Involvement of H2O2 in superoxide‐dismutase‐induced enhancement of endothelium‐dependent relaxation in rabbit mesenteric resistance artery

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Abstract
The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium‐dependent relaxation was investigated in rabbit mesenteric resistance arteries. SOD (200 U ml−1) increased the production of H2O2 in smooth muscle cells (as indicated by the use of an H2O2‐sensitive fluorescent dye). Neither SOD nor catalase (400 U ml−1) modified either the resting membrane potential or the hyperpolarization induced by acetylcholine (ACh, 1 μM) in smooth muscle cells. In arteries constricted with noradrenaline, the endothelium‐dependent relaxation induced by ACh (0.01–1 μM) was enhanced by SOD (200 U ml−1) (PNG‐nitroarginine (nitric oxide (NO)‐synthase inhibitor) but not by either charybdotoxin+apamin (Ca2+‐activated‐K+‐channel blockers) or diclofenac (cyclooxygenase inhibitor). Neither ascorbate (50 μM) nor tiron (0.3 mM), superoxide scavengers, had any effect on the ACh‐induced relaxation, but each attenuated the enhancing effect of SOD on the ACh‐induced relaxation. Similarly, catalase (400 U ml−1) inhibited the effect of SOD without changing the ACh‐induced relaxation. In endothelium‐denuded strips constricted with noradrenaline, SOD enhanced the relaxation induced by the NO donor 1‐hydroxy‐2‐oxo‐3‐(N‐methyl‐3‐aminopropyl)‐3‐methyl‐1‐triazene (NOC‐7) (P2O2 (1 μM) enhanced the relaxation on the noradrenaline contraction induced by NOC‐7 and that induced by 8‐bromo‐cGMP, a membrane‐permeable analogue of guanosine 3′,5′ cyclic monophosphate (cGMP). SOD had no effect on cGMP production, whether measured in endothelium‐intact strips following an application of ACh (0.1 μM) or in endothelium‐denuded strips following an application of NOC‐7 (0.1 μM). It is suggested that in rabbit mesenteric resistance arteries, SOD increases the ACh‐induced, endothelium‐dependent relaxation by enhancing the action of NO in the smooth muscle via its H2O2‐producing action (rather than via a superoxide‐scavenging action). British Journal of Pharmacology (2003) 139, 444–456. doi:10.1038/sj.bjp.0705255