Cellular mechanism underlying hydrogen sulfide induced mouse tracheal smooth muscle relaxation: Role of BKCa

doi:10.1016/j.ejphar.2014.07.004

European Journal of Pharmacology

Volume 741, 15 October 2014, Pages 55-63

https://doi.org/10.1016/j.ejphar.2014.07.004 Get rights and content

Abstract

Recent studies have suggested that hydrogen sulfide (H₂S), an important endogenous signaling gaseous molecule, participates in relaxation of smooth muscle. Nevertheless, the mechanism of this relaxation effect on respiratory system is still unclear. The present study aims to investigate the physiological function as well as cellular mechanism of H₂S in tracheal smooth muscle. Application of the H₂S donor, sodium hydrosulphide (NaHS) and the precursor of H₂S, l-cysteine (l-Cys) induced mouse tracheal smooth muscle (TSM) relaxation in an epithelium-independent manner. The relaxation of TSM induced by NaHS was abrogated by iberiotoxin (IbTX), the large conductance calcium activated potassium channel (BK_Ca) blocker. In primary cultured mouse TSM cells, NaHS remarkably increased potassium outward currents in whole-cell patch clamp, hyperpolarized TSM cells and inhibited the calcium influx. All of these effects were significantly blocked by IbTX. Consistent with the results in vitro, administration of NaHS in vivo also reduced airway hyperresponsiveness in Ovalbumin (OVA)-challenged asthmatic mice. Our present study indicates that NaHS can induce mouse TSM relaxation by activating BK_Ca. These observations reveal the physiological function of H₂S in airway, which provides a promising pharmacological target for the treatment of asthma and other respiratory diseases associated with over-contraction of TSM.

Introduction

Hydrogen sulfide (H₂S) has been known as a toxic pollutant for long until recent years when studies have successively demonstrated H₂S as an important endogenous signaling gaseous neurotransmitter (Kawabata et al., 2007, Li et al., 2005). Now H₂S is recognized as a mediator of physiological and pathological processes, but the underlying mechanisms are still unclear (Bhatia et al., 2005, Zhong et al., 2003). Mammalian cells possess two pyridoxal-5-phosphate dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ lyase (CSE) (Stipanuk and Beck, 1982, Swaroop et al., 1992), which catalyze the generation of H₂S from l-cysteine intracellularly. These tissue-specific enzymes are responsible for the majority of endogenous production of H₂S (d׳Emmanuele di Villa Bianca et al., 2009, Wang, 2002). It had been proved that CBS as well as CSE was expressed in porcine airways and H₂S could be produced when tracheal tissues were exposed to l-cysteine or 3-mercaptopyruvate in vitro (Rashid et al., 2013).

Recent investigations have showed that H₂S is involved in the function of relaxation in different smooth muscles by affecting a variety of molecular targets, mainly including ion channels (Jiang et al., 2010, Tang et al., 2010, Telezhkin et al., 2010, Zhao et al., 2001). For example, in vasculature smooth muscle cells, H₂S activates the ATP-dependent K⁺ channels which can induce hyperpolarization and vasodilatation of resistance arterioles (Cheng et al., 2004). In small arteries isolated from the rat mesentery, NaHS causes vasodilatation mediated by activation of TRPA1 channels (White et al., 2013). In human penis, it has also been suggested that the H₂S-induced corpus cavernosum smooth muscle relaxation is mediated by potassium conductance channels (d׳Emmanuele di Villa Bianca et al., 2009). On the other hand, it has been reported that in mouse distal colonic smooth muscle, the relaxation caused by H₂S is related to neither of the two major known K⁺ channels, indicating that the H₂S -induced relaxations are mediated via calcium desensitization mechanisms unrelated to inhibition of Rho-kinase or activation of MLCP (Dhaese et al., 2010). However, the mechanisms of H₂S-induced modulation of airway smooth muscle remained unclear though some evidence showed that the NaHS-induced relaxation in the mouse bronchial rings was resistant to blockers of ATP-sensitive K⁺ channels, soluble guanylyl cyclase, cyclooxygenase COX-1 or COX-2, and antagonists of tachykinin receptors (Kubo et al., 2007a).

Therefore we hypothesized that H₂S could relax tracheal smooth muscle (TSM) in an epithelium-independent manner. To test this idea, we measured the smooth muscle contractility of mouse trachea, the whole-cell current, membrane potential and intracellular Ca²⁺ concentration of isolated smooth muscle cells in the absence and presence of a variety of pharmacological modulators. In addition, we established an OVA-challenged asthmatic model and airway hyperresponsiveness reaction was measured in the absence and presence of H₂S. According to our results, we propose a model to explain the regulation of smooth muscle relaxation in mouse trachea in response to H₂S.

Section snippets

Animals and ethics statement

SPF male mice of 20–30 g were purchased from the Experimental Animal Center of Guangdong Province. Animals were housed in a constant-temperature (26 °C) room with a 12 h light–12 h dark photoperiod, according to the guidelines of the Sun Yat-sen University Animal Use Committee. All procedures were approved by the Sun Yat-sen University Animal Use Committee.

Reagents

Carbamylcholine chloride (CCH), sodium hydrosulfide (NaHS), l-cysteine (l-cys), aminoxyacetic acid (AOAA), propargylglycine (PAG),

Effect of NaHS and l-Cys on tracheal smooth muscle

Carbachol (CCH, 10 μM) was added to induce a long-term contraction on TSM. Subsequently, NaHS (1 mM), the donor of H₂S, was administrated in the bathing solution and it evoked a relaxing effect on the pre-contracted TSM (Fig. 1A). In addition, CCH-precontracted TSM was examined in six concentration increments of 0.1 μM, 1 μM, 10 μM, 100 μM, 1 mM, 10 mM NaHS and the relaxing effect of NaHS was concentration-dependent with an EC₅₀ of 1.74×10⁻⁴ mol L⁻¹ (Fig. 1B). Similarly, l-cysteine (l-Cys, 5 mM), the

Discussion

H₂S had historically been known as a toxic gas. Recent evidence have suggested it as a new emerging gaseous signaling molecule (Lefer, 2007, Wagner, 2009, Wagner et al., 2009). H₂S targets different ion channels and receptors and plays an important role in modulating the functions of different systems (Leffler et al., 2006). The role of H₂S in airway smooth muscle is a new issue for investigation, and data accumulated in recent years suggested the relaxant effects of H₂S in airway smooth

Acknowledgments

This study is supported by the National 973 projects (Nos. 2009CB522102, 2010CB945401), the State Key Program of National Natural Science Foundation of China (No. 31230034), and the National Natural Science Foundation of China (Nos. 31271247 and 31100846). We wish to thank Miss Yun-xin Zhu for critical reading of this manuscript and valuable discussion of these data.

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Pulmonary, gastrointestinal and urogenital pharmacologyCellular mechanism underlying hydrogen sulfide induced mouse tracheal smooth muscle relaxation: Role of BKCa

Abstract

Introduction

Section snippets

Animals and ethics statement

Reagents

Effect of NaHS and l-Cys on tracheal smooth muscle

Discussion

Acknowledgments

Biochim. Biophys. Acta

Cytokine

Eur. J. Pharmacol.

Cell Calcium

Pain

J. Pharmacol. Sci.

J. Biol. Chem.

Respir. Physiol. Neurobiol.

Role of hydrogen sulfide in acute pancreatitis and associated lung injury

FASEB J.

The role of the epithelium in modulating the responses of guinea-pig trachea induced by bradykinin in vitro

Br. J. Pharmacol.

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

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

Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle

J. Physiol.

Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats

Am. J. Physiol. Heart Circ. Physiol.

Cellular mechanisms of carbachol-stimulated Cl- secretion in rat epididymal epithelium

Biol. Reprod.

Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation

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

The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

Nature

Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical

Circ. Res.

Molecular mechanism for H(2)S-induced activation of K(ATP) channels

Antioxid. Redox Signal.

Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats

Inflammopharmacology

Hyperpolarization of isolated capillaries from guinea-pig heart induced by K+ channel openers and glucose deprivation

J. Physiol.

A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide

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

Pulmonary, gastrointestinal and urogenital pharmacology
Cellular mechanism underlying hydrogen sulfide induced mouse tracheal smooth muscle relaxation: Role of BK_Ca

Hydrogen sulphide inhibits Ca²⁺ release through InsP₃ receptors and relaxes airway smooth muscle

Cellular mechanisms of carbachol-stimulated Cl^- secretion in rat epididymal epithelium

Hyperpolarization of isolated capillaries from guinea-pig heart induced by K⁺ channel openers and glucose deprivation