Hydrogen sulfide in the mouse ductus arteriosus: a naturally occurring relaxant with potential EDHF function

Abstract

We have previously reported that bradykinin relaxes the fetal ductus arteriosus via endothelium-derived hyperpolarizing factor (EDHF) when other naturally occurring relaxants (prostaglandin E2, nitric oxide, and carbon monoxide) are suppressed, but the identity of the agent could not be ascertained. Here, we have examined in the mouse whether hydrogen sulfide (H2S) is a relaxant of the ductus and, if so, whether it may also function as an EDHF. We found in the vessel transcripts for the H2S synthetic enzymes, cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), and the presence of these enzymes was confirmed by immunofluorescence microscopy. CSE and CBS were distributed across the vessel wall with the former prevailing in the intimal layer. Both enzymes occurred within the endoplasmic reticulum of endothelial and muscle cells, whereas only CSE was located also in the plasma membrane. The isolated ductus contracted to inhibitors of CSE (d,l-propargylglycine, PPG) and CBS (amino-oxyacetic acid), and PPG contraction was attenuated by removal of the endothelium. EDHF-mediated bradykinin relaxation was curtailed by both PPG and amino-oxyacetic acid, whereas the relaxation to sodium nitroprusside was not affected by either treatment. The H2S donor sodium hydrogen sulfide (NaHS) was also a potent, concentration-dependent relaxant. We conclude that the ductus is endowed with a H2S system exerting a tonic relaxation. In addition, H2S, possibly via an overriding CSE source, qualifies as an EDHF. These findings introduce a novel vasoregulatory mechanism into the ductus, with implications for antenatal patency of the vessel and its transitional adjustments at birth.

Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors

“…Al-Magableh and Hart (2011) and Hedegaard et al 2014)). As a result of these studies, H 2 S is often described as a "potent vasodilator" (Bhatia 2005;Pushpakumar et al 2014;Ariyaratnam et al 2013;Jang et al 2014;Baragatti et al 2013;Ghasemi et al 2012) despite data clearly showing otherwise. However, the addition of GYY4137 at concentrations and incubation times which deliver nM to low μM H 2 S also leads to vasodilation in vitro and in vivo (Table 1) suggesting blood vessels are acutely sensitive to small fluxes of H 2 S when it is generated in a manner and a level comparable to enzymatic (e.g.…”

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

“…In addition to bradykinin, which has been shown to have the same relaxation efect as EDHF, there could be more agents potentially qualiied as EDHF. A more recent study reported that hydrogen sulide (H 2 S) also acts as EDHF by expressing its synthetic enzymes cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) in the intima, likely ECs of the DA [54].…”

Microcirculation of the Newborn

“…In VSMCs, opening of K ATP channels leads to hyperpolarisation of the cell membrane, inactivating voltage-dependent calcium channels and resulting in VSMC relaxation [81]. Thus, H 2 S has been implicated as a crucial physiological mediator of vascular tone that represents an alternative pathway of vascular tone control to NO and CO. Like all the gasotransmitters, H 2 S is lipophilic, ensuring rapid diffusion of the gas throughout the endothelium and VSMCs, despite its intrinsic reactivity with a diverse range of substrates [82,83]. This diffuse production across the vessel wall and its mechanism of action qualify H 2 S as an EDHF [84].…”

“…Recent studies, however, suggest that this developmental expression pattern may not be consistent across different tissues and vascular networks. Baragatti et al [82] have recently demonstrated gene expression of CSE, CBS and MST in the ductus arteriosus in fetal mice (MST expression was very low compared with CSE and CBS). The expression of CSE and CBS was localised to the ductus with a specific distribution: CSE staining was more intense in the endothelial layer (45% higher than in the smooth muscle layer).…”