Hydrogen sulfide and cerebral microvascular tone in newborn pigs

Abstract

drogen sulfide (H2S) is a gaseous signaling molecule that appears to be involved in numerous biological processes, including regulation of blood pressure and vascular tone. The present study is designed to address the hypothesis that H2S is a functionally significant, endogenous dilator in the newborn cerebrovascular circulation. In vivo experiments were conducted using newborn pigs with surgically implanted, closed, cranial windows. Topical application of H2S concentration-dependently (10 Ϫ6 to 2 ϫ 10 Ϫ4 M) dilated pial arterioles. This dilation was blocked by glibenclamide (10 Ϫ6 M). L-Cysteine, the substrate of the H2S-producing enzymes cystathionine ␥-lyase (CSE) and cystathionine ␤-synthase (CBS), also dilated pial arterioles. The dilation to L-cysteine was blocked by the CSE inhibitor D,L-propargylglycine (PPG, 10 mM) but was unaffected by the CBS inhibitor amino-oxyacetate (AOA, 1 mM). Western blots detected CSE, but not CBS, in cerebral microvessels, whereas CBS is detected in brain parenchyma. Immunohistological CSE expression is predominantly vascular while CBS is expressed mainly in neurons and astrocytes. L-Cysteine (5 mM) increased H2S concentration in cerebrospinal fluid (CSF), measured by GC-MS, from 561 Ϯ 205 to 2,783 Ϯ 818 nM before but not during treatment with PPG (1,030 Ϯ 70 to 622 Ϯ 78 nM). Dilation to hypercapnia was inhibited by PPG but not AOA. Hypercapnia increased CSF H2S concentration from 763 Ϯ 243 to 4,337 Ϯ 1789 nM before but not during PPG treatment (357 Ϯ 178 vs. 425 Ϯ 217 nM). These data show that H2S is a dilator of the newborn cerebral circulation and that endogenous CSE can produce sufficient H2S to decrease vascular tone. H2S appears to be a physiologically significant dilator in the cerebral circulation.

The therapeutic potential of hydrogen sulfide: separating hype from hope

“…This has been confirmed repeatedly and even observed in pulmonary arteries of diving mammals (119). H 2 S-induced relaxation appears to depend on extracellular Ca 2ϩ (203), and although K ATP channels, are frequently assumed to mediate the H 2 S relaxation (63,86,203,204), this mechanism typically accounts for no more than half of the relaxation in most vessels. In some animals, such as the mouse, K ATP channels are not involved at all in the response.…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…In addition to the well-defined nitrogen-related gaseous species described above, carbon monoxide (CO) and hydrogen sulfide (H 2 S) have also been shown to have potent effects in the blood vessel wall as specific cellular signaling molecules that can alter local vasoconstriction/dilation and blood pressure [e.g., CO (Suematsu et al, 1994;Johnson et al, 1997;Caudill et al, 1998;Leffler et al, 1999); H 2 S (Zhao et al, 2001;Yang et al, 2008;Leffler et al, 2011a;Liang et al, 2011)]. Both gases are produced by ubiquitously expressed enzymes.…”

Microcirculation of the Newborn

“…This supports an endothelial, CSE-derived source of H 2 S in the mammalian foetus. Leffler et al [88] showed that H 2 S may also be important in the transitional cerebral circulation of newborn piglets with endogenous H 2 S produced by CSE, but not CBS, in concentrations capable of eliciting pial arteriolar dilatation.…”