The role of hydrogen sulphide in the cardiovascular system emphasis on haemorrhagic shock

ROLE OF HYDROGEN SULPHIDE IN THE CARDIOVASCULAR SYSTEM: EMPHASIS ON HAEMORRHAGIC SHOCK MOK YING-YUAN, PAMELA (B.Sc(Hons.), NUS) A THESIS SUMBITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 2007 Acknowledgements I would like to express my sincere appreciation and gratitude to my supervisor, Professor Philip K. Moore for his invaluable guidance, constant encouragement and support throughout these years of my PhD studies. Without his mentorship, I would not have finished the project. I would like to thank my laboratory officer Yoke Ping for her efficiency and expedience in purchasing laboratory supplies, and my co-workers Farhana, Yusuf, Li Ling and Baskar for their invaluable help and technical assistance, and most importantly, their friendship. Many thanks to Associate Professor Madhav Bhatia and his laboratory staff and students, as well as Associate Professor Zhu Yi-Zhun and his laboratory staff and students, for their technical assistance and the loan of laboratory equipment. My thanks to my family. Without their understanding, support and forbearance throughout my studies, I would not have achieved anything. Last but not least, I wish to thank the Agency for Science, Technology and Research for their award of a post-graduate scholarship, without which I would not have been able to pursue a PhD. I CONTENTS Acknowledgements . I Contents II Summary . VI List of figures . VIII List of publications X Abbreviations . XI Introduction 1.1 Haemorrhagic shock 1.1.1 Compensatory phase 1.1.2 Decompensatory phase 1.1.3 Overview of hypoxic responses leading to inflammation 1.1.4 Inflammatory mediators of haemorrhagic shock .10 1.1.5 Reperfusion injury – role of ROS/RNS .22 1.2 Hydrogen sulphide .24 1.2.1 Biosynthesis of H2S 24 1.2.2 Regulation of H2S biosynthesis 25 1.2.3 Metabolism of H2S .26 1.2.4 Mechanisms of action of H2S .27 1.2.5 H2S and the cardiovascular system 28 1.2.6 H2S and inflammation 32 1.2.7 H2S and the nervous system .35 1.2.8 H2S and the gastrointestinal system .36 1.2.9 H2S and diabetes mellitus 38 1.3 Premise for the current thesis .39 Drugs, chemicals, materials & equipment .40 2.1 Drugs and Chemicals .40 II 2.2 Materials 41 2.3 Equipment 41 Methodology .44 3.1 Experiments measuring blood pressure .44 3.1.1 PowerLab calibration 44 3.1.2 Surgical cannulation 45 3.1.3 Haemorrhagic shock & resuscitation 47 3.1.4 Drug administration .48 3.1.5 Blood sampling & organ harvesting 48 3.2 Organ bath experiments .49 3.2.1 PowerLab calibration 49 3.2.2 Aortic ring preparation 50 3.2.3 Measurement of rat aorta contractility 51 3.3 Biochemical assays 52 3.3.1 Plasma cytokines 52 3.3.2 Plasma organ injury markers 54 3.3.3 Nitrate / nitrite .55 3.3.4 Myeloperoxidase activity .56 3.3.5 Inducible nitric oxide synthase protein 58 3.3.6 Hydrogen sulphide .61 3.3.7 Cystathionine γ-lyase mRNA 63 3.4 Statistical analysis and representation .65 The interaction of H2S with KATP channels and NO in the vascular system .66 4.1 Introduction 66 4.2 Experimental design .67 4.2.1 4.3 Drug preparation .67 Results 68 4.3.1 Effect of NaHS on rat aorta contractility: Role of KATP channels .68 4.3.2 Effect of NaHS / H2S on blood pressure & heart rate .73 4.3.3 Role of KATP channels in the cardiovascular effects of NaHS / H2S 78 III 4.3.4 Role of NO and prostaglandins in NaHS-induced vasorelaxation 79 4.3.5 NaHS effect on rat aorta contractility: Role of NO .85 4.3.6 Role of NO and KATP channels in NaHS-induced increase in blood pressure .86 4.4 Discussion 92 4.4.1 NaHS-induced relaxation of isolated rat aorta .92 4.4.2 NaHS-induced contraction of isolated rat aorta .94 4.4.3 NaHS-induced fall in mean arterial pressure in the anaesthetized rat .96 4.4.4 NaHS-induced increase in mean arterial pressure in the anaesthetized rat .98 Changes in endogenous H2S production in haemorrhagic shock 101 5.1 Introduction 101 5.2 Results 102 5.2.1 Changes in H2S levels and biosynthesis in haemorrhagic shock .102 5.2.2 Effect of PAG & BCA on MAP & HR in haemorrhagic shock 106 5.2.3 Effect of PAG & BCA on H2S levels & biosynthesis in haemorrhagic shock 107 5.2.4 Effect of glibenclamide on MAP, HR & H2S levels in haemorrhagic shock 110 5.2.5 Effect of PAG and aminoguanidine on MAP and HR in haemorrhagic shock 111 5.2.6 Effect of PAG on organ damage & inflammation in haemorrhagic shock 111 5.3 Discussion 116 5.3.1 H2S formation in haemorrhagic shock .116 5.3.2 Use of CSE inhibitors in haemorrhagic shock .117 5.3.3 H2S and nitric oxide in haemorrhagic shock .118 5.3.4 Use of glibenclamide in haemorrhagic shock 119 5.3.5 H2S and inflammation in haemorrhagic shock 120 Implications of increased H2S production in haemorrhagic shock .123 6.1 Introduction 123 6.2 Experimental Design 124 6.3 Results 125 6.3.1 Effect of PAG on contractility of the isolated rat aorta .125 6.3.2 Effect of PAG on vasoconstrictor response .131 6.3.3 Effect of reinfusion of shed blood on MAP and HR of shocked rats 136 IV 6.3.4 Effect of PAG on inflammatory mediators in haemorrhagic shock .136 6.3.5 Effect of PAG on plasma lactate & organ injury in haemorrhagic shock .143 6.4 Discussion 149 6.4.1 H2S & contractility of the isolated haemorrhagic-shocked rat aorta 149 6.4.2 H2S & cardiovascular responses in haemorrhagic shock .151 6.4.3 H2S & inflammation in haemorrhagic shock .153 6.4.4 H2S & haemorrhagic shock-induced organ injury 156 General discussion & summary 159 7.1 H2S and cardiovascular responses in haemorrhagic shock 159 7.2 H2S and inflammatory responses in haemorrhagic shock 160 7.3 Concluding remarks .162 References .163 V Summary Haemorrhagic shock is a condition of reduced perfusion of organs resulting in inadequate delivery of oxygen and nutrients necessary for normal tissue and cellular function, due to an excessive loss of blood volume. It is characterized by marked hypotension, vascular hyporesponsiveness to vasoconstrictors, and an inflammatory response. Hydrogen sulphide (H2S) is a vasodilator and is endogenously produced in vascular tissues. It has been implicated in cardiovascular disorders (e.g. pulmonary hypertension) and is a mediator of inflammation. Therefore, H2S may play a role in the aetiology of haemorrhagic shock. The cardiovascular effects of H2S were examined using sodium hydrogen sulphide (NaHS; H2S donor), henceforth referred to as H2S. In accordance with published literature, H2S relaxes phenylephrine pre-contracted aortic rings and causes a fall in mean arterial pressure (MAP) in anaesthetized rats. However, the present study suggests that whilst H2S causes vasorelaxation by opening KATP channels in vitro, H2S causes a fall in MAP that is independent of KATP channels or the synthesis of nitric oxide (NO) and prostaglandin I2 (PGI2). In addition, low concentrations/doses of H2S increases the tone of phenylephrine pre-contracted aortic rings, and causes a small but significant increase in MAP in anaesthetized rats. This effect of H2S is possibly due to an interaction with NO (i.e. NO “quenching”), as H2S reverses acetylcholine and sodium nitroprusside (SNP)-induced relaxation of phenylephrine pre-contracted aortic rings. In the healthy rat, H2S may not actively modulate vascular tone, as inhibition of H2S biosynthesis with D,Lpropargylglycine (PAG) did not affect the MAP of anaesthetized rats. Haemorrhagic-shocked rats had increased plasma H2S levels and increased liver H2S biosynthesis h after blood withdrawal, both of which subsequently decreased to basal VI levels. Increased liver H2S biosynthesis was likely due to upregulation of cystathionine-γlyase (CSE) enzyme as haemorrhagic-shocked livers had increased liver CSE mRNA levels compared to non-shocked livers. H2S partially mediates the hypotension in haemorrhagic shock, as PAG given both prophylactically and therapeutically could partially restore the lowered MAP. Haemorrhagic-shocked aortic rings were hyporesponsive to phenylephrine as well as to acetylcholine and SNP, and incubation with PAG further decreased the sensitivity to acetylcholine and SNP but did not affect the response to phenylephrine. Thus, H2S may increase vascular response to acetylcholine/NO in haemorrhagic shock. Haemorrhagic shock was also associated with an increase in plasma concentrations of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), alanine aminotransferase (ALT) activity, urea and creatinine. PAG-treated, haemorrhagic-shocked rats had lower plasma concentrations of IL-1β and ALT activity compared to saline/untreated rats. Resuscitated, haemorrhagic-shocked rats had increased plasma concentrations of TNF-α, IL-1β, IL-6, IL-10, ALT, urea, creatinine, amylase, lactate and nitrate/nitrite, increased liver and lung myeloperoxidase (MPO) activity, and lung inducible nitric oxide synthase (iNOS) protein. Rats pre-treated with PAG had decreased plasma concentrations of TNF-α, IL-6, ALT and nitrate/nitrite, reduced liver and lung MPO activity, and decreased lung iNOS protein compared to saline/untreated rats. This suggest that H2S is pro-inflammatory in haemorrhagic shock and may contribute to haemorrhagic shockassociated multiple organ injury, thus inhibitors of H2S biosynthesis may be therapeutic. VII List of Figures Figure 1.1 H2S production from L-cysteine 25 Figure 1.2 H2S metabolism . 26 Figure 4.1 Effect of NaHS and cromakalim on pre-contracted isolated rat aortic rings .70 Figure 4.2 Effect of glibenclamide on pre-contracted isolated rat aortic rings .71 Figure 4.3 Effect of glibenclamide on NaHS and cromakalim-induced relaxation of precontracted isolated rat aortic rings .72 Figure 4.4 Representative traces showing drug-induced changes in arterial blood pressure .74 Figure 4.5 Representative traces showing drug-induced changes in heart rate .75 Figure 4.6 Effect of NaHS and H2S on MAP in the anaesthetized rat .76 Figure 4.7 Effect of NaHS and H2S on heart rate in the anaesthetized rat 77 Figure 4.8 Effect of glibenclamide on cromakalim-induced changes in MAP and heart rate 80 Figure 4.9 Effect of glibenclamide on NaHS-induced changes in MAP and heart rate 81 Figure 4.10 Effect of glibenclamide on H2S-induced changes in MAP and heart rate .82 Figure 4.11 Effect of glibenclamide on NaHS infusion-induced changes on MAP and heart rate 83 Figure 4.12 Effect of glibenclamide on cromakalim-induced changes on MAP and heart rate. .84 Figure 4.13 Effect of L-NAME and ODQ on NaHS-induced relaxation of precontracted isolated rat aortic rings. Effect of NaHS on acetylcholine and SNP-induced relaxation of pre-contracted isolated rat aortic rings 88 Figure 4.14 Effect of glibenclamide on NaHS-induced increase in MAP and heart rate. .89 Figure 4.15 Representative traces of arterial blood pressure changes caused by i.v. injection of a mixture of SNP and NaHS 90 Figure 4.16 Effect of L-NAME pre-treatment on NaHS-induced increase in MAP and on heart rate 91 Figure 5.1 H2S biosynthesis in haemorrhagic shock .104 Figure 5.2 Liver CSE mRNA levels in haemorrhagic shock .105 VIII Figure 5.3 Effect of PAG and BCA on MAP and heart rate in haemorrhagic shock 108 Figure 5.4 Effect of PAG and BCA on plasma & tissue H2S 109 Figure 5.5 Effect of PAG, AG and both drugs on MAP and heart rate .113 Figure 5.6 Effect of PAG on inflammatory markers .114 Figure 5.7 Effect of PAG on organ injury markers. 115 Figure 6.1 Effect of phenylephrine on pre-contracted isolated rat aortic rings .128 Figure 6.2 Effect of acetylcholine and SNP on pre-contracted isolated rat aortic rings 129 Figure 6.3 Effect of NaHS on pre-contracted isolated rat aortic rings 130 Figure 6.4 Effect of PAG on phenylephrine and angiotensin II-induced changes in MAP .133 Figure 6.5 Effect of PAG on phenylephrine and angiotensin II-induced increase in MAP 134 Figure 6.6 Effect of PAG on phenylephrine and angiotensin II-induced changes in heart rate 135 Figure 6.7 Effect of PAG on MAP in reinfused rats 137 Figure 6.8 Effect of PAG on heart rate in reinfused rats .138 Figure 6.9 Effect of PAG on plasma and organ NOX levels 140 Figure 6.10 Effect of PAG on plasma TNF-α and IL-1β .141 Figure 6.11 Effect of PAG on IL-6 and IL-10. 142 Figure 6.12 Effect of PAG on plasma lactate levels 145 Figure 6.13 Effect of PAG on liver injury .146 Figure 6.14 Effect of PAG on kidney injury 147 Figure 6.15 Effect of PAG on lung and pancreatic injury .148 IX References Hellwig-Burgel, T., Stiehl, D.P., Wagner, A.E., Metzen, E., Jelkmann, W., 2005. 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Med. 190: 135-139. 184 [...]... inhibition of iNOS with N6-(iminoethyl)-L-lysine could inhibit the activation of NFκB as 17 Introduction well as inhibit the increase in IL-6 and granulocyte-colony stimulating factor mRNA levels in haemorrhagic- shocked lung and liver In addition, the authors showed that inhibition of iNOS with N6-(iminoethyl)-L-lysine also led to a reduction of lung and liver injury caused by haemorrhagic shock In a... vasopressin respectively Xu and Liu (2005) also demonstrated the involvement of protein kinases C and G in the aetiology of Ca2+ desensitization in isolated haemorrhagic- shocked rat mesenteric artery The authors showed that agonists of protein kinase C and antagonists of protein kinase G could inhibit the 6 Introduction reduction in Ca2+ sensitivity in haemorrhagic- shocked rat mesenteric artery Furthermore,... Furthermore, the authors also demonstrated that the attenuation of the reduction in Ca2+ sensitivity in haemorrhagic- shocked rat mesenteric artery by protein kinase C and Rho-kinase could be augmented by myosin light chain kinase inhibitors The findings of Xu and Liu (2005) suggest that biochemical modification or modulation of some components of the contractile apparatus may contribute to the decrease in calcium...List of Publications 1 Mok, Y.Y., Atan, M.S., Yoke Ping, C., Zhong Jing, W., Bhatia, M., Moochhala, S., Moore, P.K., 2004 Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide biosynthesis Br J Pharmacol 143: 881-889 2 Mok, Y.Y., Moore, P.K Hydrogen sulphide (H2S) plays a role in haemorrhagic shock in the rat The 7th World Congress on Inflammation,... co-workers (1995) demonstrated that the ROS source leading to the increase in TNF-α concentration in haemorrhagic shock was likely the ROS produced by xanthine oxidase as the increase in TNF-α concentration was inhibited by allopurinol (xanthine oxidase inhibitor) TNF-α production in haemorrhagic shock also promotes the production of pro-inflammatory IL-6 (see below) Treatment of mice with anti-TNF-α... and aminoguanidine increased the survival rate of haemorrhagic- shocked rats In addition, the authors demonstrated that L-NAME and aminoguanidine reduced macroscopic and microscopic organ injuries, and decreased PGE2 and creatinine production in haemorrhagic- shocked animals Furthermore, these beneficial effects were reversed by L-arginine, suggesting the involvement of NO in the pathophysiology of hemorrhagic... authors showed that the increase in IL-10 concentration in haemorrhagic shock was dependent upon IL-4 production In haemorrhagic shock, IL-10 appears to down-regulate the pro-inflammatory cytokines IL-6 and TNF-α Karakozis and co-workers (2000) demonstrated that administration of IL-10 to haemorrhagic- shocked rats could inhibit haemorrhagic shockinduced increase in TNF-α levels In another study, Yokoyama... of rats with mercaptoethylguanidine, a dual inhibitor of inducible NOS and COX and a scavenger of ONOO-, attenuated the vascular hyporesponsiveness to norepinephrine in haemorrhagic shocked aortas and also reduced ONOO- formation in these vessels, as evidenced by a decrease in nitrotyrosine staining in these vessels (Zingarelli et al, 1997) 1.1.3 Overview of hypoxic responses leading to inflammation... enhance inflammatory responses (e.g cytokine production) by inducing the degradation of IκB and increasing the nuclear binding activity of NFκB (Parikh et al, 2000) IL-6 Haemorrhagic shock is associated with an increase in IL-6 production in the liver, peritoneum, kidney and lung (Ayala et al, 1992; Jiang et al, 1997; Zhu et al, 1994) The production of IL-6 in haemorrhagic shock appears to be dependent on. .. adaptive immune responses, and their effects may include the up-regulation and/or down-regulation of gene transcription, which in turn affects the production of other cytokines, the number of surface receptors for other molecules, or causes feedback inhibition In addition, cytokines have "redundancy" as many cytokines share similar functions 10 Introduction Cytokines TNF-α Haemorrhagic shock has been associated . angiotensin II hyporesponsiveness. Emerging evidence indicates that the mechanisms involved in the decrease in response to norepinephrine in haemorrhagic shock despite an increase in sympathetic. M.S., Yoke Ping, C., Zhong Jing, W., Bhatia, M., Moochhala, S., Moore, P.K., 2004. Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide. by the metabolic activity of the tissue as well as by inflammatory responses. 1.1 Haemorrhagic shock Haemorrhagic shock is a condition of reduced perfusion of vital organs resulting in inadequate