Extracellular nitric oxide release mediates soluble guanylate cyclase-independent vasodilator action of spermine NONOate: comparison with other nitric oxide donors in isolated rat femoral arteries.
Nitric oxide (NO) and NO donors exhibit actions that are not entirely mediated by soluble guanylate cyclase (sGC). The site of NO release may influence the involvement of sGC-independent effects. Here we use spermine NONOate (SPER/NO) to release NO extracellularly, compared with other NO donors. Isolated rat femoral arteries were perfused luminally and perfusion pressure monitored. Vessels were contracted with phenylephrine (2-14 microM) in the presence of an NO synthase inhibitor (N(omega)-nitro-L-arginine methyl ester; 20 microM). Vasodilator responses to NO donors were assessed before and after perfusion of an sGC inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ; 20 microM), NO scavengers (hemoglobin; Hb & hydroquinone; HQ), and a superoxide generator (duroquinone; DQ). ODQ (20 microM) abolished the vasodilator responses to glyceryl trinitrate (10(-8) - 10(-3) M), and sodium nitroprusside (10(-8) - 10(-4) M), which release NO intracellularly. ODQ (20 microM) attenuated, but failed to abolish, the vasodilator responses to SPER/NO (10(-6) - 10(-3) M). ODQ abolished responses to S-nitrosoglutathione and S-nitroso-N-valeryl-D-penicillamine (10(-8) - 10(-4) M), but a small residual vasodilatation remained in response to 10(-3) M. In the presence of ODQ, the remaining vasodilatation to SPER/NO was all but abolished by scavengers of extracellular NO (Hb; 10 microM, HQ; 100 microM). Superoxide generation (DQ; 100 microM) also attenuated ODQ-resistant vasodilatation. The data suggest that, in rat femoral arteries, NO donors that are capable of releasing extracellular NO cause vasodilatation that is only partially mediated by sGC. Lack of augmentation of sGC-independent effects by superoxide suggests that they are not mediated by peroxynitrite.
Miller
M R
MR
Centre for Cardiovascular Science, Hugh Robson Building, University of Edinburgh, Edinburgh, Scotland, UK.
Okubo
K
K
Roseberry
M J
MJ
Webb
D J
DJ
Megson
I L
IL
D000818:Animals; D004347:Drug Interactions; D005263:Femoral Artery; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009589:Nitrogen Oxides; D051381:Rats; D017208:Rats, Wistar; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D006162:Guanylate Cyclase