Hydrogen sulfide (H(2)S) is an endogenous mediator with peripheral vasorelaxant effects; however, the mechanism of H(2)S-induced vasorelaxation in cerebral blood vessels has not been extensively studied. Vasorelaxation studies were performed on middle cerebral arteries from male Sprague Dawley rats using wire myography. Immunofluorescence staining was used to detect the presence of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE). CSE was present in the endothelium and smooth muscle of middle cerebral arteries. The CSE substrate, L-cysteine, induced vasorelaxation that was sensitive to the CSE inhibitor DL-propargylglycine. This relaxation was independent of endothelium, suggesting that H(2)S was produced in the vascular smooth muscle. The H(2)S donor, sodium hydrogen sulfide (NaHS; 0.1-3.0 mM) produced concentration-dependent relaxation, which was unaffected by endothelium removal. Nifedipine (3 μM) significantly reduced the maximum relaxation elicited by NaHS. Inhibiting potassium (K(+)) conductance with 50 mM K(+) significantly attenuated NaHS-induced relaxation, however, selective blockers of ATP sensitive (K(ATP)), calcium sensitive (K(Ca)), voltage dependent (K(V)), or inward rectifier (K(ir)) channels alone or in combination did not affect the response to NaHS. 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS; 300 μM) caused a significant rightward shift of the NaHS concentration-response curve, but this effect could not be explained by inhibition of Cl(-) channels or Cl(-)/HCO (3)(-) exchange, as selective blockade of these mechanisms had no effect. These findings suggest endogenous H(2)S can regulate cerebral vascular function. The H(2)S-mediated relaxation of middle cerebral arteries is DIDS sensitive and partly mediated by inhibition of L-type calcium channels, with an additional contribution by K channels but not K(ATP), K(Ca), K(V), or K(ir) subtypes.

Hydrogen sulfide is a novel mediator with the unique properties of a gasotransmitter and many and varied physiological effects. Included in these effects are a number of cardiovascular effects that are proving beneficial to vascular health. Specifically, H2S can elicit vasorelaxation, prevention of inflammation and leukocyte adhesion, anti-proliferative effects and anti-thrombotic effects. Additionally, H2S is a chemical reductant and nucleophile that is capable of inhibiting the production of reactive oxygen species, scavenging and neutralising reactive oxygen species and boosting the efficacy of endogenous anti-oxidant molecules. These result in resistance to oxidative stress, protection of vascular endothelial function and maintenance of blood flow and organ perfusion. H2S has been shown to be protective in hypertension, atherosclerosis and under conditions of vascular oxidative stress, and deficiency of endogenous H2S production is linked to cardiovascular disease states. Taken together, these effects suggest that H2S has a physiological role as a vasculoprotective factor and that exogenous H2S donors may be useful therapeutic agents. This review article will discuss the vascular effects and anti-oxidant properties of H2S as well as examine the protective role of H2S in some important vascular disease states.

Hydrogen sulfide (H2S) is produced endogenously in vascular tissue and has both vasoregulation and antioxidant effects. This study examines the effect of diabetes-induced oxidative stress on H2S production and function in rat middle cerebral arteries. Diabetes was induced in rats with streptozotocin (50 mg/kg, i.v.). Middle cerebral artery function was examined using a small vessel myograph and superoxide anion generation measured using nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lucigenin-enhanced chemiluminescence. Cystathionine-γ-lyase (CSE) mRNA expression was measured via RT-PCR. Diabetic rats had elevated blood glucose and significantly reduced cerebral artery endothelial function. Maximum vasorelaxation to the H2S donor NaHS was unaffected in diabetic cerebral arteries and was elicited via a combination of K+, Cl−, and Ca2+ channel modulation, although the contribution of Cl− channels was significantly less in the diabetic cerebral arteries. Vasorelaxation to the H2S precursor l-cysteine and CSE mRNA were significantly increased in diabetic cerebral arteries. Cerebral artery superoxide production was significantly increased in diabetes, but this increase was attenuated ex vivo by incubation with the H2S donor NaHS. These data confirm that cerebral artery endothelial dysfunction and oxidative stress occurs in diabetes. Endogenous H2S production and activity is upregulated in cerebral arteries in this model of diabetes. Vasorelaxation responses to exogenous H2S are preserved and exogenous H2S attenuates the enhanced cerebral artery generated superoxide observed in the diabetic group. These data suggest that upregulation of endogenous H2S in diabetes may play an antioxidant and vasoprotective role.

Hydrogen sulfide (H2S) is now recognized as an important signaling molecule and has been shown to have vasodilator and cardio-protectant effects. More recently it has been suggested that H2S may also act within the brain to reduce blood pressure (BP). In the present study we have demonstrated the presence of the H2S-producing enzyme, cystathionine-β-synthase (CBS) in the rostral ventrolateral medulla (RVLM), and the hypothalamic paraventricular nucleus (PVN), brain regions with key cardiovascular regulatory functions. The cardiovascular role of H2S was investigated by determining the BP, heart rate (HR), and lumbar sympathetic nerve activity (LSNA) responses elicited by a H2S donor sodium hydrogen sulfide (NaHS) or inhibitors of CBS, microinjected into the RVLM and PVN. In anesthetized Wistar Kyoto rats bilateral microinjections of NaHS (0.2–2000 pmol/side) into the RVLM did not significantly affect BP, HR, or LSNA, compared to vehicle. Similarly, when the CBS inhibitors, amino-oxyacetate (AOA; 0.1–1.0 nmol/side) or hydroxylamine (HA; 0.2–2.0 nmol/side), were administered into the RVLM, there were no significant effects on the cardiovascular variables compared to vehicle. Microinjections into the PVN of NaHS, HA, and AOA had no consistent significant effects on BP, HR, or LSNA compared to vehicle. We also investigated the cardiovascular responses to NaHS microinjected into the RVLM and PVN in spontaneously hypertensive rats. Again, there were no significant effects on BP, HR, and LSNA. Together, these results suggest that H2S in the RVLM and PVN does not have a major role in cardiovascular regulation.

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