The possible role of sarcoplasmic reticulum (SR) Ca²⁺ stores in hypoxic pulmonary vasoconstriction (HPV) is not well understood. In order to assess the possible role of intracellular Ca²⁺ release from SR Ca²⁺ stores in HPV, we examined the effects of: (1) ryanodine (10 μM) depletion of intracellular Ca²⁺ stores, and (2) thapsigargin (THAPS, 2 μM) or cyclopiazonic acid (CPA, 10 μM) depletion of intracellular Ca²⁺ stores on HPV in canine pulmonary artery.

Isometric tension was measured from arterial ring suspended in Krebs‐Henseliet solution (K‐H) bubbled with 95%O₂/5%CO₂. Hypoxia was induced by bubbling phenylephrine (PE, 1 μM) precontracted rings with 95%N₂/5%CO₂. HPV was observed in both intact and endothelial‐denuded arteries and expressed as % of maximal KCl contraction (%T_kmax)=21.3±3.2%; n=13 and 21.7±4%; n=4, respectively.

When SR caffeine sensitive Ca²⁺ stores were depleted by pretreatment with ryanodine and brief caffeine (15 mM) exposure, the hypoxic response was signifcantly reduced to 19.1±9.2% of the control hypoxic contraction (n=7; P<0.001) with little or no effect on PE or KCl contractions. On the other hand, in normoxic rings pretreated with THAPS or CPA, the PE responses were significantly reduced (%T_kmax=18.2±3.1% compared to 39.0±3.9% in control; n=16; P<0.001; %T_kmax=3.4±1.6% compared to 49.9±7.9% in control; n=6; P<0.001; respectively) with no significant effect on caffeine‐induced contractions, suggesting that both THAPS and CPA preferentially deplete InsP₃‐sensitive Ca²⁺ stores, without affecting the caffeine‐sensitive Ca²⁺ store; consistent with the existence of separate and independent InsP₃ and caffeine‐sensitive Ca²⁺ stores in this preparation.

When hypoxia was induced in the presence of THAPS or CPA, developed tension was significantly larger than control (%T_kmax=64.5±6.0%; n=16; P<0.05%; %T_kmax=78.2±15%; n=6; P<0.05; respectively), was partially blocked by nisoldipine (10 μM) and ryanodine (%T_kmax=20.3±3.7%; n=6), and nearly completely blocked by SK&F 96365 (50 μM). However, the actions of SK&F 96365 appeared to be nonselective since this compound also significantly reduced contractions elicited by KCl, PE and caffeine.

Finally, evidence was obtained suggesting: (a) that at least some of the Ca²⁺ released from the caffeine‐ and ryanodine‐sensitive Ca²⁺ stores by hypoxia may be taken up and buffered by the InsP₃‐sensitive Ca²⁺ stores, and (b) the apparent dependence of HPV on extracellular Ca²⁺ entry pathways may be partially due to the dependence of the Ca²⁺ content of intracellular SR Ca²⁺ stores on sarcolemmal Ca²⁺ entry pathways.

These data suggest that caffeine‐ and ryanodine‐sensitive SR Ca²⁺ stores contribute significantly to HPV under normal conditions and, in the presence of THAPS or CPA, an additional nisoldipine‐ and ryanodine‐insensitive Ca²⁺ entry pathway is evoked by hypoxia.