3.

Evidence consistent with nitric oxide–H₂S cross-talk in the cardiovascular system

Cardiovascular observation
Involvement in common cardiovascular pathology
Endogenous H2S and nitric oxide levels negatively correlate with blood pressure and cardiac function
Haemorrhagic and endotoxic shock induce elevated H2S and nitric oxide synthesis; prophylactic and therapeutic pharmacological inhibition of CSE or NOS2 is protective
Inflammation and oedema are associated with elevated H2S and nitric oxide levels; inhibition of CSE or NOS decreases inflammation and swelling
Stimulatory effects of H2S on nitric oxide synthesis and nitric oxide mediated vasorelaxation
The nitric oxide donor sodium nitroprusside (SNP) enhanced CBS activity and H2S levels in vitro and increased H2S synthesis in rat aortic, liver and ileum [63, 112]
The vasorelaxant effect of the nitric oxide donors SNP and SIN-1 were enhanced by incubating rat aortic tissue with NaHS [64]
L-NAME inhibited H2S-mediated vasorelaxation in rat aorta and the conversion of L-cysteine to H2S in rat aortic tissue. This effect was enhanced by treatment with the nitric oxide donor SNP [73]
NaHS [64, 65] or slow release H2S donor GYY4137 [79] prevented and reversed L-NAME-mediated hypertension in rats
H2S potentiated expression of NOS2 following stimulation of cultured rat vascular muscle cells with interleukin (IL)-1β
H2S inhibited nitric oxide generation in isolated aortic tissues and in vivo[109] H2S down-regulated NOS3 (eNOS) but not NOS2 (iNOS) expression however, NOS2 was not induced [107, 108]
H2S, NaHS inhibited L-arginine uptake in human umbilical vein endothelial (HUVE) cells [109, 110]
L-cysteine / pyridoxdal phosphate inhibited L-arginine uptake in HUVE cells; inhibited by PAG [109, 110]
L-Arginine increased CSE mRNA expression in pulmonary vascular endothelial and smooth muscle cells [110]
Nitric oxide donors up-regulated the expression and activity of CSE in vascular tissues and cultured aortic smooth muscle cells [74, 124]
Synergistic effect of nitric oxide and H2S on stonustoxin-induced relaxation of isolated rat aorta [123]
Synergistic effect of nitric oxide and H2S on rat pulmonary artery relaxation [64]
H2S-mediated ischemic after conditioning involved activation of NOS3 [121]
Inhibitory effects of H2S on nitric oxide synthesis and nitric oxide mediated vasorelaxation
NaHS inhibited recombinant NOS1 (nNOS) and NOS3 (eNOS) activity through interaction with BH4 and NOS2 through unknown mechanisms [107–109]
L-NAME inhibited CSE expression and H2S synthesis in thoracic artery and superior mesenteric artery in rats [80]
Nitric oxide dependent relaxation of rat aortic rings through either nitric oxide donors (SNP, SNAP or SIN-1) or nitric oxide dependent (acetyl- choline, histamine) but not nitric oxide independent (i.e. isoprenaline) mediators was inhibited by exogenous (H2S gas, NaHS) and endogenous
(L-cysteine/pyridoxal phosphate) H2S; an effect reversed by PAG [65]
L-NAME inhibited H2S-induced increase in mean arterial blood pressure in anaesthetized rats [65]
H2S inhibited vasorelaxation of isolated human internal mammary artery; induced by nitric oxide dependent mechanisms (i.e. acetylcholine) [57]
PAG inhibited SNP-mediated vasorelaxation of isolated rat aorta [114]
Other evidence of RNS-H2S interaction
Scavenging’ of ONOO−; inhibition of ONOO−-mediated cell death, intracellular protein nitration and tyrosine nitration in vitro[11]
Inhibition of tyrosine nitration in vivoin animal model of myocardial ischemia reperfusion [99]
Several nitric oxide donors react with NaHS in vitro to form a species resembling an inert ‘nitrosothiol’[11, 26, 57, 65]
H2S-dependent nitrosothiol formation during lipopolysaccharide-induced septic shock in the rat [26]
NaHS-mediated decrease of O2− formation in human vascular smooth muscle cells was inhibited by the nitric oxide donor spermine
NONOate [77]