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

1. It has been proposed that hypoxic pulmonary vasoconstriction (HPV) is me diated via K+ channel inhibition and Ca2+ influx through voltage-gated chan nels. HPV depends strongly on the degree of preconstriction, and Lte theref ore examined thtr effect of Ca2+ channel blockade on tension and intracellu lar [Ca2+] ([Ca2+](i)) during HPV in rat intrapulmonary arteries (IPAs), wh ilst maintaining preconstriction constant. We also investigated the role of intracellular Ca2+ stores. 2. HPV demonstrated a transient constriction (phase I) superimposed on a su stained constriction (phase II). Nifedipine (1 mu M) partially inhibited ph ase I, but did not affect phase II. In arteries exposed to 80 mM K+ and nif edipine 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 mu M), La3+ almost abolished the phase I cons triction and rise in [Ca2+](i), but had no effect on phase II, or constrict ion in response to 80 mM K+. Phase II was inhibited by higher concentration s of La3+ (IC50 similar to 50 mu M). 4. IPA treated with thapsigargin (1 mu M) in Ca2+-free solution to deplete Ca2+ stores showed sustained constriction upon re-exposure to Ca2+ and an i ncrease in the rate of Mn2+ influx, suggesting capacitative Ca2+ entry The concentration dependency of the block of constriction by La3+ was similar t o that for phase I of HPV. Pretreatment of TPA with 30 mu M CPA reduced pha se I by > 80%, but had no significant effect on phase II. 5. We conclude that depolarization-mediated Ca2+ influx plays at best a min or role in the transient phase I constriction of HPV, and is not involved i n the sustained phase II constriction. Instead, phase I appears to be mainl y dependent on capacitative Ca2+ entry related to release of thapsigargin-s ensitive Ca2+ stores, whereas phase II is supported by Ca2+ entry via a sep arate voltage-independent pathway.