Opposing effects of oxidants and antioxidants on K+ channel activity and tone in rat vascular tissue

Abstract

SUMMARYK+ channels regulate tone in both the systemic and pulmonary circulations. K+ channel inhibition leads to membrane depolarization, Ca2+ influx and vasoconstriction; K+ channel activation leads to hyperpolarization and vasodilatation. The sulfhydryl oxidant diamide opens K+ channels in pulmonary smooth muscle and acts as a potent vasodilator in perfused lungs. We examined the hypothesis that antioxidants cause constriction and oxidants cause relaxation through their effects on K+ channels in vascular smooth muscle. The oxidant diamide (380 #/M and 3-8 mM) inhibited the reduction of cytochrome C by ferrous sulphate in vitro whilst the antioxidants co-enzyme Qlo (770 /M) and duroquinone (700 uM) increased the rate of reduction. Both antioxidants caused dose-dependent constriction of endothelium-intact and -denuded rat pulmonary artery and aortic rings. This constriction could be reversed by 1 /M diamide. Co-enzyme Qlo and duroquinone (both at 100 /SM) partially inhibited (-30%) whole-cell K+ channel currents and depolarized membranes of isolated pulmonary artery smooth muscle cells recorded using the amphotericinperforated-patch-clamp technique. Diamide (100 /LM) increased whole-cell K+ channel currents and hyperpolarized the membrane. The data suggest that oxidants and antioxidants may modulate vascular tone via an effect on K+ channels.

Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1α-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer

“…These particular ETC inhibitors are unique in mimicking hypoxia, causing the opposing effects on pulmonary versus systemic arteries (constriction vs. dilatation) and activating the carotid body. The other class of agents that mimic hypoxia are reducing/oxidizing agents, which emulate hypoxia and normoxia, respectively (76).…”

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

“…The concept of K v channels being directly regulated by redox-changes has been proposed by POST et al [39]. The K v channels may be regulated by: 1) reducing agents [45][46][47][48], such as glutathione (GSH) [49]; 2) an associated haemoprotein; 3) membrane depolarisation; or 4) a calcium increase triggered by intracellular calcium release from intracellular stores or via NSCCs. Thus NSCCs may be key channels for hypoxic signalling, for example, in the regulation of potassium channels, of L-type calcium channels or the calcium level.…”

“…Inhibition of K v channels results in membrane depolarisation and activation of L-type calcium channels [89,110,150,151]. Moreover, K v channels have been shown to be inhibited by antioxidants [45]. However, even the importance of ROS itself was questioned [152] and cADP-ribose, for example, has been suggested as another signalling molecule [115].…”

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

“…Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K ϩ channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxiainducible factor (HIF) (12).…”