Prostacyclin contributes to inhibition of hypoxic pulmonary vasoconstriction by alkalosis

The mechanism by which extracellular alkalosis inhibits hypoxic pulmonary vasoconstriction is unknown. We investigated whether the inhibition was due to intrapulmonary production of a vasodilator prostaglandin such as prostacyclin (PGI₂). Hypoxic vasoconstriction in isolated salt-solution-perfused rat lungs was blunted by both hypocapnic and NaHCO₃_induced alkalosis (perfusate pH increased from 7.3 to 7.7). The NaHCO₃-induced alkalosis was accompanied by a significant increase in the perfusate level of 6-keto-prostaglandin F_1α (6-keto-PGF_1α), an hydrolysis product of PGI₁. Meclofenamate, an inhibitor of cyclooxygenase, counteracted both the blunting of hypoxic vasoconstriction and the increased level of 6-keto-PGF_1α. In intact anesthetized dogs, hypocapnic alkalosis (blood pH increased from 7.4 to 7.5) blunted hypoxic pulmonary vasoconstriction before but not after administration of meclofenamate. In separate cultures of bovine pulmonary artery endothelial and smooth muscle cells stimulated by bradykinin, the incubation medium levels of 6-keto-PGF_1α were increased by both hypocapnia and NaHCO₃-induced alkalosis (medium pH increased from 7.4 to 7.7). These results suggest that inhibition of hypoxic pulmonary vasoconstriction by alkalosis is mediated at least partly by PGI_2.     

Dissociation of maximal O2 uptake from O2 delivery in canine gastrocnemius in situ

To test the hypothesis that maximal O2 uptake (VO2max) can be limited by O2 diffusion in the peripheral tissue, we kept O2 delivery [blood flow X arterial O2 content (CaO2)] to maximally contracting muscle equal between 1) low flow-high CaO2 and 2) high flow-low CaO2 conditions. The hypothesis predicts, because of differences in the capillary PO2 profile, that the former condition will result in both a higher VO2max and muscle effluent venous PO2 (PVO2). We studied the relations among VO2max, PVO2, and O2 delivery during maximal isometric contractions in isolated, in situ dog gastrocnemius muscle (n = 6) during these two conditions. O2 delivery was matched by varying arterial O2 partial pressure and adjusting flow to the muscle accordingly. A total of 18 matched O2 delivery pairs were obtained. As planned, O2 delivery was not significantly different between the two treatments. In contrast, VO2max was significantly higher [10.4 +/- 0.5 (SE) ml.100 g-1.min-1; P = 0.01], as was PVO2 (25 +/- 1 Torr; P less than 0.01) in the low flow-high CaO2 treatment compared with the high flow-low CaO2 treatment (9.1 +/- 0.4 ml.100 g-1.min-1 and 20 +/- 1 Torr, respectively). The rate of fatigue was greater in the high flow-low CaO2 condition, as was lactate output from the muscle and muscle lactate concentration. The results of this study show that VO2max is not uniquely dependent on O2 delivery and support the hypothesis that VO2max can be limited by peripheral tissue O2 diffusion.     

Effect of hemoglobin concentration on maximal O2 uptake in canine gastrocnemius muscle in situ

O2 delivery to maximally working muscle was decreased by altering hemoglobin (Hb) concentration and arterial PO2 (PaO2) to investigate whether the reductions in maximal O2 uptake (VO2max) that occur with lowered [Hb] are in part related to changes in the effective muscle O2 diffusing capacity (DmO2). Two sets of experiments were conducted. In the initial set (n = 8), three levels of Hb [5.8 +/- 0.3, 9.4 +/- 0.1, and 14.4 +/- 0.6 (SE) g/100 ml] in the blood were used in random order to pump perfuse, at equal muscle blood flows and PaO2, maximally working isolated dog gastrocnemius muscle. VO2max declined with decreasing [Hb], but the relationship between VO2max and both the effluent venous PO2 (PvO2) and the calculated mean capillary PO2 (PcO2) was not linear through the origin and, therefore, not compatible with a single value of DmO2 (as calculated by Bohr integration using a model based on Fick's law of diffusion). To clarify these results, a second set of experiments (n = 6) was conducted in which two levels of Hb (14.0 +/- 0.6 and 6.9 +/- 0.6 g/100 ml) were each combined with two levels of oxygenation (PaO2 79 +/- 8 and 29 +/- 2 Torr) and applied in random sequence to again pump perfuse maximally working dog gastrocnemius muscle at constant blood flow. In these experiments, the relationship between VO2max and both PvO2 and calculated PcO2 for each [Hb] was consistent with a constant estimate of DmO2 as PaO2 was reduced, but the calculated DmO2 for the lower [Hb] was 33% less than that at the higher [Hb] (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)