Leukotrienes in the lung circulation: actions and interactions.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
J T Reeves
Publications and source records attributed to J T Reeves.
Nonimmunological production of leukotrienes induced by platelet-activating factor.
Platelet-activating factor caused rapid pulmonary vasoconstriction and edema in isolated lungs perfused with albumin-free salt solution devoid of formed blood elements. These effects may be due in part to the action of leukotrienes D4 and C4, which were identified by bioassay and high-pressure liquid chromatography in the lung effluent after stimulation by platelet-activating factor. These findings help illuminate some of the deleterious effects that platelet-activating factor elicits in anaphylactic reactions and possibly in other forms of lung injury.
Animals↗
Maternal hyperventilation helps preserve arterial oxygenation during high-altitude pregnancy.
We examined arterial oxygenation during pregnancy and 3 mo postpartum in 35 nonsmoking residents of Leadville, CO (elevation 3,100 m) to determine how well and by what mechanisms maternal arterial oxygenation was maintained during pregnancy at high altitude. Hyperventilation raised arterial O2 saturation above that in the nonpregnant state. Respiratory alkalosis persisted throughout pregnancy, shifting the O2-hemoglobin dissociation curve to the left, further facilitating O2 loading in the lung. However, a decrease in blood hemoglobin concentration and a slight increase in the alveolar-arterial O2 gradient in the late pregnancy caused the arterial O2 content to fall below that in the nonpregnant state. Compared to published sea level values, the Leadville women had higher ventilation and hemoglobin values, yielding arterial O2 contents as high as in pregnant women at sea level. Thus, ventilation and hemoglobin concentration were important variables contributing to O2 ttransport during pregnancy at high altitude.
Adult↗
Infant birth weight is related to maternal arterial oxygenation at high altitude.
Infant birth weight is reported to decrease at high altitude as a reulst of fetal growth retardation (McCullough, Reeves, and Liljegren. Arch. Environ, Health. 32: 36--39, 1977) but not all babies born at high altitude are small. We hypothesized that maternal characteristics acting to lower arterial O2 content would contribute to smaller infant birth weight. To test this hypothesis, we measured arterial oxygenation serially during pregnancy and again postpartum in 44 residents of Leadville, CO (elevation 3,100 m). We identified three maternal characteristics--ventilation, hemoglobin concentration, and smoking habits--that were related to the birth weight of the offspring. Mothers of smaller babies (less than 2,900 g) compared to mothers of larger babies (greater than 3,500 g) were characterized by hypoventilation, no change or a decrease in ventilation and arterial O2 saturation from early to late gestation, and a falling hemoglobin concentration that combined to lower arterial O2 content in the 3rd trimester. Maternal smoking at 3,100 m was associated with a two to threefold greater reduction in infant birth weight (-546 g) than reported from sea level. Thus, maternal arterial oxygenation during pregnancy may be important for predicting fetal growth retardation and the process of adaptation to high altitude.
Adaptation, Physiological↗
Pulmonary pressor response after prostaglandin synthesis inhibition in conscious dogs.
Recent studies have shown that vasodilator prostaglandins are continually produced by the isolated rat lung. We postulated that these vasodilators may contribute to maintenance of normal low pulmonary arterial pressure. Pulmonary pressure and cardiac output were measured in conscious dogs prior to and 30 to 60 min following administration of meclofenamate (2 mg/kg iv, followed by infusion at 2 mg . kg-1 . h-1) or the structurally dissimilar inhibitor RO-20-5720 (1 mg/kg iv, followed by infusion at 1 mg . kg-1 . h-1). The animals were also made hypoxic with inhalation of 10% O2 before and after inhibition. Time-control experiments were conducted in which only the saline vehicle was administered. Meclofenamate or RO-20-5720 caused an increase in mean pulmonary arterial pressure and total pulmonary resistance. Cardiac output and systemic pressure were unaffected. The mild hypoxic pulmonary pressor response observed was not affected by meclofenamate. Animals breathing 30% O2 to offset Denver's altitude also demonstrated increased pulmonary pressure and resistance when given meclofenamate. It is concluded that endogenous vasodilator prostaglandins may contribute to normal, low vascular tone in the pulmonary circulation.
Animals↗
Fluid retention and relative hypoventilation in acute mountain sickness.
The presence of pulmonary, cerebral, and/or peripheral edema in acute mountain sickness (AMS) implies a derangement in the body's handling of water. Previously, we demonstrated water retention and increased symptoms of AMS when hypocapnia was prevented in subjects exposed to simulated high altitude. This led us to the hypothesis that upon ascent to high altitude, those persons who fail to increase their ventilation adequately and hence do not become hypocapnic will retain water reflected as weight gain and will develop AMS. To test this hypothesis, we studied in Kathmandu, Nepal (1,377 m) 42 healthy western tourists; all were restudied in Pheriche (4,243 m) within 6 days of exposure to high altitude. Symptoms of AMS were highly correlated (p less than 0.001) with weight change, suggesting that persons becoming symptomatic retained fluid. On going from low to high altitude, those persons who lost weight and remained well increased their resting ventilation, whereas those who gained weight did not (p = 0.03). This relative hypoventilation in the latter group was confirmed by higher values of Pco2 (heated hand vein blood) and lower values of arterial saturation (ear oximeter) at Pheriche. Vital capacity measured in Kathmandu was correlated with arterial saturation at Pheriche (p = 0.02); persons with low vital capacity were more hypoxemic with more symptoms of AMS. We conclude that relative hypoventilation and weight gain appear early in the development of AMS suggesting links between altitude hypoxia, hyperventilation, hypocapnia, and the body's handling of water.
Acute Disease↗
Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension.
To evaluate the effects of prostacyclin (prostaglandin I2) on pulmonary vascular tone in primary pulmonary hypertension (PPH), we performed right-heart catheterization on seven patients with PPH and made hemodynamic measurements before and after infusing incremental doses of prostacyclin. In maximal doses of 2-12 mg/kg/min (mean 5.7 +/0 3.1 ng/kg/min), prostacyclin reduced mean pulmonary arterial pressure from 62 +/- 15 to 55 +/- 16 mm Hg (p less than 0.05) and total pulmonary resistance from 17.1 +/- 8.7 to 9.7 +/- 5.9 units (p less than 0.005), and increased cardiac output from 4.22 +/- 1.64 to 6.57 +/- 2.04 l/min (p less than 0.01). Heart rate increased from 83 +/- 13 to 94 +/- 11 beats/min (p = 0.1) and mean systemic arterial pressure decreased from 90 +/- 12 to 77 +/- 4 mm Hg (p = 0.055). Three patients who received a continuous infusion of prostacyclin for 24-48 hours had sustained reductions in total pulmonary resistance during the infusion period. These data demonstrate that prostacyclin can increase cardiac output and reduce pulmonary arterial pressure and resistance in PPH.
Adolescent↗
Emphysema mortality is increased in Colorado residents at high altitude.
Emphysema mortality is higher in Colorado than in the nation as a whole despite the younger age of Colorado's population Colorado death records from 1959 to 1976 were examined to determine if emphysema mortality increases with altitude within the state and if altitude adversely affects survival from chronic lung disease. Because the proportion of persons older than 65 yr of age in Colorado decreases with altitude (r = -0.6, p less than 0.01), emphysema mortality was age-standardized. The age-standardized rate increases with altitude among males (r = 0.9, p less than 0.01; y = 0.003(x) + 42.1). Emphysema deaths at higher altitudes in Colorado (greater than or equal to 7,000 ft) occur at a younger age (68.1 +/- 0.6 yr (mean +/- SEM) versus 70.1 +/- 0.6 yr at lower altitudes), after a shorter duration of illness, and more commonly from cor pulmonale than at lower altitudes (less than or equal to 4,500 ft) where pneumonia is more common as the immediate cause of death. The mechanism by which high altitude residence interacts unfavorably with survival is not known but may stem from augmented pulmonary hypertension caused by the hypoxia of lung disease added to the hypoxia of high altitude.
Adult↗
Factors influencing lung histamine content.
Histamine is an important amine within the lung. The purpose of the present study was to evaluate in rats the factors that affect the measurement of lung histamine concentration. We found that the lung content was not clearly altered by pentobarbital anesthesia or by freezing of the lung. Heparin administration and inhalational ether anesthesia appeared to result in elevated lung histamine contents by an unknown mechanism. Pulmonary edema rapidly lowered the histamine content. The histamine content is better related to DNA content than to the amount of protein in the lung.
Animals↗
Glucose metabolism accelerates the decline of hypoxic vasoconstriction in rat lungs.
Isolated lungs lose the vasoconstrictor response to airway hypoxia with time of perfusion. In isolated rat lungs this loss was accelerated by the addition to perfusate of glucose or pyruvate. The addition of 3-0-methyl glucoside (a non-metabolizable glucose analog) or saline (a solvent control) did not change the rate of decline of hypoxic vasoconstriction. An inhibitor of glucose metabolism (2-deoxy-D-glucose) augmented the hypoxic pressor response. Vasoconstrictor responses to angiotensin II and KCL were not affected by any of the additions. There were no differences in perfusate osmolality among groups of lungs. These results suggest that glucose accelerated the decline of hypoxic pulmonary vasoconstriction by a metabolic, not an osmotic, effect. There may be an important link between lung glucose metabolism and the hypoxic pressor response.
3-O-Methylglucose↗
Acute mountain sickness and the edemas of high altitude: a common pathogenesis?
Within days of ascent to high altitude when symptoms of acute mountain sickness (AMS) are common, pulmonary and cerebral edema may also develop. Although peripheral edema of the hands, face or feet may also appear, its association with AMS is unclear. In addition, persons with high altitude pulmonary edema often report an antidiuresis. Hence, altitude sickness appears to result from abnormalities in the handling of body water. To test this hypothesis, we studied 102 men and women who were trekking in the Mount Everest region of Nepal. Most were seen both at low (1377 m) and at high (4243 m) altitude. Severity of AMS was measured by an established Symptom Score derived from a questionnaire and physical examination. Change in body water was inferred from change in body weight in less than 10 days. Peripheral edema was assessed separately by physical examination. AMS Symptom Score correlated directly with weight change; those who remained well lost weight, whereas increasing signs and symptoms of AMS occurred in those with increasing weight gain. The symptomatic subjects also developed peripheral edema and reported decreased urinary output. These findings support the hypothesis that with rapid ascent to high altitude, abnormalities in the handling of body water, with antidiuresis, result in fluid retention (weight gain) manifest as peripheral, pulmonary, and/or cerebral edema.
Adolescent↗
Blunted pulmonary pressor responses to hypoxia in blood perfused, ventilated lungs isolated from oxygen toxic rats: possible role of prostaglandins.
To determine the effects of high oxygen (O2) tension on pulmonary vascular reactivity, we exposed rats either to 100% O2 for 48 hours or 40% O2 for 3 to 5 weeks. Lungs from all rats were isolated, blood perfused and ventilated, and pressor responses to airway hypoxia and to infused angiotensin II were measured. We found that chronic subtoxic hyperoxia did not augment subsequent hypoxic vasoconstriction, and that 48 hrs of 100% O2 markedly blunted hypoxic vasoconstriction. Meclofenamate restored hypoxic vasoconstriction to control levels in the lungs with blunted responses. Evidence for O2 toxicity in the lungs exposed to 100% O2 included interstitial swelling with alveolar exudates seen by light microscopy, and lung edema by water content calculations. We conclude that 1) chronic subtoxic hyperoxia does not influence subsequent hypoxic vasoconstriction, and 2) a dilator prostaglandin produced in the lung is a potent inhibitor of hypoxic vasoconstriction in O2 toxic lungs.
Angiotensin II↗
Sensitivity of breath-to-breath gas exchange measurements to expiratory flow errors.
Explore the source record for details and available documents.
Humans↗
Effects of hypoxia on density of beta-adrenergic receptors.
Exposure to chronic hypoxia results in a lower resting heart rate and a blunted cardiovascular responsiveness to beta-adrenergic receptor stimulation. Possible effects of acclimatization to high altitude on the binding of [125I]iodohydroxybenzylpindolol to beta-adrenergic receptors on membranes of right and left ventricles of rat heart were determined. Chronic high-altitude exposure led to a decrease in the density of beta-adrenergic receptors in nonhypertrophied left ventricles as well as in hypertrophied right ventricles. The affinity of the receptor for the radioligand was not changed by the exposure to high altitude, suggesting that the properties of the receptor were not affected. Basal and isoproterenol-stimulated adenylate cyclase activities were decreased in membranes prepared from hearts and pulmonary arteries of rats acclimatized to high altitude. The loss of cardiac beta-adrenergic receptors in rats adapted to high altitude was prevented by the chronic coadministration of a low dose of DL-propranolol. The results suggest that changes in beta-adrenergic receptor density may partially explain the hemodynamic adaptation that occurs with chronic hypoxia. These decreases may be due to a loss of functional beta-adrenergic receptors caused by chronically elevated concentrations of circulating neurally released catecholamines.
Adenylyl Cyclases↗
Release of vasodilator prostaglandin, PGI2, from isolated rat lung during vasoconstriction.
Prostaglandins are generated by the lungs and released into the circulation. Since inhibitors of prostaglandin synthesis enhance hypoxic pulmonary vasoconstriction, we wondered whether vasodilator prostacyclin was synthesized by the lungs in response to vasoconstriction. To test this hypothesis, we measured vasoconstriction induced by angiotensin II in isolated rat lungs before and after inhibition of prostaglandin synthetase. We found that sodium meclofenamate enhanced and prostacyclin and its precursor arachidonate abolished pulmonary vasoconstriction. In lungs labeled with 14C-arachidonate, effluent radioactivity increased after angiotensin II-induced vasoconstriction. Hypoxic vasoconstriction, but not hypoxia per se, caused an increase in lung effluent radioactivity. Chromatographic analysis of lung effluent showed that 6-keto-prostaglandin F1 alpha was the major arachidonic acid metabolite released during pulmonary vasoconstriction. We concluded that prostacyclin is produced by the lungs in response to vasoconstriction. Hypoxia per se seems not to be the adequate stimulus for enhanced lung prostacyclin formation. Lung prostacyclin may protect the pulmonary circulation against excessive vasoconstriction.
Angiotensin II↗
Hypoxia impairs vasodilation in the lung.
Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.
Angiotensin II↗
High-altitude pulmonary edema in persons without the right pulmonary artery.
Explore the source record for details and available documents.
Adult↗