Calcium sulfide (CaS), a donor of hydrogen sulfide (H2S): A new antihypertensive drug?

Medical Hypotheses 73 (2009) 445–447

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Calcium sulfide (CaS), a donor of hydrogen sulfide (H2S): A new antihypertensive drug? Ya-Feng Li a, Chuan-Shi Xiao a, Ru-Tai Hui b,c,d,e,* a

Department of Cardiology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan 030001, PR China Hypertension Division, FuWai Hospital and Cardiovascular Institute, 167 Beilishilu, Beijing 100037, PR China c Key Laboratory of Clinical Cardiovascular Genetics Ministry of Education, 167 Beilishilu, Beijing 100037, PR China d Sino-German Laboratory for Molecular Medicine, 167 Beilishilu, Beijing 100037, PR China e Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China b

a r t i c l e

i n f o

Article history: Received 19 March 2009 Accepted 22 March 2009

s u m m a r y Hypertension is the leading cause of cardiovascular diseases, and an estimated 972 million people in the world are suffering from this problem. Indubitably, hypertension is an important worldwide publichealth challenge. In recent years many efforts have been made to devise novel therapies involving new targets implicated in cardiovascular diseases. Hydrogen sulfide (H2S) is a member of a growing family of ‘‘gasotransmitters”. It is clear that H2S plays a pivotal role in the basal regulation of vessels tone. Also studies demonstrate that intravenous sodium hydrosulfide (NaHS), a donor of H2S, dose-dependently decreases systolic blood pressure. However, because of its active chemical property, NaHS can be easily oxidized, even spontaneously ignited in the open air. Moreover, its solution is not stable. So the pharmacal use of NaHS is limited by its properties. Calcium sulfide (CaS), one of the effective components in a traditional herb, is another donor of H2S. It has more stable chemical properties than NaHS. We hypotheses that CaS might be given by mouth as a new antihypertensive drug through certain dosage form designing. To test this hypothesis, we should establish animal models for studies including drug efficacy, drug safety, drug toxicology, drug metabolism and drug kinetics. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction

Hydrogen sulfide

Hypertension is the leading cause of cardiovascular disease, constituting the most common cause of death in industrialized countries, and an estimated 972 million people in the world are suffering from this problem [1]. Indubitably, hypertension is an important worldwide public-health challenge. In recent years many efforts have been made to devise novel therapies involving new targets implicated in hypertension [2–5]. A multi-target approach, consisting of the synthesis of single chemical entities endowed with double pharmacodynamic profiles, has been one of the main methods to develop new drugs for hypertension. This approach is based on the ability of the new entities to interact simultaneously with more than one target involved in hypertension [6]. Hydrogen sulfide (H2S) is such a single chemical entity.

Historically, H2S is best known as a toxic gas. Now it is increasingly recognized as a member of a growing family of ‘‘gasotransmitters”, together with its two counterparts, nitric oxide (NO) and carbon monoxide (CO) [7]. Compared with NO and CO, the study of the biology of H2S is still in its infancy. Nevertheless, many studies have been already devoted to a better understanding of the physiological and pathophysiological significance of this gas. H2S is formed in mammalian cells largely by the activity of two pyridoxal phosphate-dependent enzymes, cystathionine-c-lyase (CSE) and cystathionine-b-synthetase (CBS) [8]. The expression of CSE and/or CBS is tissue specific and has been identified in various mammalian cells including those from liver, kidney, brain, lung, arteries, skin fibroblasts and blood lymphocytes [9–12]. Physiological concentrations of circulating H2S have been reported in the range of 45–300 mM [7]. H2S in the cardiovascular system

* Corresponding author. Address: Hypertension Division, FuWai Hospital and Cardiovascular Institute, 167 Beilishilu, Beijing 100037, PR China. Tel.: +86 10 88398154; fax: +86 10 68331730. E-mail address: [email protected] (R.-T. Hui). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.03.030

The physiological function of H2S in the cardiovascular system has recently been studied. Endogenous H2S in rat vascular tissues, as a vascular relaxant factor, could maintain the basal blood

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pressure balance in a physiological condition [9]. Also, it could suppress the proliferation of cultured vascular smooth muscle cells (VSMCs) through the mitogen-activated rotein kinase (MAPK) pathway in a dose-dependant manner in vitro [9,13–15]. Meanwhile, H2S could be endogenously produced by cardiac tissue, as a physiological cardiac function regulator, mediated by the KATP (ATP sensitive potassium channels) channel pathway [16]. Negative inotropic effects and the central venous pressure reducing activity of H2S were shown by in vitro and in vivo experiments, and the above effects were partly blocked by glibenclamide, a KATP channel blocker [16]. Yang and colleagues demonstrate that intravenous NaHS dosedependently decreases systolic blood pressure in both CSE / and wild-type (CSE+/+). Such effect is more significant in the mutant mice (a model of H2S deficiency). They show that H2S has properties in common with physiological endothelium derived relaxing factors (EDRFs). Thus, blood vessel relaxation in response to muscarinic stimulation is profoundly reduced in CSE-deficient mice. Moreover, CSE is predominantly localized to the endothelial layer of blood vessels. The EDRF activity of H2S reflects muscarinic activation of intracellular calcium release, with calcium–calmodulin physiologically stimulating CSE [17]. Endogenous H2S is not only a vasorelaxant, but also a novel inhibitor that dose-dependently suppresses the proliferation of VSMCs through the extracellular signal-related kinase (ERK) pathway of MAPKs. It has been found that ERK is involved in the mediation of endothelin-induced VSMC proliferation of thoracic aorta cells in vitro. MAPK activity is significantly inhibited by the addition of NaHS, a donor of H2S, at 5  10 5, 1  10 4 and 5  10 4 mol/L (P < 0.01) in a dose-dependant manner [18]. Pathophysiological processes that H2S participates in have been shown by recent studies. In cardiovascular system, the endogenous CSE/H2S pathway contributes to the pathogenesis of diseases such as spontaneous hypertension [14], L-arginine methyl ester (LNAME)-induced hypertension [19] and pulmonary hypertension induced by hypoxia and high pulmonary blood flow [20]. H2S in pharmacotherapy H2S is a colorless, flammable gas with a characteristic odor of rotten eggs. It is soluble in water. NaSH looks like hygroscopic solid scales with yellow color and sulfurous odor. Its chemical properties are active. It can be easily oxidized, even self-ignited (>90 °C) in the open air. When either NaHS or H2S is dissolved in physiological solution (pH 7.4, 37 °C), it will form approximately 18.5% H2S and 81.5% hydrosulfide anion (HS ), as predicted by the Henderson– Hasselbach equation [21]. Most researchers have accustomed to using NaHS in their experiments instead of using H2S gas dissolved in water, even though there might be differences in the potency of the two [22]. To date, in most experiments, the NaHS dissolution is injected intraperitoneally, transvenously or transarterially. Inhibitors of CSE and CBS have been used extensively. However, they are not completely specific and also can inhibit other vitamin B6-dependent enzymes with pyridoxal phosphate binding site [8]. Recently, several alternative H2S donors have been studied, such as H2S releasing derivatives of diclofenac [23,24] and mesalamine [25–27]. Meanwhile, Fiorucci and associates found that Non-steroidal anti-inflammatory drugs (NSAIDs) could inhibit the generation of hydrogen sulfide [28].

an odor of H2S. The high melting point is also consistent with its description as an ionic solid. CaS is used in homeopathy. An herb, named ‘‘Hepar sulphuris calcareum” (Hepar sulf.) and commonly known as CaS, is used in this homeopathic remedy. It is prepared chemically by heating together oyster-shell powder and flowers of sulfur in an airtight container [29].

Hypothesis Firstly, it should be emphasized that CaS has never been mentioned as an H2S donor in any published studies until now. Then we postulate that CaS might be a new oral drug for hypertension. Our arguments are as follows: 1. CaS decomposes upon contacting with water, releasing H2S. When it happens in stomach, such an acid environment, the chemical equilibrium: H2S M H+ + HS (pH 7.4, 37 °C, 18.5% H2S and 81.5% HS ) will be broken and more H2S will be produced. H2S is a highly lipophilic molecule and freely penetrates cells of all types. This property endows H2S with, at least the potential for, biological activity. 2. When catabolism of CaS is mentioned, what we really care is the catabolism of H2S. Many studies have been done to provide consistent evidence of a link between calcium supplementation and blood pressure [30,31]. This minor dosage Ca2+ is not harmful, but even beneficial. There are two pathway of H2S metabolism, one is in mitochondria and the other is in the cytosol. In the first path, H2S is rapidly oxidized mainly in mitochondria, initially to thiosulfate which is further converted to sulfite and sulfate. Then they are excreted in urine [32,33]. Among them, sulfate is the major end-product of H2S metabolism under physiological conditions. In the other path, H2S is methylated to methanethiol and dimethylsulfide, and may bind to methemoglobin to form sulfhemoglobin [33,34]. 3. Defective synthesis of H2S is involved in various human diseases not merely systemic hypertension. H2S has been demonstrated to be protective in diseases such as pulmonary hypertension [20,35], myocardial ischemia/reperfusion injury [36,37], erectile dysfunction [38], gastric mucosal injury [28], colitis, irritable bowel syndrome [26] and neuronal damage induced by febrile seizures [39]. 4. In history, the ‘‘calcium antihypertension theory” is heatedly debated [40,41]. There have been many randomized controlled trials of calcium supplementation on blood pressure and metaanalysis of them [31,42,43]. The US Food and Drug Administration (FDA) conducted an evidence-based review to evaluate the role of supplemental calcium in reducing the risk of hypertension, pregnancy-induced hypertension and preeclampsia. Based on the review, the FDA concluded that the relationship between calcium and risk of hypertension is inconclusive [44]. Here we do not want to continue this debate. We just clarify that appropriate supplemental calcium does no harm to a hypertensive patient. 5. Through certain dosage form designing, CaS can be isolated from moist air. Furthermore, there will be depot preparations of CaS, helping H2S releasing more sustainedly. 6. CaS is traditional used as the effective component of a herb named ‘‘Hepar sulf.”. It is mainly used when there is an infection [29].

Calcium sulfide Discussion CaS, like NaSH as a simple sulfide salt, when dissolved in water, dissociates instantly to yield HS and H+, as follows: CaS + H2O ? Ca(SH)(OH) + H2S; Ca(SH)(OH) + H2O ? Ca(OH)2 + H2S; H2S M H+ + HS . This white material crystallizes in cubes like rock salt, with

To test this hypothesis, we have to do much more work including experimental and clinical studies. Catabolism of H2S is less recognized and most data were obtained by using exogenous H2S;

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thus these studies have revealed important toxicological but not necessarily physiological implications. We should confirm the pathway of H2S metabolism in the gastrointestinal tract. Furthermore, we need to design a dosage form isolating CaS from moist air. Meanwhile, if possible, a depot preparation is much better. The single molecule H2S exerts widely different effects. Chemical tools are required before we can completely make clear roles of H2S in physiology and pathology. CaS is such a weapon. Acknowledgements We express our gratitude to Shao-Hua Li and Li-Li Guo for their assistance. References [1] Hajjar I, Kotchen JM, Kotchen TA. Hypertension: trends in prevalence, incidence, and control. Annu Rev Public Health 2006;27:465–90. [2] Grandi AM. Antihypertensive therapy: role of aldosterone antagonists. Curr Pharm Des 2005;11:2235–42. [3] Brown MJ, Coltart J, Gunewardena K, et al. Randomized double-blind placebocontrolled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects. Clin Sci (Lond) 2004;107:167–73. [4] Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111: 1012–8. [5] Breschi MC, Calderone V, Digiacomo M, et al. New no-releasing pharmacodynamic hybrids of losartan and its active metabolite: design, synthesis, and biopharmacological properties. J Med Chem 2006;49:2628–39. [6] Balsamo A, Calderone V, Rapposelli S. New emerging prospects in the pharmacotherapy of hypertension. Cardiovasc Hematol Agents Med Chem 2008;6:1–19. [7] Wang R. Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 2002;16:1792–8. [8] Stipanuk MH, Beck PW. Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J 1982;206:267–77. [9] Yan H, Du J, Tang C. The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun 2004;313:22–7. [10] Hui Y, Du J, Tang C, et al. Changes in arterial hydrogen sulfide (H2S) content during septic shock and endotoxin shock in rats. J Infect 2003;47:155–60. [11] Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 1996;16:1066–71. [12] Mariggiò MA, Pettini F, Fumarulo R. Sulfide influence on polymorphonuclear functions: a possible role for Ca2+ involvement. Immunopharmacol Immunotoxicol 1997;19:393–404. [13] Zhao W, Zhang J, Lu Y, et al. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. J EMBO 2001;20:6008–16. [14] Hosoki R, Matsiki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 1997;237:527–31. [15] Zhao W, Wang R. H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 2002;283:H474–80. [16] Geng B, Yang J, Qi Y, et al. H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun 2004;313:362–8. [17] Yang G, Wu L, Jiang B, et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 2008;322:587–90. [18] Du J, Hui Y, Cheung Y, et al. The possible role of hydrogen sulfide as a smooth muscle cell proliferation inhibitor in rat cultured cells. Heart Vessels 2004;19:75–80. [19] Zhong G, Chen F, Cheng Y, et al. The role of hydrogen sulfide generation in the pathogenesis of hypertension in rats induced by inhibition of nitric oxide synthase. J Hypertens 2003;21:1879–85.

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