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

Background and Purpose Whether NO, carbon monoxide (CO) and hydrogen sulfide (H<inf>2</inf>S) compensate for each other when one or more is depleted is unclear. Inhibiting NOS causes hypertension and kidney injury. Both global depletion of H<inf>2</inf>S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H<inf>2</inf>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 H<inf>2</inf>S and increased CO after 4 weeks. PAG abolished H<inf>2</inf>S, always enhanced CO and reduced NO, but not when used in combination with other inhibitors. SnPP always increased NO, enhanced H<inf>2</inf>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 H<inf>2</inf>S and/or CO-producing enzymes appeared to be associated with secondary increases in renal CO or NO production.