Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway.

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.