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. 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. 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). 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. 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.
Pulmonary hypertension due to long-term hypoxia occurs as a result of both chronic obstructive pulmonary disease and habitation at high altitudes. Studies in animal models of chronic hypoxia have demonstrated the development of a persistent depolarization of pulmonary artery (PA) smooth muscle cells (SMCs). In seeking to explain this effect, we compared under normoxic conditions the K+ currents in SMCs isolated from small PA of chronically hypoxic and normoxic rats. Chronic hypoxia was associated with a marked (40-50%) reduction in amplitude of a K+ current, which had the pharmacological and kinetic characteristics of a delayed rectifier. The resting potential of the isolated PA cells from chronically hypoxic animals was significantly more positive (-43.5 +/- 2 mV) than that of cells from normoxic animals (-54.3 +/- 2 mV), and this depolarization could be approximately mimicked in the cells from normoxic animals by application of 1 mM 4-aminopyridine, a blocker of the delayed rectifier K+ current. Glibenclamide (1 microM), a blocker of ATP-sensitive K+ (KATP) channels, also caused a substantial (14.5 +/- 2.2 mV) depolarization of the membrane. These results suggest that both delayed rectifier and ATP-dependent K+ currents contribute to setting the membrane potential in these cells and are consistent with the possibility that downregulation of the delayed rectifier K+ current contributes to the depolarization and altered responsiveness to vasoactive agents of PAs that occurs during long-term hypoxia.
We have examined the eects of Y-27632, a speci®c inhibitor of Rho-activated kinases (ROCK I and ROCK II) upon sustained hypoxic pulmonary vasoconstriction (HPV) in both rat isolated small intrapulmonary arteries (IPA) and perfused rat lungs in situ. Y-27632 (100 nM ± 3 mM) was found to cause a concentration-dependent inhibition of acute sustained HPV in rat IPA. Application of Y-27632 (10 ± 600 nM) in perfused rat lungs caused no change in basal perfusion pressure, but was found to inhibit HPV in a concentration-dependent manner, resulting in complete ablation of the pressor response to hypoxia at a concentration of 600 nM. Furthermore, addition of Y-27632 at any point during hypoxia caused a reversal of HPV in perfused rat lungs. These results suggest that activation of Rho-associated kinase may be a pivotal step in the generation of sustained HPV.
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