Differential sensitivity to hydroxyl radicals of pre- and postjunctional neurovascular transmission in the isolated canine mesenteric vein

In some pathophysiological conditions, the first target of reactive oxygen intermediates is the vascular system. Superoxide anions, when generated in the vascular circulation, may then escape into the extracellular space via an anion channel and, following dismutation to hydrogen peroxide (H2O2), fo rm hydroxyl radicals (HO.). In an attempt to understand the role of HO. in the regulation of transmission at the sympathetic neurovascular junction, t he effect of HO. at nerve terminals was examined by measuring the amount of noradrenaline (NA) released from isolated, spirally cut, superfused canine mesenteric vein during basal and electrical stimulation (ES; 5 Hz, 2 ms, 9 V); tension development evoked by ES was also recorded simultaneously. HO. was generated from Fenton's reagent (1.5x10(-4) M H2O2 plus 10(-4) M FeSO4 ); generation of HO. from H2O2/FeSO4 in the superfusate was monitored by el ectron spin resonance spectroscopy using the spin-trap 5,5-dimethyl-1-pyrro line-N-oxide throughout the experimental time course. Exposure to HO of the helical strips produced an irreversible decrease in tension development ev oked by ES with no effect on NA release, suggesting that the observed effec t is elicited postjunctionally. The susceptibility of the processes of NA-m ediated contraction to HO may differ greatly from that of the NA release me chanism at the prejunctional site. Exposure of the strip preparation to HO leads to a substantial stimulation of basal release of NA without affecting ES-evoked NA release, possibly due to enhanced non-exocytotic Ca2+-indepen dent release elicited by HO.. A direct demonstration of this concept was ob tained by showing a significant increase in the basal response of NA releas e in Ca2+-free solution. The major conclusion of the present study is that HO. can damage NA-mediated contraction of the vascular preparations at the postjunctional site, and may selectively induce a non-exocytotic release of NA from the prejunctional site of sympathetic neurotransmission. (C) 2000 Elsevier Science Ltd. All rights reserved.