BACKGROUND AND PURPOSEHypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. EXPERIMENTAL APPROACHMale Sprague Dawley rats were infused with Ang II (435 ng kg min −1 ) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). KEY RESULTSCompared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. CONCLUSIONS AND IMPLICATIONSAng II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx

Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTR). Elevated plasma asymmetric dimethylarginine (pADMA), an endogenous nitric oxide synthase inhibitor produced from the turnover of methylated arginine moieties in proteins, is a risk factor for CVD and mortality. It is unknown how urinary ADMA excretion (uADMA), one of the main ADMA elimination routes, is associated with long-term survival. Furthermore, the association of pADMA and uADMA with markers for turnover of arginine-methylated proteins is unknown. We analyzed ADMA using a validated GC-MS/MS method in plasma and 24-h urine samples of 685 RTR, included ≥ 1 year after transplantation. We also analyzed urine symmetric dimethylarginine (uSDMA) using the same method. Urinary creatinine and urea excretions were used as markers for turnover of muscle protein and amino acids, respectively. We applied Cox regression analyses to study associations of pADMA, uADMA, and uSDMA with all-cause and CVD mortality. Mean pADMA was 0.61 ± 0.12 µM, uADMA was 31 ± 13 µmol/24 h, and uSDMA was 52 ± 19 µmol/24 h. Over median follow-up of 5.4 [4.9-6.1] years, 147 RTR died, of which 58 (39%) from CVD. High pADMA was associated with high all-cause mortality (HR per SD [95% CI]: 1.45 [1.26-1.67], P < 0.001), while high uADMA was associated with low all-cause and CVD mortality (HR per SD [95% CI]: 0.57 [0.47-0.69], P < 0.001, and 0.55 [0.40-0.74], P < 0.001, respectively). The associations were independent of adjustment for potential confounders. Creatinine excretion was associated with both pADMA (st. β:− 0.21, P = 0.003) and uADMA (st. β: 0.49, P < 0.001), and urea excretion was associated with uADMA (st. β: 0.56, P < 0.001). Associations of uSDMA with outcomes and with creatinine excretion and urea excretion were comparable to those of uADMA. The associations of pADMA, uADMA and uSDMA with mortality were strongly affected by adjustment for creatinine excretion and urea excretion. We found for the first time that high uADMA and high uSDMA are associated with less risk of all-cause and CVD mortality. The links of uADMA and uSDMA with markers of muscle protein and amino acid turnover may serve to further understand ADMA and SDMA homeostasis and their clinical implications. Keywords Kidney transplantation • ADMA • SDMA • Muscle mass • Protein turnover • Long-term survival Abbreviations ADMA Asymmetric dimethylarginine AGXT2 Alanine-glyoxylate aminotransferase 2 BMI Body mass index BSA Body surface area CI Confidence interval CKD-EPI Chronic kidney disease epidemiology collaboration CVD Cardiovascular disease DDAH Dimethylarginine dimethylaminohydrolase D-NAME N G-Nitro-d-arginine methyl ester eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate Handling Editor: P. Beltran-Alvarez. M. Yusof Said and A. Bollenbach shared first authorship.

Hydrogen sulfide (H 2 S), carbon monoxide (CO) and nitric oxide (NO) share signaling and vasorelaxant properties and are involved in proliferation and apoptosis. Inhibiting NO production or availability induces hypertension and proteinuria, which is prevented by concomitant blockade of the H 2 S producing enzyme cystathionine γ-lyase (CSE) by D,L-propargylglycine (PAG). We hypothesized that blocking H 2 S production ameliorates Angiotensin II (AngII)-induced hypertension and renal injury in a rodent model.Effects of concomitant administration of PAG or saline were therefore studied in healthy (CON) and AngII hypertensive rats.In CON rats, PAG did not affect systolic blood pressure (SBP), but slightly increased proteinuria. In AngII rats PAG reduced SBP, proteinuria and plasma creatinine (180±12 vs. 211±19 mmHg; 66±35 vs. 346±92 mg/24h; 24±6 vs. 47±15 µmol/L, respectively; p<0.01). Unexpectedly, kidney to body weight ratio was increased in all groups by PAG (p<0.05). Renal injury induced by AngII was reduced by PAG (p<0.001).HO-1 gene expression was increased by PAG alone (p<0.05). PAG increased inner cortical tubular cell proliferation after 1 week and decreased outer cortical tubular nucleus number/field after 4 weeks. In vitro proximal tubular cell size increased after exposure to PAG. In summary, blocking H 2 S production with PAG reduced SBP and renal injury in AngII infused rats.

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