In order to investigate the protective mechanism of hydrogen sulfide (H2S) in sepsis-associated acute kidney injury (SA-AKI), ten AKI patients and ten healthy controls were enrolled. In AKI patients, levels of creatinine (Cre), urea nitrogen (BUN), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and myeloperoxidase (MPO) activity as well as concentrations of malondialdehyde (MDA) and hydrogen peroxide (H2O2) were significantly increased compared with those of controls. However, plasma level of H2S decreased and was linearly correlated with levels of Cre and BUN. After that, an AKI mouse model by intraperitoneal lipopolysaccharide (LPS) injection was constructed for in vivo study. In AKI mice, H2S levels decreased with the decline of 3-MST activity and expression; similar changes were observed in other indicators mentioned above. However, the protein expressions of TLR4, NLRP3, and caspase-1 in mice kidney tissues were significantly increased 6 h after LPS injection. NaHS could improve renal function and kidney histopathological changes, attenuate LPS-induced inflammation and oxidative stress, and inhibit expressions of TLR4, NLRP3, and caspase-1. Our study demonstrated that endogenous H2S is involved in the pathogenesis of SA-AKI, and exogenous H2S exerts protective effects against LPS-induced AKI by inhibiting inflammation and oxidative stress via the TLR4/NLRP3 signaling pathway.

Flow-induced dilation of gracilis muscle arterioles was examined in both genders of control rats and rats chronically treated with N(omega)-nitro-L-arginine methyl ester (L-NAME). After L-NAME treatment (4 wk), systolic blood pressure was significantly increased compared with control, whereas the plasma concentration of nitrate/nitrite was significantly reduced. Isolated and pressurized arterioles dilated significantly in response to increases in flow (0-25 microl/min). Flow-induced dilation was comparable in arterioles of control and L-NAME-treated rats but was significantly greater in female than in male rats. L-NAME + indomethacin, which abolished flow-induced dilation in arterioles of male control rats, inhibited the dilation by only ~75% in female control rats. The residual portion of the response was eliminated by additional administration of miconazole, an inhibitor of cytochrome P-450. Indomethacin did not affect the dilation in female L-NAME-treated rats but completely inhibited the response in male L-NAME-treated rats. The indomethacin-insensitive, flow-induced dilation in female L-NAME-treated arterioles was abolished by miconazole, 6-(2-proparglyoxyphenyl)hexanoic acid, or charybdotoxin. Thus an augmented release of endothelial prostaglandins accounts for the preserved flow-induced dilation in arterioles of male rats, whereas a metabolite of cytochrome P-450 is responsible for the maintenance of flow-induced dilation in female rats, suggesting important differences in the adaptation of the endothelium of arterioles from male and female rats to the lack of nitric oxide (NO) synthesis.

To investigate the role of estrogen in flow-induced dilation (FiD) in nitric oxide (NO) deficiency, FiD was examined in isolated gracilis arterioles of ovariectomized (OVX) and OVX rats with estrogen replacement (OVE). Both groups of rats were treated chronically with N(omega)-nitro-L-arginine methyl ester. Plasma concentration of NO(2)/NO(3) was reduced in both groups. Plasma concentration of estradiol was lower in OVX than in OVE rats. FiD was similar in vessels of the two groups; calculated wall shear stress and basal tone were significantly greater in OVX vs. OVE rats. Indomethacin did not affect FiD in vessels from OVE rats but abolished dilation in vessels from OVX rats. Valeryl salicylate or NS-398 inhibited FiD by approximately 50%, whereas their simultaneous administration eliminated the response in arterioles from OVX rats. In vessels from OVE rats, miconazole or charybdotoxin eliminated FiD. Thus, in NO deficiency, prostaglandins derived from both cyclooxygenase isoforms mediate FiD in gracilis arterioles of OVX rats. Estrogen replacement switches the mediation, showing dependence on endothelium-derived hyperpolarizing factor in the arterioles of OVE rats.

Reductions in hydrogen sulfide (HS) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N-nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the K channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by K channels. Impact statement 1. We found that HS ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. HS activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of HS was mediated by ATP-sensitive potassium channels.