Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide biosynthesis

1 Haemorrhagic shock (60 min) in the anaesthetized rat resulted in a prolonged fall in the mean arterial blood pressure (MAP) and heart rate (HR). 2 Pre-treatment (30 min before shock) or post-treatment (60 min after shock) with inhibitors of cystathionine gamma lyase (CSE; converts cysteine into hydrogen sulphide (H2S)), dl-propargylglycine or beta-cyanoalanine (50 mg kg(-1), i.v.), or glibenclamide (40 mg kg(-1), i.p.), produced a rapid, partial restoration in MAP and HR. Neither saline nor DMSO affected MAP or HR. 3 Plasma H,S concentration was elevated 60 min after blood withdrawal (37.5 +/- 1.3 mum, 11 = 18 c.f. 28.9 +/- 1.4 mum, n = 15, P < 0.05). 4 The conversion of cysteine to H2S by liver (but not kidney) homogenates prepared from animals killed 60 min after withdrawal of blood was significantly increased (52.1 +/- 1.6 c.f. 39.8 +/- 4.1 nmol mg protein(-1), n = 8, P < 0.05), as was liver CSE mRNA (2.7x). Both PAG (IC50, 55.0 +/- 3.2 mum) and BCA (IC50, 6.5 +/- 1.2 mum) inhibited liver H2S synthesizing activity in vitro. 5 Pre-treatment of animals with PAG or BCA (50 mg kg(-1), i.p.) but not glibenclamide (40 mg kg(-1), i.p., K-ATP channel inhibitor) abolished the rise in plasma H2S in animals exposed to 60 min haemorrhagic shock and prevented the augmented biosynthesis of H2S from cysteine in liver. 6 These results demonstrate that H2S plays a role in haemorrhagic shock in the rat. CSE inhibitors may provide a novel approach to the treatment of haemorrhagic shock.