Even though there are still uncertainties on whether Ca2+ release is an early event in HPV, it is rather clear that RyR-gated Ca2+ stores play a central role in the process. Inhibition of RyRs has been shown to completely abolish or to partially inhibit hypoxia-induced Ca2+ responses in PASMCs (15, 49) and hypoxia-induced vasoconstriction in isolated perfused lung (31), pulmonary arteries (18, 25). Recently, some have proposed that hypoxia causes a change in the cellular redox-state, in particular a reduction of the P-NAD+:P-NADH ratio, which stimulates ADP-ribosyl cyclase and inhibits cyclic ADP-ribose hydrolase, leading to accumulation of cyclic ADP-ribose, an endogenous activator of RyRs to activate Ca2+ release from the SR (12, 54). Circumstantial evidence also suggest that increased reactive oxygen species (perhaps hydrogen peroxide)
production in the proximal sites of electron transport chain in mitochondria during hypoxia may trigger Ca2+release from the SR (51). Since RyR activity is modulated by multiple mechanisms,including Ca2+-induced Ca2+ release, cyclic ADP-ribose, sulfhydryl oxidation, phosphorylation, calmodulin, FK506-binding proteins, and SR luminal Ca2+ content, detailed future studies are required to delineate the exact contributions of all these mechanisms in RyR activation during hypoxia.
Ca2+ release from RyR-gated stores may participate in the hypoxic response by i) providing Ca2+ to directly activate myofilaments, ii) acting as a trigger to initiate a chain of Ca2+ events, or iii) responding synergistically with other mechanisms to generate pulmonary vasoconstriction. Application of a high concentration of caffeine is known to generate large Ca2+ transients and to cause contraction of pulmonary arteries, indicating that the RyR-gated store of PASMCs is capable of providing sufficient global Ca2+ for direct myofilament activation. On the other hand, local Ca2+ release in the form of Ca2+ sparks can serve as the vehicle for the latter two possibilities.
In the case where hypoxia elicits a moderate activation of RyRs, the increase in Ca2+ spark frequency may cause a membrane depolarization which exceeds the activation threshold (-40 mV) of L-type Ca2+ channel to increase Ca2+ influx and contraction (33). This is analogous to the hypothesis that Ca2+ release is the initial event of HPV, and elevated [Ca2+]j inhibits Kv channels to cause membrane depolarization and contraction (15). Activation of Ca2+ sparks may also lead to local SR Ca2+ depletion, resulting in activation of store-operated Ca2+ channels andcapacitative Ca2+entry (41,42). This notion is consistent with the observation that the transient phase I of hypoxia-induced contraction in isolated pulmonary arteries is mainly dependent on capacitative Ca2+ entry, which can be blocked by a low concentration ofLa3+ (42). Moreover, because of the non-selective nature of store-operated channels, their activation may amplify vasoconstriction by causing further membrane depolarization, and Ca2+influx via L-type voltage-dependent Ca2+ channel (53); providing a plausible explanation as to why the phase I hypoxic vasoconstriction can also be partially inhibited by nifedipine (41).
In the case of mild RyR activation, membrane depolarization induced by Ca2+ sparks may be insufficient to cross the threshold for L-type Ca2+ channel activation, and the reduction in SR Ca2+ may not be enough to elicit capacitative Ca2+ entry. However, it may set the Em close to the activation threshold of L-type Ca2+ channels, to potentiate synergistically other hypoxia-induced voltage-dependent mechanisms, such as Kv channel inhibition (55) and Ca2+ channel activation (13), and/or help to sustain a vasoconstriction by reducing the rate of Ca2+ removal through Na+/Ca2+ exchange. Indeed, it has been shown previously in some studies that a "priming" depolarization is required for hypoxia induced membrane depolarization and [Ca2+]j elevation in PASMCs (4, 48). To this effect, we have found that a subthreshold concentration of ET-1 (10"10 M), which causes a 2-fold increase in spark frequency (56), but itself does not cause an increase in global [Ca2+]j or contraction, potentiates hypoxia-induced contraction 6-fold in porcine PASMCs, and restores acute hypoxic constriction in endothelium-denuded porcine distal pulmonary arteries which are otherwise unresponsive to hypoxia (25, 44).
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