Beneficial effects of diminished production of hydrogen sulfide or carbon monoxide on hypertension and renal injury induced by NO withdrawal

British Journal of Pharmacology (Impact Factor: 4.99). 03/2014; 172(6). DOI: 10.1111/bph.12674

ABSTRACT Background and PurposeWhether nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) back-up for each other when one or more are depleted is unclear. Inhibiting NO synthase (NOS) causes hypertension and kidney injury. Both global depletion of H2S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H2S causes hypertension. Inhibiting CO-producing enzyme heme oxygenase-1 (HO-1) makes rodents hypersensitive to hypertensive stimuli. We hypothesize that combined inhibition of NOS and HO-1 aggravate hypertension and renal injury, but how combined inhibition of NOS and CSE affect hypertension and renal injury was uncertain. Experimental ApproachRats (n=6/group) were treated with inhibitors of NOS (L-nitroarginine; LNNA), CSE (DL-propargylglycine; PAG), or HO-1 (Tin protoporphyrin; SnPP) singly for one or four weeks or in combinations for four weeks. Key ResultsLNNA always reduced NO, and decreased H2S and increased CO after four weeks. PAG abolished H2S, always enhanced CO, and reduced NO but not when used in combined inhibition. SnPP always increased NO, and enhanced H2S and inhibited CO after one week. LNNA, but not PAG and SnPP, rapidly developed hypertension followed by renal dysfunction. LNNA-induced hypertension was ameliorated and renal dysfunction was prevented by all additional treatments. Renal HO-1 expression was increased with LNNA in injured tubules and was increased in all tubules by all other treatments. Conclusions and ImplicationsThe amelioration of LNNA-induced hypertension and renal injury by additional inhibition of H2S and/or CO producing enzymes appeared to be associated with secondary increases in renal CO or NO production.

  • Source
    • "Reduced renal damage and proteinuria might be partly related to the decrease in blood pressure. PAG reduced blood pressure induced by NO synthesis blockade by 15%, however proteinuria was reduced much more (81%) [15]. In AngII infused mice PAG did not affect the high blood pressure, but neither proteinuria nor renal damage were measured in this study [43]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydrogen sulfide (H2S), 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 H2S producing enzyme cystathionine γ-lyase (CSE) by D,L-propargylglycine (PAG). We hypothesized that blocking H2S 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 H2S production with PAG reduced SBP and renal injury in AngII infused rats. Independent of the cardiovascular and renal effects, PAG increased HO-1 gene expression and kidney weight. PAG alone increased tubular cell size and proliferation in-vivo and in-vitro. Our results are indicative of a complex interplay of gasotransmitter signaling/action of mutually compensatory nature in the kidney. Copyright © 2015. Published by Elsevier Inc.
    Nitric Oxide 05/2015; 47:S53. DOI:10.1016/j.niox.2015.02.127 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hydrogen sulfide (H2S), a colorless gas that is endogenously generated in mammals from cysteine, has important biological functions. Within the vasculature it regulates vessel tone and outgrowth of new vessels. This review summarizes recent literature on H2S signaling in the vasculature and its therapeutic potential in vascular disorders RECENT FINDINGS: H2S is able to induce vasorelaxation via ATP-sensitive potassium channels in vascular smooth muscle cells. Large-conductance calcium-dependent K-channels and Kv7 voltage-gated K-channels are also involved in H2S signaling. Vascular endothelial growth factor is the key downstream mediator that is involved in H2S induced angiogenesis. By having both direct effects on its receptor and increasing the bioavailability of vascular endothelial growth factor, H2S is proangiogenic. H2S-based therapies in vascular diseases are an expanding area of research. The applications of several compounds, such as natural donors and synthetic slow release compounds, have been extensively studied in vascular diseases such as hypertension, ischemia-reperfusion disorders and preeclampsia. H2S has a key role in vascular homeostasis during physiology and in pathological states. H2S-based therapies may have a role in several vascular diseases.
    Current Opinion in Nephrology and Hypertension 01/2015; 24(2). DOI:10.1097/MNH.0000000000000096 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 03/2015; 172(6). DOI:10.1111/bph.13005 · 4.99 Impact Factor