Background-The potential biological significance of hydrogen sulfide (H 2 S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H 2 S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas. Methods and Results-The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H 2 S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle K ATP channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce N G -nitro-L-arginine methyl ester-evoked hypertension in the anesthetized rat and after chronic (14-day) administration in spontaneously hypertensive rats. Conclusions-These results identify GYY4137 as a slow-releasing H 2 S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H 2 S. GYY4137 may also prove of therapeutic value in cardiovascular disease.

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We previously reported that hydrogen sulfide (H(2)S) preconditioning (SP) produces cardioprotective effects against ischemia in rat cardiac myocytes. The present study aims to elucidate the signaling mechanisms involved in SP-induced cardioprotection by investigating the role of extracellular signal regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt. We found that preconditioning with NaHS (a H(2)S donor) for three cycles significantly decreased myocardial infarct size and improved heart contractile function in the isolated rat hearts. NaHS (1-100 microM) concentration-dependently increased cell viability and percentage of rod-shaped cardiac myocytes. Blockade of ERK1/2 with PD 98059 or PI3K/Akt with LY-294002 or Akt inhibitor III during either preconditioning or ischemia periods significantly attenuated the cardioprotection of SP, suggesting that both ERK1/2 and PI3K/Akt triggered and mediated the cardioprotection of SP. Moreover, SP induced ERK1/2 and Akt phosphorylation in isolated hearts. The phosphorylation of ERK1/2 induced by SP was attenuated by either glibenclamide, an ATP-sensitive K(+) channel (K(ATP)) blocker, or chelerythrine, a specific protein kinase C (PKC) blocker. In addition, ischemic-preconditioning-induced ERK1/2 activation was reversed by inhibiting endogenous H(2)S production, suggesting that ERK1/2 activation induced by ischemic preconditioning was, at least partly, mediated by endogenous H(2)S. In conclusion, K(ATP)/PKC/ERK1/2 and PI3K/Akt pathways contributed to SP-induced cardioprotection.

Yong QC, Lee SW, Foo CS, Neo KL, Chen X, Bian JS. Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning.

Hydrogen sulphide (H 2 S), which is produced endogenously from L-cysteine in mammalian tissues, has been suggested to function as a neuromodulator in the brain. However, the role of H 2 S in microglial cells is unclear. In this study, the effect of exogenous and endogenous H 2 S on intracellular calcium homeostasis was investigated in primary cultured microglial cells. Sodium hydrosulphide (NaHS), a H 2 S donor, caused a concentration-dependent (0.1-0.5 mM) increase in intracellular calcium concentration ([Ca 21 ] i ). This effect was significantly attenuated in the presence of a calcium-free extracellular solution, Gd 31 (100 lM), a nonselective Ca 21 channel blocker, or thapsigargin (2 lM), an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca 21 -ATPase. These observations suggest that the increase in [Ca 21 ] i in response to H 2 S involves both calcium influx across the plasma membrane and calcium release from intracellular stores. The H 2 S-induced calcium elevation is partly attenuated by H-89, a selective cAMP-dependent protein kinase (PKA) inhibitor, but not by U73122, a phospholipase C (PLC) inhibitor, and chelerythrine, a selective protein kinase C (PKC) inhibitor, suggesting the involvement of cAMP/PKA, but not PLC/PKC/phosphoinositol-3,4,5-inositol (IP 3 ) pathway. Using RT-PCR, only cystathionine g-lyase (CSE), a H 2 S producing enzyme, was detected in primary cultures of microglia. Lowering endogenous H 2 S level with, D,L-propargylglycine and b-cyano-L-alanine, two CSE inhibitors, significantly decreased [Ca 21 ] i , suggesting that endogenous H 2 S may have a positive tonic influence on [Ca 21 ] i homeostasis. These findings support the possibility that H 2 S may serve as a neuromodulator to facilitate signaling between neurons and microglial cells.