Hydrogen sulfide regulates intracellular Ca2+ concentration in endothelial cells from excised rat aorta.

Hydrogen sulphide (H2S) is a recently discovered gasotransmitter that may regulate a growing number of endothelial functions, including nitric oxide (NO) release, proliferation, adhesion and migration, which are the key steps of angiogenesis. The mechanism whereby H2S impacts on endothelial physiology is still unclear: however, the aforementioned processes are driven by an increase in intracellular Ca2+ concentration ([Ca2+]i). In the present study, we exploited the excised rat aorta to gain insights into the regulation of [Ca2+]i by H2S within in situ endothelial cells (ECs). Sodium hydrosulphide (NaHS), a H2S donor, caused an elevation in [Ca2+]i, which disappeared in absence of extracellular Ca2+. NaHSinduced Ca2+ inflow was sensitive to high doses of Gd3+, but not BTP-2. Inhibition of the reverse-mode of the Na+-Ca2+ exchanger (NCX), with KB-R7943 or upon removal of extracellular Na+, abrogated the Ca2+ response to NaHS. Moreover, NaHS-elicited Ca2+ entry was significantly reduced by TEA and glybenclamide, which hinted at the involvement of ATP-dependent K+ (KATP) channels. Conversely, NaHS-evoked Ca2+ signal was not affected by the reducing agent, dithiothreitol. Acute addition of NaHS hindered both Ca2+ release and Ca2+ entry induced by ATP, a physiological agonist of ECs. Consistently, inhibition of endogenous H2S synthesis with DL-propargylglycine impaired ATP-induced Ca2+ inflow, whereas it did not affect Ca2+ mobilization. These data provide the first evidence that H2S may stimulate Ca2+ influx into ECs by recruiting the reverse-mode of NCX and KATP channels. In addition, they show that such gasotransmitter may modulate the Ca2+ signals elicited by physiological stimuli in intact endothelium.

Old and new gasotransmitters in the cardiovascular system: focus on the role of nitric oxide and hydrogen sulfide in endothelial cells and cardiomyocytes.

The functional relevance of nitric oxide (NO) in the cardiovascular system is well established since the end of the 80', when it was firstly proposed as a key controller of vasodilation. More recent evidences, still debated and partly conflicting, point to a role of NO in the angiogenic progression. On the other hand hydrogen sulfide is a new entry as a gasotransmitter in the cardiovascular system. The variety of its biological functions seems to grow day after day. The first to be described is surely its reversible and poisoning binding of the cytochrome c oxidase that leads to impairment of the respiratory chain in mitochondria. However, sub-toxic concentrations have been later proved to be essential to maintain fundamental physiological functions in several tissues. The basal production of H2S is determined by the activity of, at least, three constitutively expressed enzymes (CBS, CSE, and 3-MPT) with tissue specificity for CBS and CSE in the central nervous and cardiovascular system, respectively. The assumption of a pivotal role of H2S in regulating physiological function is supported by the demonstration that reduced production of this gaseous molecule by CSE induces hypertension in mice. The increasing number of studies showing the regulatory functions of H2S reveals that maintaining the normal blood pressure levels is only one of its multiple biological actions. In this review, we would like to explore the recent literature on NO and H2S roles on cardiovascular system and to elucidate potential outcomes in the use of pharmacological drugs interfering with their metabolism.