchinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BK Ca channels and reducing intracellular Ca 2+ levels Aim: Sustained pulmonary vasoconstriction as experienced at high altitude can lead to pulmonary hypertension (PH). The main purpose of this study is to investigate the vasorelaxant effect of echinacoside (ECH), a phenylethanoid glycoside from the Tibetan herb Lagotis brevituba Maxim and Cistanche tubulosa, on the pulmonary artery and its potential mechanism. Methods: Pulmonary arterial rings obtained from male Wistar rats were suspended in organ chambers filled with Krebs-Henseleit solution, and isometric tension was measured using a force transducer. Intracellular Ca 2+ levels were measured in cultured rat pulmonary arterial smooth muscle cells (PASMCs) using Fluo 4-AM. Results: ECH (30-300 μmol/L) relaxed rat pulmonary arteries precontracted by noradrenaline (NE) in a concentration-dependent manner, and this effect could be observed in both intact endothelium and endothelium-denuded rings, but with a significantly lower maximum response and a higher EC 50 in endothelium-denuded rings. This effect was significantly blocked by L-NAME, TEA, and BaCl 2 . However, IMT, 4-AP, and Gli did not inhibit ECH-induced relaxation. Under extracellular Ca 2+ -free conditions, the maximum contraction was reduced to 24.54%±2.97% and 10.60%±2.07% in rings treated with 100 and 300 μmol/L of ECH, respectively. Under extracellular calcium influx conditions, the maximum contraction was reduced to 112.42%±7.30%, 100.29%±8.66%, and 74.74%±4.95% in rings treated with 30, 100, and 300 μmol/L of ECH, respectively. After cells were loaded with Fluo 4-AM, the mean fluorescence intensity was lower in cells treated with ECH (100 μmol/L) than with NE. Conclusion: ECH suppresses NE-induced contraction of rat pulmonary artery via reducing intracellular Ca 2+ levels, and induces its relaxation through the NO-cGMP pathway and opening of K + channels (BK Ca and K IR ).

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Section: Discussionmentioning

confidence: 99%

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

et al. 2015

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“…However, the results of the experiments using HMOX-2 null mice show that other hypoxia sensing mechanisms exist (38). Although the exact role of modulation of Slo1 BK channels by CO in acute oxygen sensing remains uncertain (38), it is clear that CO does activate Slo1 BK channels and contributes to many other physiological processes, including vasodilation (9,11,(13)(14)(15). The ability of the Slo1 BK channel to directly respond to CO at physiological voltages at low to moderate [Ca 2ϩ ] i via the high-affinity RCK1 Ca 2ϩ sensor further illustrates the channel's remarkable modulatory repertoire.…”

Section: Discussionmentioning

confidence: 99%

“…The modulation of Slo1 BK channels by CO is physiologically and pathophysiologically important. For example, the stimulatory effect of CO on Slo1 BK channels underlies its well documented vasodilatory effect (9,11,(13)(14)(15), and the use of CO has been suggested as a potential therapeutic strategy against pulmonary hypertension (11). Production of CO by HMOXs requires oxygen (1), and this oxygen dependence raises the possibility that changes in cellular oxygen tension regulate the Slo1 BK channel activity indirectly by regulating the availability of CO (16).…”

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confidence: 99%

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The RCK1 high-affinity Ca ²⁺ sensor confers carbon monoxide sensitivity to Slo1 BK channels

Hou

Heinemann

et al. 2008

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

105

126

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Carbon monoxide (CO) is a lethal gas, but it is also increasingly recognized as a physiological signaling molecule capable of regulating a variety of proteins. Among them, large-conductance Ca 2؉ -and voltage-gated K ؉ (Slo1 BK) channels, important in vasodilation and neuronal firing, have been suggested to be directly stimulated by CO. However, the molecular mechanism of the stimulatory action of CO on the Slo1 BK channel has not been clearly elucidated. We report here that CO reliably and repeatedly activates Slo1 BK channels in excised membrane patches in the absence of Ca 2؉ in a voltage-sensor-independent manner. The stimulatory action of CO on the Slo1 BK channel requires an aspartic acid and two histidine residues located in the cytoplasmic RCK1 domain, and the effect persists under the conditions known to inhibit the conventional interaction between CO and heme in other proteins. We propose that CO acts as a partial agonist for the high-affinity divalent cation sensor in the RCK1 domain of the Slo1 BK channel.C arbon monoxide (CO) is a deadly poisonous gas. However, CO is physiologically produced during the course of heme catabolism by heme oxygenases (HMOXs) in an oxygendependent manner, and it is increasingly recognized as a biological signaling molecule important in numerous physiological and pathophysiological processes, including synaptic plasticity, regulation of vascular tone, and tumor proliferation (1). To regulate the wide array of cellular functions, CO typically exerts its action by binding to the reduced heme iron center (Fe 2ϩ ) in hemoproteins (2, 3), thereby altering the way the heme prosthetic group is coordinated (4). The heme-dependent action of CO is exemplified by its stimulatory effect on soluble guanylate cyclase, in which binding of CO to the reduced heme iron center increases the catalytic activity, leading to an enhanced production of cGMP (4, 5).Large-conductance Ca 2ϩ -and voltage-activated K ϩ (Slo1 BK or K Ca 1.1) channels, important in many physiological phenomena, including oxygen sensing, vasodilation, and neuronal firing (6, 7), are also stimulated by . The modulation of Slo1 BK channels by CO is physiologically and pathophysiologically important. For example, the stimulatory effect of CO on Slo1 BK channels underlies its well documented vasodilatory effect (9,11,(13)(14)(15), and the use of CO has been suggested as a potential therapeutic strategy against pulmonary hypertension (11). Production of CO by HMOXs requires oxygen (1), and this oxygen dependence raises the possibility that changes in cellular oxygen tension regulate the Slo1 BK channel activity indirectly by regulating the availability of CO (16). HMOX-2, one member of the HMOX family, may colocalize with Slo1 to allow efficient modulation of the channel by CO according to the local oxygen level (16).Gating of the Slo1 BK channel involves allosteric interactions among the main pore gate, voltage sensor domains, and cytoplasmic RCK1 and RCK2 domains with multiple divalent cation sensors (17,18). Although incre...

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“…Why the expression of ␣-subunit is increased in cirrhotic rats remains to be clarified. Dubuis et al (2002Dubuis et al ( , 2005 and Wu and Wang (2005) have hypothesized that the expression of BK Ca channels may be induced by high CO levels, a condition that might be present in the mesenteric circulation of cirrhotic rats. In conclusion, an overexpression of BK Ca ␣-subunits, together with HO-1 upregulation and increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.…”

Section: Mesenteric Vasodilatation In Cirrhosis 193mentioning

confidence: 99%

Carbon Monoxide-Mediated Activation of Large-Conductance Calcium-Activated Potassium Channels Contributes to Mesenteric Vasodilatation in Cirrhotic Rats

Bolognesi

Sacerdoti²,

Piva³

et al. 2007

J Pharmacol Exp Ther

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Large-conductance calcium-activated potassium channels (BK Ca s) are important regulators of arterial tone and represent a mediator of the endogenous vasodilator carbon monoxide (CO). Because an up-regulation of the heme oxygenase (HO)/CO system has been associated with mesenteric vasodilatation of cirrhosis, we analyzed the interactions of BK Ca and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170 -350 m) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BK Ca , HO, and guanylylcyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BK Ca subunit protein expression. Inhibition of HO and of BK Ca reduced acetylcholine-induced vasodilatation more in cirrhotic rats than in control rats, whereas inhibition of guanylyl-cyclase had a similar effect in the two groups. CO was more effective in cirrhotic rats than in control rats, and the effect was hindered by BK Ca inhibition. The expression of HO-1 and of BK Ca ␣-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BK Ca ␤1-subunit was lower. In conclusion, an overexpression of BK Ca ␣-subunits, possibly due to HO up-regulation with increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.Mesenteric arterial vasodilation is a key mechanism in the pathophysiology of the hyperdynamic circulatory syndrome of cirrhosis. This syndrome is responsible for serious complications, such as ascites, hepatorenal syndrome, and gastrointestinal hemorrhage. The pathophysiological mechanism that supports the vasodilation of mesenteric arteries in cirrhosis is a decrease in the response of the arteries to vasoconstricting agents (Sieber et al., 1993), caused by an increase in vasodilating substances of endothelial origin, such as nitric oxide (NO), prostacyclin, and, as recently demonstrated, carbon monoxide (CO) (Wiest and Groszmann, 1999;Fernandez et al., 2001;Gonzales-Abraldes et al., 2002).We have recently shown that an increased action of the heme oxygenase (HO)/CO system plays a role in the hyporesponsiveness of small resistance mesenteric arteries to phenylephrine (PE) only in the advanced stage of experimental cirrhosis (Bolognesi et al., 2005). Therefore, the increased activity of the HO/CO system may participate in the evolution of cirrhosis from compensated to decompensated.HO is a microsomal enzyme with two main distinct isoforms: the inducible isoenzyme HO-1 and the constitutive one HO-2 (Zhang et al., 2001;Johnson et al., 2003a). It is the rate-limiting enzyme in the degradation of heme to biliverdin, CO, and free iron (Motterlini et al., 1998). CO, generated by HO in endothelial and smooth muscle layers of arterial vessels, modulates vascular tone by inducing relaxation of vascular smooth muscle cells through stimulation on soluble guanylyl cyclase (sGC) and ope...

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Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BK channels

Cited by 65 publications

References 58 publications

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

The RCK1 high-affinity Ca ²⁺ sensor confers carbon monoxide sensitivity to Slo1 BK channels

Carbon Monoxide-Mediated Activation of Large-Conductance Calcium-Activated Potassium Channels Contributes to Mesenteric Vasodilatation in Cirrhotic Rats

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Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BK channels

Cited by 65 publications

References 58 publications

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular Ca2+ levels

The RCK1 high-affinity Ca 2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels

Carbon Monoxide-Mediated Activation of Large-Conductance Calcium-Activated Potassium Channels Contributes to Mesenteric Vasodilatation in Cirrhotic Rats

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The RCK1 high-affinity Ca ²⁺ sensor confers carbon monoxide sensitivity to Slo1 BK channels