Hydrogen sulfide mediates the vasoactivity of garlic

Abstract

The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H2S), an endogenous cardioprotective vascular cell signaling molecule. This H2S production, measured in real time by a novel polarographic H2S sensor, is supported by glucosemaintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H2S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the ␣ carbon of the allyl substituent, thereby forming a hydropolysulfide (RSnH), a key intermediate during the formation of H2S. Organic polysulfides (R-Sn-R; n > 2) also undergo nucleophilic substitution at a sulfur atom, yielding RSnH and H2S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H2S. The vasoactivity of garlic compounds is synchronous with H2S production, and their potency to mediate relaxation increases with H2S yield, strongly supporting our hypothesis that H2S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H2S can be used to standardize garlic dietary supplements.Allium ͉ aorta ͉ polysulfides ͉ red blood cells ͉ vasorelaxation

Arylthioamides as H2S Donors: l-Cysteine-Activated Releasing Properties and Vascular Effects in Vitro and in Vivo

“…19,20 In this work, a small library of arylthioamides (compounds 1−12, Chart 1) was easily prepared through suitable synthetic routes and evaluated for their H 2 S-releasing properties. The phydroxybenzothioamide 1 19,20 was selected as lead compound to build the library by inserting a number of modifications on the aromatic moiety: (i) introduction of different groups (Cl, F, CF 3 , NO 2 , and CH 3 ) at the 2-and/or 5-position of the phenyl ring (2−6); (ii) replacement of the 4-hydroxy group with an amino moiety (7); and (iii) replacement of the phenyl ring with electron poor or electron rich heterocycles such as pyridine (8) and piperazine (9), or furane (10), thiophene (11), and indole (12), respectively (Chart 1). Finally, compound 1 was submitted to further experimental protocols aimed to evaluate the vasorelaxing effects on rat aortic rings, the membrane hyperpolarizing activity on human vascular smooth muscle (VSM) cells and the effects on the blood pressure of normotensive rats.…”

“…The generation of H 2 S was evaluated by an amperometric approach, allowing to have a real-time determination of the H 2 S-release and thus to perform a qualitative/quantitative description of the process. In addition, since the release of H 2 S from DADS is reported to be a process, which requires the presence of organic thiols such as reduced glutathione, 12 the experiments were also performed in the presence of 4 mM L-cysteine. NaHS, DADS, and GYY4137 were also assayed for comparison purposes.…”

A new gaseous signaling molecule emerges: Cardioprotective role of hydrogen sulfide

“…Very recently, a third endogenously produced gaseous signaling molecule, hydrogen sulfide (H 2 S), has emerged as a potentially important mediator of CV homeostasis and cytoprotection (3). In this issue of PNAS, Benavides et al (4) reveal that the vasculoprotective and antihypertensive effects of dietary garlic (Allium sativum) are mediated in large part via the generation of H 2 S.…”

“…However, the mechanism(s) by which consumption of garlic attenuates CV disease has in large part remained a mystery. Benavides et al (4) elegantly demonstrate that garlic-derived organic polysulfides are converted by red blood cells (RBCs) into hydrogen sulfide gas. Interestingly, the garlic bulbs used for this study were obtained from local supermarkets in the city of Birmingham, AL, and then pressed by the investigators to obtain garlic juice on the day of the experiment.…”

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

“…The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17)(18)(19)(20)(21). H 2 S can be physiologically generated by two enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).…”