Decrease in Ca2+ sensitivity as a mechanism of hydrogen peroxide-induced relaxation of rabbit aorta.
OBJECTIVE
In vascular strips, hydrogen peroxide (H2O2) relaxes alpha 1-adrenergic agonist-induced but not high-K(+)-induced contractions. The aim of this study was to explore H2O2-induced changes in [Ca2+]i of vascular smooth muscle and to elucidate the mechanisms of action of H2O2.


METHODS
Isolated rabbit aortic strips were isometrically contracted with high-K+ (64.7 mM) or phenylephrine (PE, 0.3 microM). The effects of 300 microM H2O2 on [Ca2+]i of endothelium-denuded vascular smooth muscle and tension were determined simultaneously by the fura-2 method. Changes in [Ca2+]i were expressed as percentages of high-K(+)-induced values measured at the beginning of the experiments. In another series of experiments, the relaxant effect of 300 microM H2O2 was examined in high-K+ (20 mM)-induced contraction in the presence of the protein kinase C activator, phorbol 12,13-dibutyrate (PDBu).


RESULTS
Hydrogen peroxide caused a reversible rise in [Ca2+]i of vascular smooth muscle under both resting conditions and in the precontracted state. During high-K(+)-induced contraction, H2O2 further increased [Ca2+]i by 26.6(s.e.m. 1.7)% accompanied by a small increase in tension of 6.5(1.9)% of high-K(+)-induced tension. By contrast, during PE-induced contraction, although H2O2 caused a comparable additional increase in [Ca2+]i (26.4(4.7)%), muscle tension fell by 28.9(2.2)% of the steady-state PE-induced tension. Hydrogen peroxide had a relaxant effect on augmented high-K(+)-induced contraction in which Ca2+ sensitivity of the contractile apparatus was elevated by PDBu.


CONCLUSIONS
In spite of its effect of increasing [Ca2+]i of vascular smooth muscle, hydrogen peroxide causes relaxation of endothelium-denuded, PE-precontracted rabbit aorta. The mechanism is probably through suppression of agonist-induced augmentation of Ca2+ sensitivity of the contractile apparatus.
Iesaki
T
T
Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Okada
T
T
Shimada
I
I
Yamaguchi
H
H
Ochi
R
R
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D013757:Tetraethylammonium Compounds; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D006861:Hydrogen Peroxide; D011188:Potassium; D002118:Calcium