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: 4.84). 03/2014; 172(6). DOI: 10.1111/bph.12674


Background and purpose:
Whether NO, carbon monoxide (CO) and hydrogen sulfide (H2 S) compensate for each other when one or more is depleted is unclear. Inhibiting NOS causes hypertension and kidney injury. Both global depletion of H2 S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H2 S cause hypertension. Inhibiting CO-producing enzyme haeme oxygenase-1 (HO-1) makes rodents hypersensitive to hypertensive stimuli. We hypothesized that combined inhibition of NOS and HO-1 exacerbates hypertension and renal injury, but how combined inhibition of NOS and CSE affect hypertension and renal injury was unclear.

Experimental approach:
Rats were treated with inhibitors of NOS (L-nitroarginine; LNNA), CSE (DL-propargylglycine; PAG), or HO-1 (tin protoporphyrin; SnPP) singly for 1 or 4 weeks or in combinations for 4 weeks.

Key results:
LNNA always reduced NO, decreased H2 S and increased CO after 4 weeks. PAG abolished H2 S, always enhanced CO and reduced NO, but not when used in combination with other inhibitors. SnPP always increased NO, enhanced H2 S and inhibited CO after 1 week. Rats treated with LNNA, but not PAG and SnPP, rapidly developed hypertension followed by renal dysfunction. LNNA-induced hypertension was ameliorated and renal dysfunction prevented by all additional treatments. Renal HO-1 expression was increased by LNNA in injured tubules and increased in all tubules by all other treatments.

Conclusions and implications:
The amelioration of LNNA-induced hypertension and renal injury by additional inhibition of H2 S and/or CO-producing enzymes appeared to be associated with secondary increases in renal CO or NO production.

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    • "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]. "
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    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 · 3.52 Impact Factor
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    • "Comprehensive and conceptually challenging reviews in this issue also summarize the anti-inflammatory and tissue protective activity of CO in specific conditions, such as acute gastrointestinal inflammation (Babu et al., 2015) and preeclampsia (Ahmed and Ramma, 2015), where both H2S and CO exert anti-angiogenic properties. The interaction of NO, H2S, and CO at the cellular level can be observed in several pathologies, such as ischaemic heart disease and hypertension, allowing several pharmacological approaches for modulation of these gasotransmitters in order to protect the ischaemic heart with or without co-morbidities (Andreadou et al., 2015) and to regulate blood pressure (Wesseling et al., 2015). Cardiovascular co-morbidities may alter cardioprotective signaling including gasotransmitters, therefore, co-morbidities have to be taken into account when developing cardioprotective therapies as reviewed recently elsewhere (Ferdinandy et al., 2014). "
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    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 · 4.84 Impact Factor
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    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 · 3.86 Impact Factor