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

Abstract

BACKGROUND AND PURPOSEWhether NO, carbon monoxide (CO) and hydrogen sulfide (H2S) compensate for each other when one or more is depleted is unclear. Inhibiting NOS causes hypertension and kidney injury. Both global depletion of H2S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H2S 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 APPROACHRats 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 RESULTSLNNA always reduced NO, decreased H2S and increased CO after 4 weeks. PAG abolished H2S, always enhanced CO and reduced NO, but not when used in combination with other inhibitors. SnPP always increased NO, enhanced H2S 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 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. 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

dl-propargylglycine reduces blood pressure and renal injury but increases kidney weight in angiotensin-II infused rats

“…The latter effect was possibly caused by a reduction in inflammation [16; 17; 18]. Blocking H 2 S production resulted in an increase in CO production in-vivo [15] and in-vitro [19]. Similar in-vivo effects on CO production were observed when H 2 S inhibition was combined with NO synthase blockade [15].…”

“…PAG (dissolved in saline 30 mg/mL, 37.5 mg/kg BW) was administered daily intraperitoneally (ip) for one or four weeks in healthy rats (n=6, CON + PAG), while healthy saline treated rats served as control group (n=6, CON) as previously described [15]. Hypertension-driven renal injury was induced by AngII infusion (435 ng/kg/min, Bachem, Weil am Rhein, Germany) for three weeks via a subcutaneous osmotic minipump (model 2004, Alzet, Cupertino, CA) which were implanted under isoflurane anesthesia with buprenorphine analgesia [12].…”

“…Blocking H 2 S production resulted in an increase in CO production in-vivo [15] and in-vitro [19]. Similar in-vivo effects on CO production were observed when H 2 S inhibition was combined with NO synthase blockade [15]. Remarkably, H 2 S donors are also able to increase hemeoxygenase-1 expression (HO-1) [20; 21].…”

“…Based on our previous finding that PAG ameliorated hypertension and renal injury induced by NO inhibition [15], we hypothesized that PAG also decreases blood pressure and ameliorates renal injury in the AngII model. Moreover, because we found PAG to enhance renal mass and affect cell proliferation, we also studied effects of PAG on epithelial cell number and size in-vivo and in-vitro.…”

“…Pretreatment of rats with PAG caused an increased infarct size after myocardial ischemia induced by vasoconstriction [14]. However, hypertension and proteinuria caused by blocking NO synthesis could be prevented by concomitant PAG administration [15].…”