Iron-sulphur cluster nitrosyls, a novel class of nitric oxide generator: mechanism of vasodilator action on rat isolated tail artery.
1. Two iron-sulphur cluster nitrosyls have been investigated as potential nitric oxide (NO.) donor drugs (A: tetranitrosyltetra-mu 3-sulphidotetrahedro-tetrairon; and B: heptanitrosyltri-mu 3-thioxotetraferrate(1-)). Both compounds are shown to dilate precontracted, internally-perfused rat tail arteries. 2. Bolus injections (10 microliters) of compound A or B generate two kinds of vasodilator response. Doses below a critical threshold concentration (DT) evoke transient (or T-type) responses, which resemble those seen with conventional nitrovasodilators. Doses > DT produce sustained (or S-type) responses, comprising an initial, rapid drop of pressure, followed by incomplete recovery, resulting in a plateau of reduced tone which can persist for several hours. 3. T- and S-type responses are attenuated by ferrohaemoglobin (Hb) and by methylene blue (MB), but not by inhibitors of endothelial NO. synthase. Addition of either Hb or MB to the internal perfusate can restore agonist-induced tone when administered during the plateau phase of an S-type response. Moreover, subsequent removal of Hb causes the artery to re-dilate fully. 4. We conclude that T- and S-type responses are both mediated by NO.. It is postulated that S-type responses represent the sum of two vasodilator components: a reversible component, superimposed upon a non-recoverable component. The former is attributed to free NO., preformed in solution at the time of injection; and the latter to NO. generated by gradual decomposition of a 'store' of iron-sulphur-nitrosyl complexes within the tissue. This hypothesis is supported by histochemical studies which show that both clusters accumulate in endothelial cells.
Flitney
F W
FW
School of Biological & Medical Sciences, University of St Andrews, Fife, Scotland.
Megson
I L
IL
Flitney
D E
DE
Butler
A R
AR
D000818:Animals; D001158:Arteries / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology*; D058085:Iron Compounds; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D013623:Tail / Q000098:blood supply; D014665:Vasodilator Agents / Q000494:pharmacology*
D007502:Iron Chelating Agents; D058085:Iron Compounds; D009603:Nitroso Compounds; D014665:Vasodilator Agents; C078951:tetranitrosyltetra-mu3-sulfidotetrahedro-tetrairon; D009599:Nitroprusside; D009569:Nitric Oxide; C078952:Roussin's Black Salt; D026423:S-Nitroso-N-Acetylpenicillamine; D002217:Carbachol; D010396:Penicillamine