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First published online August 22, 2008
Journal of Experimental Biology 211, 2727-2734 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.010066
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Hydrogen sulfide and oxygen sensing: implications in cardiorespiratory control

Kenneth R. Olson

Indiana University School of Medicine, South Bend Center, South Bend, Indiana 46617, USA


Figure 1
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  		Fig. 1. Hypoxia (100% N2) and H2S (1 mmol l–1; as total sulfide, H2S and HS–) produce identical contractions in lamprey dorsal aorta (DA; A), relaxations in norepinephrine (NE, 10–6 mol l–1) pre-contracted rat thoracic aorta (TA; B), and tri-phasic contraction–relaxation–contraction (1, 2, 3) in norepinephrine pre-contracted rat pulmonary artery (PA; C). Air indicates return to normoxia; w, wash. In U-46619 (thromboxane A2 mimetic, 10–7 mol l–1) pre-contracted bovine pulmonary artery (PA; D) H2S produces relaxation at low concentrations and contractions at higher concentrations. The left panel shows an individual trace, and in the right panel the two phases are separated into individual dose–response curves (N=8); stippled rectangle indicates range of reported [H2S] (measured in mol l–1) in rat plasma. Horizontal time bar in all figures is 10 min, vertical tension scale is 0.5 g. Adapted from Olson et al. (Olson et al., 2006Go) with permission.

 

Figure 2
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  		Fig. 2. Inhibition of hypoxic responses by inhibitors of H2S synthesis. (A) Three consecutive exposures to hypoxia (N2) produce identical contractions in lamprey dorsal aorta (DA; left bars) whereas in parallel experiments the second and third hypoxic contractions are significantly (*) inhibited after addition of hydroxylamine (H), an inhibitor of cystathionine β-synthase (CBS) and cystathionine {gamma}-lyase (CSE). (B) Hypoxic relaxation of a norepinephrine-contracted (NE; 10–6 mol l–1) rat thoracic aorta (TA) is significantly (*) inhibited by the CSE inhibitor propargyl glycine (P). (C) Hypoxic contractions of bovine pulmonary arteries (PA) are not affected by propargyl glycine (P) but are increasingly inhibited by the CBS inhibitor aminooxy acetate (A), hydroxylamine (H), or a combination of all three inhibitors (HPA). Means ± s.e.m.; responses are normalized to an initial KCl (80 mmol l–1) or NE contraction. (Adapted from Olson et al., 2006Go.)

 

Figure 3
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  		Fig. 3. Proposed mechanism of O2 sensing via H2S metabolism. H2S is constitutively produced from cysteine (Cys) metabolism in the cytosol. During normoxia (left panel) H2S is continuously oxidized to sulfite in the mitochondria thereby maintaining low intracellular [H2S]. A fall in oxygen availability (right panel) decreases mitochondrial H2S oxidation resulting in an increase in biologically active [H2S] and initiation of hypoxic responses. The enzymes generating H2S from cysteine, cystathionine β-synthase (CBS) and cystathionine {gamma}-lyase (CSE) also have the potential of O2 sensitivity, thereby enabling either short-term regulation of [H2S] or placing a long-term bias on the rate of H2S metabolism.

 

Figure 4
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  		Fig. 4. O2-dependent H2S production and consumption measured in real-time with a polarographic H2S sensor. (A,B) H2S production (as total sulfide) by minced trout heart increases with increasing concentrations of cysteine (mmol l–1) at PO2~0 and is transiently inhibited by injection of oxygen (O2) into the reaction chamber. H2S production resumes, presumably after the oxygen has been depleted (post O2). (A) A single representative trace, (B) pooled results expressed as means ± s.e.m. (N=4). (C,D) H2S is consumed by addition of purified trout heart mitochondria (M). The rate of sulfide consumption is greater when the reaction mixture is equilibrated with room air (O2) than with nitrogen (N2) or if the mitochondria are heat denatured (Heat). w, wash. (C) Single representative trace, (D) pooled results expressed as means ± s.e.m. (N=4 replicates). A, B adapted from Whitfield et al. (Whitfield et al., 2008Go), with permission; C, D adapted from Olson et al. (Olson et al., 2008bGo), with permission.

 

Figure 5
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  		Fig. 5. Evidence for H2S involvement in trout gill chemoreceptors. (A) Injection of 5 µmol H2S into the buccal cavity of an unanesthetized 600 g trout previously implanted with a pressure cannula in, and flow probe around, the bulbus arteriosus produces a bradycardia within 5 s that mimics a hypoxic bradycardia. Pva, ventral aortic pressure; CO cardiac output. (B) Heart rate following intrabuccal injection of a 1 ml bolus of H2S in intact trout (black bars; N=13–15) or trout with either the first (Gill 1; white bars; N=7) or second (Gill 2; stippled bars; N=6) pair of gills removed. Dashed lines indicate mean ± s.e.m. heart rate of all fish prior to H2S. H2S produced a dose-dependent bradycardia in control trout that was similar to that produced in trout with the second pair of gills removed. Removal of the first pair of gills decreased H2S sensitivity. {dagger}Significantly different from pre-H2S; *significantly different from intact trout after H2S injection. The bradycardia at 5 and 10 mmol l–1 is significantly (*) attenuated in trout with the first pair of gills removed relative to the two other groups. Adapted from Olson (Olson et al., 2008bGo), with permission.

 

Figure 6
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  		Fig. 6. Exogenous H2S is rapidly consumed by trout (A) or rat (B) blood in vitro effectively maintaining H2S concentration close to 0. The concentration of H2S (as total sulfide) was measured in real-time with a polarographic H2S sensor. Serial additions of H2S (as Na2S), each sufficient to raise total sulfide to 10 µmol l–1, did not increase sulfide by more than ~1.5 µmol l–1. The rate of sulfide consumption in trout blood was tenfold greater, presumably due to the presence of mitochondria in trout erythrocytes. (C) Effect of exogenous sulfide (as Na2S) on sulfide concentration of dorsal aortic blood in an unanesthetized trout. An extracorporeal pump circulated blood from the dorsal aorta across the sensor and returned it to the caudal vein. The arrow indicates bolus injection of Na2S into the caudal vein cannula. The amount of Na2S injected was theoretically sufficient to raise plasma sulfide to 30 µmol l–1 when fully mixed in the plasma. Inset shows injection of the same amount of sulfide into a recirculated volume of Hepes buffer equivalent to the trout's plasma volume and pH. Sulfide is rapidly removed from the plasma in vivo, but not from the buffer. w, wash. Adapted from Whitfield et al. (Whitfield et al., 2008Go), with permission.

 

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