Hypoxia and smooth muscle function: key regulatory events during metabolic stress

Abstract

A, phasic contractions produced by action potentials following electrical stimulation. B, tonic contraction produced by high K¤ depolarization. The Ca¥ measurements were made from the ratio of the fluorescence signals of indo-1 emitted at 400 and 500 nm. Adapted from Bullock & Wray, 1998. and voltage. The activity and distribution of ion channels depend not just upon the particular smooth muscle preparation, but on developmental and gestational state (Khan, Smith, Morrison & Ashford, 1993;Weir & Archer, 1995;Urena, Franco-Obregon & Lopez-Barneo, 1996). Such differences may well account for much of the diversity found between smooth muscles. Any effect of hypoxia on these channels will affect resting membrane potential and is therefore likely to affect force. A general point to consider is that many ion channels require a basal level of phosphorylation for activation, and hence a fall in [ATP] may reduce current flow (Tewari & Simard, 1994;Hilgemann, 1997), although some Ca¥ channels do not appear to be activated by phosphorylation (Klockner & Isenberg, 1985;Ohya, Kitamura & Kuriyama, 1988; Sperelakis, Xiong, Haddad & Musuda, 1994). The changes in metabolites and ions that occur with hypoxia and which may influence ion channel activity are summarized in Table 1. As will become apparent, in many smooth muscles increased outward K¤ current and decreased inward Ca¥ current can be demonstrated with hypoxia or cyanide, along with increased K¤ efflux and decreased Ca¥ entry.What are the effects of hypoxia on K¤ channels? ATPgated K¤ channels (KATP) are present in smooth muscle and have been proposed as a critical link between cell metabolism and electrical activity, and in particular as forming part of the mechanism underlying the dilatation of coronary and cerebral arterioles during hypoxia (Standen, Quayle, Davies, Brayden, Huang & Nelson, 1989; Daut, Maier-Rudolph, Von Beckerath, Mehrke, Gunther & GoedelMeinen, 1990;Dart & Standen, 1995;Taguchi et al. 1997). Teleologically this makes sense; this channel is inhibited by intracellular ATP (inhibition constant, ké, •10-100 ìÒ). In hypoxia, the fall in [ATP] and increase in [ADP], along with a decrease in intracellular pH (pHé) (see Table 2), will be expected to lead to the opening of the channel and hyperpolarization of the smooth muscle cell. This will result in relaxation of the vessel and increased blood flow to the hypoxic region. Recent work has drawn attention to the gating of similar channels by other nucleotide diphosphates (Zhang & Bolton, 1996), but their role in hypoxia remains to be investigated. So, do KATP channels open in hypoxia? There is good evidence that they do in the vascular studies quoted above. However, the reliance in several studies on glibenclamide to block these channels and show their involvement in the hypoxic process, has been questioned (Zhang & Bolton, 1996). It is also difficult to control for a direct effect of low oxygen on channels. It is also clear that a small membrane depolarization, rather than the predicted hyperpolarizatio...

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