Peroxynitrite Inhibits Ca ²⁺ -Activated K ⁺ Channel Activity in Smooth Muscle of Human Coronary Arterioles

Abstract

Abstract-We examined the hypothesis that ONOOϪ , a product of the interaction between superoxide (O 2 ·Ϫ ) and nitric oxide (NO), inhibits calcium-activated K ϩ (K Ca ) channel activity in vascular smooth muscle cells (VSMCs) of human coronary arterioles (HCAs), thereby reducing hyperpolarization-mediated vasodilation. HCAs were dissected from right atrial appendages. The interaction of ONOO Ϫ with microvessels was determined by immunohistochemistry using a nitrotyrosine antibody. Strong staining was observed in arteries exposed to authentic ONOO Ϫ or to sodium nitroprusside (SNP)ϩxanthine (XA)ϩxanthine oxidase (XO). Dilation to 10 Ϫ8 mol/L bradykinin (BK) was abolished in vessels exposed to ONOO Ϫ (Ϫ2.5Ϯ8%; PϽ0.05) but not DC-ONOO Ϫ (65Ϯ8%). Reduced dilation to BK was also observed after application of XO and SNP. Dilation to NS1619 (K Ca channel opener) was reduced in endothelial denuded arterioles treated with ONOO Ϫ . In isolated VSMCs, whole-cell peak K ϩ current density was reduced by ONOO

Hydrogen peroxide stimulates the Ca2+-activated big-conductance K channels (BK) through cGMP signaling pathway in cultured human endothelial cells

“…Another possible interpretation for the controversial observation about H 2 O 2 effect on vasoactivity may be that the oxidation status of the tissue could affect the final effect of H 2 O 2 on BK channels. It is well established that NO could interact with superoxide to form peroxynitrite [34,35] which has been shown to inhibit Ca 2+ -activated BK channels in smooth muscle cells in rat cerebral artery and human coronary arterioles [36,37]. If tissue has a high superoxide level, increased NO release induced by H 2 O 2 could interact with superoxide to form peroxynitrite which inhibits K channels in vascular tissue and causes vasoconstriction.…”

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

“…31 Direct application of peroxynitrite to skeletal muscle resistance and human coronary arteries inhibits BK channel activity and causes vasoconstriction. 32,33 Antioxidant treatment restores impaired BK channel function. 31,33,34 NO increases BK channel activity in VSMC 35 and cslo (canine BK channel ␣-subunit) transfected HEK-293 cells.…”

Nitration and Functional Loss of Voltage-Gated K+ Channels in Rat Coronary Microvessels Exposed to High Glucose

“…Indeed, recent evidence has emphasized that NO derived from inducible NO synthase under conditions of high glucose (HG) may contribute to vasodilator dysfunction by driving the generation of ONOO Ϫ (3). In turn, ONOO Ϫ may promote oxidative and nitrosative tissue damage (4), in part by nitration of tyrosine residues to impair the function of multiple proteins, including K ϩ channels that mediate vasodilation (5,6).…”

“…In this regard, most studies have focused on ONOO Ϫ -induced inhibition of high-conductance Ca 2ϩ -activated K ϩ (K Ca ) channels as a mechanism of vasodilator impairment (5,6). However, a targeted inhibition of K Ca channels by ONOO Ϫ cannot account for some of the profound vasodilator defects that are induced by HG and seem to relate more closely to an impaired function of voltage-gated K ϩ (K v ) channels.…”