Inhibition of arterial contraction by dinitrosyl-iron complexes: critical role of the thiol ligand in determining rate of nitric oxide (NO) release and formation of releasable NO stores by S-nitrosation.
The inhibition of arterial tone produced by two nitric oxide (NO) derivatives of biological relevance, dinitrosyl-iron complexes with cysteine (DNIC-CYS) or with glutathione (DNIC-GSH), was compared. Both compounds induced vasorelaxation within the same concentration range (3-300 nM) in endothelium-denuded rat aortic rings. Consistent with a faster rate of NO release from DNIC-CYS than from DNIC-GSH, the relaxant effect of DNIC-CYS was rapid in onset and tended to recover with time, whereas the one of DNIC-GSH developed slowly and was sustained. In addition, DNIC-GSH (0.3 and 1 microM) but not DNIC-CYS (1 microM) induced, even after washout of the drug, a persistent hyporesponsiveness to vasoconstrictors and a relaxant effect of low molecular weight thiols like N-acetylcysteine (NAC, which can displace NO from preformed NO stores). Both effects of DNIC-GSH were associated with elevation of cyclic GMP content and were attenuated by NO scavengers or a cyclic GMP-dependent protein kinases inhibitor. In rings previously exposed to DNIC-GSH, addition of mercuric chloride (which can cleave the cysteine-NO bond of S-nitrosothiols) elicited relaxation, completely blunted the one of NAC and also abolished the persistent elevation of NO content. In conclusion, this study shows that whereas both DNIC-CYS and DNIC-GSH elicited a NO release-associated relaxant effect in isolated arteries, only DNIC-GSH induced an inhibition of contraction which persisted after drug removal. The persistent effect of DNIC-GSH was attributed to the formation of releasable NO stores in arterial tissue, most probably as S-nitrosothiols. Thus, the nature of the thiol ligand plays a critical role in determining the mechanisms and duration of the effect of LMW-DNIC in arteries.
Alencar
Jacicarlos L
JL
Faculté de Pharmacie, Pharmacologie and Physico-Chimie, UMR CNRS 7034, Université Louis Pasteur, 67401 Illkirch, France.
Chalupsky
Karel
K
Sarr
Mamadou
M
Schini-Kerth
Valérie
V
Vanin
Anatoly F
AF
Stoclet
Jean-Claude
JC
Muller
Bernard
B
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D008297:Male; D008627:Mercuric Chloride / Q000494:pharmacology; D008970:Molecular Weight; D009569:Nitric Oxide / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D015538:Nitrosation; D051381:Rats; D017208:Rats, Wistar; D026403:S-Nitrosothiols / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D009589:Nitrogen Oxides; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D008627:Mercuric Chloride; C073661:dinitrosyl iron complex; D007501:Iron; D005978:Glutathione; D006152:Cyclic GMP; D000111:Acetylcysteine