Low molecular mass dinitrosyl nonheme-iron complexes up-regulate noradrenaline release in the rat tail artery

Abstract

Background: Dinitrosyl nonheme-iron complexes can appear in cells and tissues overproducing nitric oxide. It is believed that due to their chemical nature these species may be implicated in certain pathophysiological events. We studied the possible role of low molecular mass dinitrosyl iron complexes in the control of noradrenaline release in electrically stimulated rat tail artery.

Results: A model complex, dinitrosyl-iron-thiosulfate (at 1-10 microM) produced a concentration-dependent enhancement of electrical field stimulated [3H]noradrenaline release (up to 2 fold). At the same time, dinitrosyl-iron-thiosulfate inhibited neurogenic vasoconstriction, consistent with its nitric oxide donor properties. A specific inhibitor of cyclic GMP dependent protein kinase, Rp-8pCPT-cGMPS, partially inhibited the effect of dinitrosyl-iron-thiosulfate on neurogenic vasoconstriction, but not on [3H]noradrenaline release. Another model complex, dinitrosyl-iron-cysteine (at 3 microM) elicited similar responses as dinitrosyl-iron-thiosulfate. Conventional NO and NO+ donors such as sodium nitroprusside, S-nitroso-L-cysteine or S-nitroso-glutathione (at 10 microM) had no effect on [3H]noradrenaline release, though they potently decreased electrically-induced vasoconstriction. The "false complex", iron(II)-thiosulfate showed no activity.

Conclusions: Low molecular mass iron dinitrosyl complexes can up-regulate the stimulation-evoked release of vascular [3H]noradrenaline, apparently independently of their NO donor properties. This finding may have important implications in inflammatory tissues.

Figure 1

Effect of DNIC-thiosulfate on electrical field stimulated [³H]noradrenaline release and vasoconstriction in the rat tail artery. Four periods (S₁–S₄) of electrical-field stimulation were delivered with intervals of 16 min. DNIC-thiosulfate was added 8 min before S₃. The effect of DNIC-thiosulfate is presented as the ratio of change of [³H]noradrenaline in the perfusate or change of perfusion pressure evoked by S₄ over S₂. Each point represents the mean ± S.E.M. from 6–7 arteries. ^* P < 0.05 and ^** P < 0.01 in comparison to control arteries.

Figure 2

Effects of PKG inhibitor, (Rp)-8-pCPT-cGMPS on the DNIC-thiosulfate-induced vascular effects in the rat tail artery. The effect of the drugs is presented as the ratio of change of [³H]noradrenaline or change in perfusion pressure evoked by S₄ over S₂. Each point represents the mean ± S.E.M. from 6–7 arteries. ^* P < 0.01 in comparison to control arteries; ^# P < 0.01 in comparison to arteries treated with DNIC-thiosulfate alone.