Abstract
Hydrogen peroxide (H(2)O(2)) is a mitochondrial-derived reactive oxygen species (ROS) that regulates vascular signalling transduction, vasocontraction and vasodilation. Although the physiological role of ROS in endothelial cells is acknowledged, the mechanisms underlying H(2)O(2) regulation of signalling in native, fully-differentiated endothelial cells is unresolved. In the present study, the effects of H(2)O(2) on Ca(2+) signalling were investigated in the endothelium of intact rat mesenteric arteries. Spontaneous local Ca(2+) signals and acetylcholine evoked Ca(2+) increases were inhibited by H(2)O(2). H(2)O(2) inhibition of acetylcholine-evoked Ca(2+) signals was reversed by catalase. H(2)O(2) exerts its inhibition on the IP(3) receptor as Ca(2+) release evoked by photolysis of caged IP(3) was supressed by H(2)O(2). H(2)O(2) suppression of IP(3)-evoked Ca(2+) signalling may be mediated by mitochondria. H(2)O(2) depolarized mitochondria membrane potential. Acetylcholine-evoked Ca(2+) release was inhibited by depolarisation of the mitochondrial membrane potential by the uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) or complex 1 inhibitor, rotenone. We propose that the suppression of IP(3)-evoked Ca(2+) release by H(2)O(2) arises from the decrease in mitochondrial membrane potential. These results suggest that mitochondria may protect themselves against Ca(2+) overload during IP(3)-linked Ca(2+) signals by a H(2)O(2) mediated negative feedback depolarization of the organelle and inhibition of IP(3)-evoked Ca(2+) release.