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Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat

T. P. Robertson, D. Hague, P. I. Aaronson and J. P. T. Ward

1. It has been proposed that hypoxic pulmonary vasoconstriction (HPV) is mediated via K⁺ channel inhibition and Ca²⁺ influx through voltage-gated channels. HPV depends strongly on the degree of preconstriction, and we therefore examined the effect of Ca²⁺ channel blockade on tension and intracellular [Ca²⁺] ([Ca²⁺]_i) during HPV in rat intrapulmonary arteries (IPAs), whilst maintaining preconstriction constant. We also investigated the role of intracellular Ca²⁺ stores.

2. HPV demonstrated a transient constriction (phase I) superimposed on a sustained constriction (phase II). Nifedipine (1 µM) partially inhibited phase I, but did not affect phase II. In arteries exposed to 80 mM K⁺ and nifedipine or diltiazem the rises in tension and [Ca²⁺]_i were blunted during phase I, but were unaffected during phase II.

3. At low concentrations (< 3 µM), La³⁺ almost abolished the phase I constriction and rise in [Ca²⁺]_i, but had no effect on phase II, or constriction in response to 80 mM K⁺. Phase II was inhibited by higher concentrations of La³⁺ (IC₅₀ ~50 µM).

4. IPA treated with thapsigargin (1 µM) in Ca²⁺-free solution to deplete Ca²⁺ stores showed sustained constriction upon re-exposure to Ca²⁺ and an increase in the rate of Mn²⁺ influx, suggesting capacitative Ca²⁺ entry. The concentration dependency of the block of constriction by La³⁺ was similar to that for phase I of HPV. Pretreatment of IPA with 30 µM CPA reduced phase I by > 80 %, but had no significant effect on phase II.

5. We conclude that depolarization-mediated Ca²⁺ influx plays at best a minor role in the transient phase I constriction of HPV, and is not involved in the sustained phase II constriction. Instead, phase I appears to be mainly dependent on capacitative Ca²⁺ entry related to release of thapsigargin-sensitive Ca²⁺ stores, whereas phase II is supported by Ca²⁺ entry via a separate voltage-independent pathway.

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