Fetal growth retardation and increased infant mortality at high altitude.
Explore the source record for details and available documents.
Altitude↗
Biomedical subjects
J T Reeves
Publications and source records attributed to J T Reeves.
Oxygen-tension-dependent pulmonary vascular responses to vasoactive agents.
There have been recent indications that oxygen may nonspecifically oppose pulmonary vasoconstriction induced by a few vasoactive agents. Therefore, we examined the effect of four inspired oxygen tensions on the pulmonary vascular responses to exogenous prostaglandin F2alpha (PGF2alpha), serotonin (5-HT), 2-methylhistamine (2-MeH)(an H1-receptor agonist), histamine (after H2-receptor blockade with metiamide), and prostaglandin E1 (PGE1) in anesthetized dogs. An oxygen tension dependency on the pulmonary vascular responses to these vasoactive agents was observed, with each agent exhibiting maximal responses at different ranges of oxygen tension. PGF2alpha and PGE1 were most effective during hypoxia, while 5-HT, histamine, and 2-MeH produced maximal responses during normoxia. A comparison of dose-response curves for PGF2alpha during breathing of two inspired oxygen tensions indicated a decreased sensitivity, but not decreased reactivity, with the higher oxygen tension. The action of variable oxygen tensions on pulmonary vascular responsiveness to vasoactive agents suggests another role for oxygen in the control of the pulmonary circulation. It is not clear if oxygen acts non-specifically on the vascular smooth muscle, or if it alters the metabolic mechanisms of vasoactive agent action.
Animals↗
Lung mast cell density and distribution in chronically hypoxic animals.
Changes in the density and distribution of pulmonary mast cells were determined in six mammalian species exposed to hypobaric hypoxia (PB = 435 Torr) for 19-48 days. Control animals were studied at 1,600 m (PB = 635 Torr). Total lung mast cell hyperplasia was observed only in calves exposed to high altitude. Pigs, rats, and sheep exhibited small, but insignificant, increases in mast cell density. Perivascular mast cell proliferation adjacent to vessels of 30-500 mum in diameter was seen in both calves and pigs. Bronchial, alveolar septal, and systemic tissue (tongue) mast cell hyperplasia was not observed in any of the species. Three indices of pulmonary hypertension (right ventricular hypertrophy, medial thickness of pulmonary arteries, and pulmonary arterial pressure) correlated with perivascular mast cell density. The findings indicate that perivascular mast cell proliferation may relate more to the morphological pulmonary vascular changes and to pulmonary hypertension than to hypoxia, leading to the speculation that mast cells increase in number in response to the hypertension, rather than to mediate and maintain the hypertension.
Animals↗
Increased pulmonary vascular pressor response to hypoxia in highland dogs.
Explore the source record for details and available documents.
Altitude↗
Platelet-mediated pulmonary hypertension: reduction by platelet inhibition.
Altering the platelet behavior with sulfinpyrazone or heparin--probably by inhibiting the platelet release reaction--reduces the emboli-induced pulmonary hypertension to the same extent as platelet depletion. Evaluation of platelet function in human pulmonary microembolism and consideration of substances which minimize or prevent platelet effects seems to be warranted on the basis of these experiments.
Animals↗
Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction.
There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.
Altitude↗
Bronchoconstriction and pulmonary hypertension during abortion induced by 15-methyl-prostaglandin F2alpha.
Patients have experienced severe breathlessness during second trimester abortion initiated by the intramuscular injection of 15-methyl-prostaglandin F2alpha (15-me-PGF2alpha). In four healthy women given 400 mug of 15-me-PGF2alpha to induce abortion, pulmonary function tests showed reductions in arterial oxygen tension, maximum expired air flow and vital capacity. Residual lung volume and the slope of phase III of the closing volume curves increased.
Abortion, Induced↗
Pulmonary microembolism: attenuated pulmonary vasoconstriction with prostaglandin inhibitors and antihistamines.
The mechanism(s) involved in the pulmonary vascular and airway responses to pulmonary microembolism have not been clearly defined. Therefore, we determined the effects of specific prostaglandin and histamine blockade on the hemodynamic and arterial blood gas tension responses to particulate microembolism (200 mu glass beads) in intact anesthetized dogs. The marked increases in pulmonary arterial pressure and pulmonary vascular resistance observed in the untreated dogs were attenuated, but not abolished, following both prostaglandin blockade (with either meclofenamate or polyphloretin phosphate) and histamine blockade (with chlorpheniramine and metiamide) at 5 minutes, and were still attenuated 30 minutes post embolization. Combined prostaglandin and histamine blockade further attenuated, but again did not abolish, the pulmonary vascular responses. Cardiac outputs and systemic arterial pressures were unchanged from control by embolism. The alveolar hypoventilation (decreased arterial oxygen tension and increased carbon dioxide tension) observed in the untreated embolized dogs was prevented only with the prostaglandin inhibitors. Pulmonary microembolism in intact dogs, therefore, appears to induce vasoconstriction mediated partially by prostaglandin and histamine action, and alveolar hypoventilation mediated by prostaglandin, but not histamine, action.
Airway Resistance↗
Prostaglandin synthesis does not mediate the pulmonary vasodilatory effect of acetylcholine.
We wondered if inhibition of hypoxic pulmonary vasoconstriction by acetylcholine was mediated by prostaglandin synthesis. In 5 calves at a simulated altitude of 4,570 m, acetylcholine (10 mug/kg/min) decreased mean pulmonary arterial pressure and total pulmonary resistance by 24 +/- 2 and 35 +/- 3% before and by 21 +/- 2 and 27 +/- 4% after the administration of meclofenamate (2 mg/kg). Since there was no difference in the effect of acetylcholine before and after meclofenamate, it was concluded that pulmonary vasodilation by activation of muscarinic receptors was not dependent on prostaglandin synthesis.
Acetylcholine↗
Measurement of cardiac output by electrical impedance at rest and during exercise.
A comparison was made between cardiac output values determined by the dye dilution and electrical impedance methods in ten subjects at rest and during graded exercise on a bicycle ergometer. The cardiac output values determined by the two methods were linearly related and significantly (P less than 0.001) correlated (r = 0.90). Movement artifact associated with exercise at maximum or near-maximum work loads caused severe distortion of the dZ/dt wave form and prevented calculation of impedance cardiac output at these levels of work. Use of the lowest value of L (distance between mean value of L in the impedance stroke volume equation (SV = p(L2/ZO2) (dZ/dt)mt), resulted in nearly identical values for the least-squares line and equalvalue line of impedance and dye cardiac outputs. Although absolute values of cardiac output determined by the two methods were not identical in all subjects the changes in cardiac output were nearly identical during the different levels of exercise. The data support the validity of the impedance method as a noninvasive, atraumatic measure of cardiac output at rest and during graded exercise.
Adult↗
Sustained venoconstriction in man supplemented with CO2 at high altitude.
Venoconstriction occurs at high altitude. This study sought to determine whether hypoxia or hypocapnia is the cause of the venoconstriction. Five male subjects were exposed to 4,000-4,400 m (PB 440-465 mmHg) with supplemental 3.77 +/- 0.02% CO2 in a hypobaric chamber for 4 days. Similar alveolar O2 tensions were obtained in four control subjects exposed to 3,500-4,100 m (PB 455-492 mmHg) without CO2. A water-filled plethysmograph was used to determine forearm flow and venous compliance. Systemic blood pressure was measured with the cuff procedure. Catecholamines were measured in 24-h urine collections. Venous compliance fell at high altitude in both groups and was less (P less than 0.01) than control values. Forearm flow and resistance were unaltered at altitude in the group with CO2 supplementation while forearm flow decreased and resistance increased in the hypocapnic group at 72 h of exposure. Urinary catecholamines increased in the group with CO2 and remained unaltered in the hypocapnic group. It is concluded that hypoxia is responsible for decreasing venous compliance, and hypocapnia for increasing resistance and decreasing flow. Group differences observed in urinary catecholamines may be explained by differences in arterial pH.
Adolescent↗
Failure of histamine antagonists to prevent hypoxic pulmonary vasoconstriction in dogs.
The role of histamine as a mediator of hypoxic pulmonary vasoconstriction was examined in intact anesthetized dogs. Antagonism of histamine vasoconstrictor (H1) receptors with a classic antihistaminic drug (chlorpheniramine) failed to prevent or modify the pulmonary vascular responses to hypoxia (10% O2). Blockade of histamine vasodilator (H2) receptors with a newly synthesized blocking agent (metiamide) potentiated the vasoconstriction induced by hypoxia and prevented the normal increase in heart rate. Combined H1- and H2-receptor blockade also did not prevent or reduce the hypoxic pulmonary pressor response, although it did effectively abolish the cardiovascular actions of infused histamine. In other dogs, histamine infused (3.6 mug/kg per min) during hypoxia attenuated the pulmonary vasoconstriction induced by hypoxia. The results imply that, in the dog, histamine does not mediate hypoxic pulmonary vasoconstriction. However, histamine does appear to be released during hypoxia, and it may play a role in modulating the pulmonary vascular responses to hypoxia by opposing the hypoxia induced vasoconstriction. The results also imply that histamine may be responsible for the increase in heart rate during hypoxia.
Animals↗
Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction.
Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressor responses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.
Animals↗
Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.
The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, blood-perfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O2) would be susceptible to inhibition by the calcium antagonists verapamil (2 X 10(-5) to 2 X 10(-1) mM) and SKF 525A (2.6 to 260 mM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II(1 or 0.5 mug) and prostaglandin F2alpha (10 myg). Since neither saralasin (0.5 muM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 muM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia greater than angiotensin II greater than prostaglandin F2alpha. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.
Angiotensin II↗
Maintained stroke volume but impaired arterial oxygenation in man at high altitude with supplemental CO2.
Hypobaric hypoxia causes hypocapina and alkalosis, hemoconcentration and increased hematocrit, and a decreased cardiac stroke volume. To assess the role of the hypocapnic alkalosis in causing these other changes, five men were exposed to hypobaric hypoxia at a barometric pressure (PB) of 440 torr with an alveolar O2 tension of 55 torr for 5 days with 3.77% CO2 added to the atmosphere to prevent alkalosis. They did not lose weight, and arterial CO2 tension, pH, and cardiac stroke volume were unchanged. An unchanged hematocrit implied an unchanged plasma volume. During exercise to maximum, stroke volumes equaled sea level values but arterial hypoxemia was profound, the arterial O2 tension being 39 torr. By contrast, three men at high altitude without CO2 supplementation (PB=455 torr; alveolar PO2=56 torr) had weight loss, hypocapnia, alkalosis, and decreased stroke volume. Increased hematocrits suggested decreased plasma volumes. During exercise, arterial PO2 (48 torr) was higher than in the group receiving CO2. Maximum oxygen uptakes were decreased to a similar degree in the two groups. Catecholamine excretion doubled in the group with CO2 but in the group without CO2 catechoamine excretion was unchanged. A normal pH at high altitude apparently maintained plasma volume, which, with the increased catecholamine excretion, may have prevented a decrease in stroke volume. However, the subjects with CO2 added did not have enhanced oxygen transport, because their arterial oxygenation was impaired.
Adult↗
Attenuation of hypoxic pulmonary vasoconstriction by verapamil in intact dogs.
The hypothesis that hypoxic pulmonary vasoconstriction is mediated directly by depolarization of the vascular smooth muscle was tested in anesthetized dogs. Pulmonary vascular responses to hypoxia were first determined in eight dogs during 20-min exposures to 10% O2. Each animal was then treated with verapamil (0.5 mg/kg, iv), to block transmembrane Ca2+ influx in an attempt to abolish the vasoconstrictor responses to hypoxia. The hypoxic exposures were then repeated, and the pulmonary vascular responses were compared to the control responses. Verapamil administration attenuated hypoxic pulmonary vasoconstriction, but did not abolish the responses to hypoxia. Pulmonary vascular resistance increased 87% during the control hypoxic exposure, but increased only 38% during hypoxia after verapamil. The response to another vasoconstrictor, prostaglandin F2alpha, was not reduced by verapamil indicating a different mechanism of mediation. These results suggest that the pulmonary vasoconstrictor response to alveolar hypoxia, in the intact dog, involves transmembrane Ca2+ influx, and are consistent with the idea that hypoxia acts primarily by directly depolarizing vascular smooth muscle, rather than acting indirectly through a chemical mediator.
Animals↗
Endotoxin and prevention of hypoxic pulmonary vasoconstriction.
Endotoxin is known both to stimulate prostaglandin production and to abolish the pulmonary vascular pressor response to hypoxia. The present study demonstrated that two inhibitors of prostaglandin synthesis, meclofenamate and indomethacin, prevent loss of pulmonary vasoconstriction due to hypoxia when sublethal doses of endotoxin are administered. This suggests that endotoxin may stimulate the production of a dilator prostaglandin which would oppose the hypoxic vasoconstriction, but other ways in which these inhibitor drugs might act are considered. Endotoxin damages platelets and leukocytes, both of which can form prostaglandins and could be the source of a dilator prostaglandin. However, in these experiments endotoxin abolished the hypoxic pressor response in dogs rendered severely thrombocytopenic by platelet antiserum. This suggests that platelets are not involved. In further experiments blood from anesthetized dogs was circulated through glass bead columns. Changes in the leukocyte count following perfusion were correlated with changes in the subsequent pressor response to hypoxia. The possibility that leukocytes may be involved in the effect of endotoxin on the hypoxic pressor response is considered.
Animals↗
Platelets are not essential for the pulmonary vascular pressor response to hypoxia.
The literature suggests that platelets might help mediate the pulmonary vascular pressor response to hypoxia. This study evaluated the hypoxic response in thrombocytopenic dogs. Platet depletion was achieved in five dogs by the use of platelet antiserum. In the normoxic state these dogs had lower cardiac outputs and higher pulmonary and systemic vascular resistances than five control dogs. The pressor response to hypoxia in these dogs was not only preserved but considerably enhanced in comparison to the control dogs. Hypoxia increased the pulmonary vascular resistance 146 +/- 17% above its normoxic value in the thrombocytopenic dogs and 64 +/- 21% in the control dogs. Thus platelets may normally produce a dilator substance or inactivate a pressor substance during hypoxia. The mechanism of the effect is not apparent but it is clear tha the pulmonary pressor response to hypoxia in the dog is not mediated by platelets.
Animals↗