prostaglandin-h2 and Hypertension--Pulmonary

Topics: Aerosols; Animals; Epoprostenol; Hypertension, Pulmonary; Injections, Intravenous; Prostaglandin H2; Sheep

Topics: Administration, Inhalation; Animals; Endothelium, Vascular; Epoprostenol; Hemoglobins; Humans; Hydroxyl Radical; Hypertension, Pulmonary; Nitrates; Nitric Oxide; Nitrogen Dioxide; Oxidation-Reduction; Pneumonia; Prostaglandin H2; Prostaglandins H; Signal Transduction; Superoxides; Tyrosine

We investigated whether the physiological effects of prostaglandin B2 (PGB2) in the pulmonary circulation might be due to stimulation of thromboxane A2-prostaglandin H2 (TxA2/PGH2) receptors. In seven anesthetized rabbits, intravenous infusion of PGB2 (5.0 micrograms/kg) caused pulmonary hypertension as evidenced by increases in right ventricular systolic blood pressure. The magnitude of the pulmonary hypertension was comparable to that observed after infusion of the TxA2 mimetic U-46619 at a significantly lower dose (0.5 micrograms/kg), indicating that the effects of PGB2 in the intact animal are similar to TxA2 but less potent. Additionally, the TxA2/PGH2-receptor antagonist SQ-29548 blocked the pulmonary blood pressure responses elicited by PGB2. Receptor-binding studies using the TxA2 receptor ligand [3H]SQ-29548 indicated that PGB2 was a potent competitor for TxA2/PGH2 receptor binding. In agreement with the results from the intact animal, however, the efficacy of inhibition with PGB2 was significantly less than that measured for the TxA2 agonist U-46619. All of these results are consistent with the hypothesis that the physiological effects of PGB2 are mediated by stimulation of TxA2/PGH2 receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins B; Prostaglandins H; Pulmonary Circulation; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

When protamine reverses heparin anticoagulation a small fraction of patients develops pulmonary hypertension. This response is variably expressed in other species and thromboxane may be one of its mediators. We have compared the pulmonary vascular responses of pigs and monkeys to protamine (3 mg/kg, i.v.) administered 15 min after heparin (300 U/kg, i.v.). The role of thromboxane A2/prostaglandin H2 (TxA2/PGH2)-receptor activation in this response was investigated with the selective TxA2/PGH2-receptor antagonist, SQ 30,741, at a dose (1 mg/kg, i.v.) shown to inhibit U-46,619-induced pulmonary vasoconstriction by greater than or equal to 99%. SQ 30,741 or vehicle (1.5 ml saline) was given 2 min before protamine in Yucatan minipigs (n = 6-7) and African green monkeys (n = 8-9). In saline-treated monkeys and pigs, protamine increased pulmonary vascular resistance (131 +/- 46 and 478 +/- 18%, respectively) primarily by increasing pulmonary artery pressures (54 +/- 19 and 166 +/- 42%, respectively). In pigs only, pulmonary artery flow was also reduced by 33 +/- 9%. These responses peaked within 1 to 3 min and returned to baseline in approximately 5 (monkey) and approximately 15 (pig) min. In monkeys and pigs pretreated with SQ 30,741 the increases in pulmonary vascular resistance (17 +/- 4 and 16 +/- 9%, respectively, p less than 0.05) and pulmonary artery pressure (10 +/- 3 and 16 +/- 9%, respectively, p less than 0.05) were significantly inhibited. SQ 30,741 also accelerated reversal of established hypertension in pigs when given 1 min after protamine. However, transient reductions in circulating monkey leukocytes (approximately 70%) and platelets (approximately 16%) were unaffected by SQ 30,741.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Chlorocebus aethiops; Drug Interactions; Heparin; Hypertension, Pulmonary; Kinetics; Lung; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Protamines; Pulmonary Artery; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Swine; Swine, Miniature; Thromboxane A2; Vascular Resistance; Vasoconstriction

Chronic pulmonary hypertension can develop in diseases associated with acute or repeated inflammation in the lungs, e.g., adult respiratory distress syndrome, chronic bronchitis. Inflammation has also been associated with some animal models of chronic pulmonary hypertension. We have previously shown that 12 days of continuous air embolization into sheep results in the functional and structural changes of chronic pulmonary hypertension. To determine whether granulocytes contribute to these changes, five sheep were granulocyte-depleted with hydroxyurea immediately before and during air embolization (AIR-PMN) and were compared with sheep receiving air embolization (AIR only). Air embolization was discontinued briefly every 4 days for monitoring of pulmonary vascular pressures and assessment of pulmonary vasoreactivity to a bolus injection of PGH2-A. After 12 days of air embolization, the lungs were removed for structural studies. AIR-PMN sheep did not develop the sustained increase in pulmonary artery pressure seen in the AIR sheep (Day 12, AIR-PMN = 20 +/- 3 cm H2O; AIR = 29 +/- 2; mean +/- SE). Similarly, the increased pulmonary pressor response to PGH2-A seen in AIR sheep was not found in the AIR-PMN group. Structural studies of the barium-injected lungs of AIR-PMN sheep revealed a twofold increase in medial thickness of normally muscular arteries and a significant increase in the percent of muscular intraacinar arteries (similar to findings in lungs from AIR sheep). The number of barium-filled arteries was increased in AIR-PMN sheep when compared with that in AIR sheep, but the number was still less than in the control sheep. We conclude that granulocytes may contribute to the functional changes of chronic pulmonary hypertension after continuous air embolization in sheep, but they do not play a role in structural changes involving pulmonary arterial smooth muscle cells and their precursors. The present data also suggest that the reduction in peripheral arterial filling is the structural alteration that contributes most to the sustained rise in pulmonary artery pressure. The data further suggest that pulmonary hypertension after air embolization may have a vasoconstrictive component that is granulocyte-dependent.

Topics: Animals; Chronic Disease; Embolism, Air; Granulocytes; Hydroxyurea; Hypertension, Pulmonary; Lung; Lymph; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Sheep; Sheep Diseases; Time Factors; Vasoconstriction

Six chronically catheterized sheep were exposed to 1,500-rad whole-lung irradiation and followed for a four-week period. Pulmonary arterial, left atrial and systemic arterial pressures, cardiac output, arterial blood gases, and pH were measured at base line and biweekly following radiation. Pulmonary vasoreactivity to 12% O2, 100% O2, and an analogue of prostaglandin H2 (PGH2-A) was also assessed. Five nonirradiated sheep served as controls. By the 2nd wk following irradiation, pulmonary vascular resistance had doubled. Final pulmonary arterial pressure was increased 50% over the base-line value (base line = 14 +/- 1 cm H2O; final 22 +/- 2; mean +/- SE; P less than 0.05). Arterial PO2 was decreased to approximately 70 Torr throughout the study. In addition, pulmonary vasoreactivity to PGH2-A, but not to breathing 12 or 100% O2, was significantly increased above base line in the irradiated animals (P less than 0.05). Morphometric techniques applied to the lungs in which the pulmonary arterial circulation was distended with barium gelatin mixture, showed extension of muscle into the distal intra-acinar arteries, and a reduction in both the external diameter and the number of barium-filled peripheral arteries in the irradiated animals. Thus thoracic irradiation results in functional and structural changes of chronic pulmonary hypertension and increased pulmonary vasoreactivity to PGH2-A. The structural changes in the peripheral pulmonary arterial bed may contribute to the increased pulmonary vascular reactivity following thoracic irradiation.

Topics: Animals; Blood Pressure; Carbon Dioxide; Hypertension, Pulmonary; Lung; Oxygen; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Sheep; Thorax; Vascular Resistance

Six chronically catheterized awake sheep were given the cyclooxygenase inhibitor indomethacin (5 mg/kg) twice a day over a 3-wk period. Three sheep receiving vehicle alone served as controls. Pulmonary arterial, left atrial, and systemic arterial pressures, cardiac output, blood gases, and pH were measured biweekly. Pulmonary vasoreactivity to 12% O2 and an analogue of prostaglandin H2 (PGH2-A) was also assessed. As a percent of base line, indomethacin caused a doubling in pulmonary vascular resistance (3 wk = 190 +/- 26%, mean +/- SE) and a 50% increase in pulmonary arterial pressure (3 wk = 151 +/- 9%). Vasoreactivity to 12% O2 increased approximately fourfold during the 1st wk of treatment and then declined. Vasoreactivity to PGH2-A increased steadily, nearly doubling by 3 wk. Light-microscopic counts of peripheral lung biopsy tissue revealed marked sequestration of granulocytes. Morphometric techniques applied to lungs removed at autopsy and fixed with the pulmonary arteries distended with barium gelatin mixture showed a significant reduction in number of barium-filled peripheral arteries and reduction in their external diameter. We conclude that repeated administration of indomethacin alters pulmonary vasoreactivity and causes sustained pulmonary hypertension. Structural studies reveal peripheral lung inflammation and changes in the arterial circulation that are perhaps more consistent with maintained vasoconstriction than chronic pulmonary hypertension.

Topics: Animals; Cyclooxygenase Inhibitors; Hypertension, Pulmonary; Indomethacin; Lipoxygenase Inhibitors; Lung; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Pulmonary Circulation; Sheep; Vasoconstriction