Acute Hypoxia Induces Membrane Depolarization by Inhibiting Kv Channels

In rat PASMC, acute hypoxia reduces K+ currents by inhibiting Kv channels (Fig. 4Ca) (5, 63, 82, 83, 117). The inhibitory effect of hypoxia on Kv channels appears to be selective to PASMC; hypoxia has little effect on Kv currents (/K(V)) in mesenteric artery smooth muscle cells (MASMC) isolated from the same rat (Fig. 4Cb). The inability of acute hypoxia to reduce /K(V) in MASMC also explains why acute hypoxia has little effect on mesenteric vascular tone (120). The acute hypoxia-mediated inhibition of Kv channels causes a sustained membrane depolarization in PASMC (Fig. 4D) andelicits Ca2+-dependent action potentials in some cells. The resultant increase in [Ca2+]cyl (Fig. 4E) due to opening of voltage-dependent Ca2+ channels triggers PASMC contraction by activating CaM and myosin light chain kinase and eventually causes pulmonary vasoconstriction (96). Consistent with the effect in rat PASMC, acute hypoxia also reduces /K(V) in canine (82, 83) and rabbit (63) PASMC.

Pulmonary Artery Pressure Rats

Figure 4. Hypoxia modulates Kv channel function, membrane potential, pulmonary vasomotor tone, and pulmonary arterial pressure (PAP). A: Decreasing Po2 to 10% caused a gradual increase in PAP that was sensitive to treatment by verapamil, a Ca channel blocker. B: Hypoxia causes vasoconstriction in an isolated small rat pulmonary artery ring. C: Hypoxia inhibits Kv currents (a) in PASMC but not in mesenteric arterial smooth muscle cells (MASMC, shaded bars, b). *** P<0.001 vs. normoxia. D and E: Change in Em (D) and [Ca2+]cyt (E) recorded upon decreasing Po2 from 149 to 8 mmHg (Hypoxia). E: Hypoxia reduces the steady-state open probability of unitary Kc channels from ~ 1.10 to ~0.25 in cell-attached patches from isolated rat PASMC (Reproduced fromRefs. 116-118).

Figure 4. Hypoxia modulates Kv channel function, membrane potential, pulmonary vasomotor tone, and pulmonary arterial pressure (PAP). A: Decreasing Po2 to 10% caused a gradual increase in PAP that was sensitive to treatment by verapamil, a Ca channel blocker. B: Hypoxia causes vasoconstriction in an isolated small rat pulmonary artery ring. C: Hypoxia inhibits Kv currents (a) in PASMC but not in mesenteric arterial smooth muscle cells (MASMC, shaded bars, b). *** P<0.001 vs. normoxia. D and E: Change in Em (D) and [Ca2+]cyt (E) recorded upon decreasing Po2 from 149 to 8 mmHg (Hypoxia). E: Hypoxia reduces the steady-state open probability of unitary Kc channels from ~ 1.10 to ~0.25 in cell-attached patches from isolated rat PASMC (Reproduced fromRefs. 116-118).

In addition to blocking Kv channels, acute hypoxia also reduces K currents by inhibiting K,. (29, 63) and KCa channels (Fig. 4F) (42, 74). A voltage-insensitive, sustained K+ current was observed in rabbit PASMC, which has been demonstrated to be generated by K+ efflux through KT channels (29, 63). Inhibition of the KT channels would also contribute to initiating membrane depolarization and [Ca2+] , rise in PASMC challenged with acute hypoxia (29).

A rise in [Ca2+]cyl induced by membrane depolarization-mediated Ca2+influx and/or agonist-induced Ca2+ release activates KCa channels in PASMC (74, 119). The resultant increase in whole-cell KCa currents limits vasoconstriction by inducing membrane hyperpolarization and concomitant vasodilation. Large conductance (200-250 pS)KCa channels in PASMC are synergistically regulated by cytoplasmic [Ca2+] and Em. In other words, the acute hypoxia-mediated membrane depolarization and increase in [Ca2+]cyl would markedly activate the large-conductance K^ channels and limit hypoxia-induced membrane depolarization and pulmonary vasoconstriction. However, the observed response of Em (Fig. 4D) or pulmonary vascular tone (Fig. 4B) to hypoxia is a sustained depolarization or persistent vasoconstriction, suggesting that the negative feedback effect of KCa channel activation is inhibited during hypoxia. Indeed, acute hypoxia, in addition to inhibiting Kv and KT channels for initiating membrane depolarization, also inhibits channels in cell attached membrane patches of rat PASMC (Fig. 4F). Similar results have been reported in rabbit PASMC (42) and carotid body cells (110). Acute hypoxia-induced inhibition of KCa channels appears to be due to an intermediate released or produced during hypoxia, since the effect disappears in excised (inside-out) membrane patches (42, 82). However, chronic hypoxia-mediated inhibition of KCa channels appears to be caused by direct effect on the channel expression and function (74). Thus, hypoxia-induced inhibition of KCa channels, although it may not be involved in triggering membrane depolarization, certainly plays an important role in maintaining membrane depolarization.

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Responses

  • OLLE
    Why does hypoxia cause depolarization in cardiac cells?
    8 years ago
  • toni stearns
    Why hypoxia causes membrane depolarization?
    2 years ago

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