Pulmonary vascular reactivity after acute lung injury.
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Angiotensin II↗
Biomedical subjects
S Rounds
Publications and source records attributed to S Rounds.
Pulmonary vascular reactivity is blunted in pregnant rats.
Pulmonary arterial pressure is decreased in pregnant women despite increased cardiac output, suggesting that pulmonary vascular resistance is decreased in pregnancy. To determine if pulmonary vascular reactivity is decreased in pregnant rats, lungs isolated from pregnant rats were perfused with blood from other pregnant rats at constant flow rate, and pressor responses to airway hypoxia and to angiotensin II were measured. Compared with responses obtained in lungs from nonpregnant female rats, hypoxic and angiotensin II pressor responses were blunted in pregnancy. To separate possible effects of pregnancy on the lung from those of substance(s) circulating in the blood in pregnancy, we perfused lungs from nonpregnant rats with blood from pregnant rats. Both the hypoxic and angiotensin II pressor responses were blunted by blood from pregnant rats. The angiotensin II pressor response was blunted also in lungs from pregnant rats perfused with blood from nonpregnant rats. These results suggest that a circulating substance is responsible for blunting of pulmonary vascular reactivity in pregnancy and that changes in the lung induced by pregnancy also depress angiotensin II responses. It is unlikely that estrogen and progesterone were responsible for these effects, since lungs and blood obtained from animals treated with these hormones did not have blunted pulmonary vascular reactivity.
Angiotensin II↗
Studies of the mechanism of hypoxic pulmonary vasoconstriction.
The intrapulmonary mechanism by which airway hypoxia causes pulmonary arterial constriction is poorly understood. It is generally believed that hypoxia either elicits the release of a chemical mediator from the lung parenchyma or has a direct excitatory effect on the smooth muscle of the peripheral pulmonary arteries. We are testing the working hypothesis that hypoxia acts directly on the vascular smooth muscle to depress the rate of mitochondrial oxidative phosphorylation and to cause shifts in cytoplasmic metabolite concentrations, which then lead to membrane depolarization, calcium influx, and contraction. Results from studies of isolated perfused rat lungs with pharmacologic inhibitors of oxidative phosphorylation, glycolysis, and calcium influx have provided indirect support for the hypothesis; but a simpler in vitro preparation allowing direct measurements of energy metabolism, membrane electrical activity, calcium fluxes, and muscle tone is needed. Additional experiments have shown that inhibitors of membrane K+ conductance allow hypoxic contractions of isolated vascular smooth muscle; and such a preparation might be useful as an in vitro model of hypoxic pulmonary vasoconstriction.
Animals↗
Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs.
We wondered if depression of oxidative adenosine triphosphate (ATP) production caused pulmonary vasoconstriction. If so, then several chemically different inhibitors of oxidative ATP production all should cause pulmonary pressor responses. The vascular reactivity of isolated, blood-perfused rat lungs was established by eliciting pressor responses to airway hypoxia and to intraarterial angiotensin II. Then, during normoxia, we added to perfusate one of five chemical inhibitors of oxidative ATP production: 10 mM azide, 1 mM cyanide, 1 mM dinitrophenol, 5 or 10 microM antimycin A, or 0.5 microM rotenone. Each of the five chemical inhibitors, but not their solvents, caused a transient pressor response, followed by loss of vascular reactivity to hypoxia, angiotensin II, and chemical inhibitors. The inhibitor pressor responses were not due to an effect on blood cells, since they also were seen in lungs perfused with plasma. The magnitudes of pressor responses to all metabolic inhibitors except azide correlated with the magnitudes of preceding pressor responses to hypoxia, but not to the preceding angiotensin II responses. When verapamil or calcium chloride was added to perfusate, the hypoxic and inhibitor pressor responses were blunted more than was the angiotensin II response. Thus, five chemically different substances, inhibiting different steps of oxidative ATP production, all caused pressor responses that were blocked readily by verapamil and by increased perfusate calcium chloride. These results support the possibility that depression of oxidative ATP production elicits pulmonary vasoconstriction that is dependent on influx of extracellular calcium. Hypoxia might also be sensed in the pulmonary circulation by decreased oxidative ATP production in some as yet unidentified lung cell.
Adenosine Triphosphate↗