11-dehydro-thromboxane-b2 and Hypertension--Pulmonary

Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.. We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration.. Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.

Topics: Animals; Blood Pressure; Epoprostenol; Hepatocyte Growth Factor; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Pyridines; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase

Patients with Down syndrome (DS) and a left-to-right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A(2) and prostacyclin (PGI(2)) in four groups of infants, cross-classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha): DS infants with a left-to-right shunt and PH (D-PH, n = 18), DS infants without congenital heart defect (D-C, n = 8), non-DS infants with a left-to-right shunt and PH (ND-PH, n = 12), and non-DS infants without congenital heart defect (ND-C, n = 22). The urinary excretion ratios of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) in the D-PH, D-C, ND-PH, and ND-C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA(2) over PGI(2), leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left-to-right shunt.

Topics: 6-Ketoprostaglandin F1 alpha; Child, Preschool; Cross-Sectional Studies; Down Syndrome; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung Diseases, Obstructive; Male; Prognosis; Pulmonary Heart Disease; Radioimmunoassay; Thromboxane A2; Thromboxane B2

The balance between prostacyclin and thromboxane plays an important role in the regulation of pulmonary vascular tone. Recently, we developed ONO-1301, a novel, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.. We investigated whether modulation of prostacyclin/thromboxane balance by ONO-1301 ameliorates monocrotaline-induced pulmonary hypertension in rats.. After subcutaneous injection of monocrotaline or vehicle, rats were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle twice per day for 3 wk.. There was significant development of pulmonary hypertension 3 wk after monocrotaline injection. Treatment with ONO-1301 significantly attenuated the increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in monocrotaline rats. Furthermore, ONO-1301 significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in monocrotaline rats. The half-life of plasma ONO-1301 concentration after a single subcutaneous administration was approximately 5.6 h. A single administration of ONO-1301 increased plasma cyclic adenosine 3', 5'-monophosphate level, which lasted at least up to 8 h. Treatment with ONO-1301 significantly decreased plasma 11-dehydro-thromboxane B2, a metabolite of thromboxane, in monocrotaline rats. Finally, Kaplan-Meier survival curves demonstrated that repeated administration of ONO-1301 improved survival rate in monocrotaline rats compared with vehicle administration (80 vs. 30% in 6-wk survival).. Subcutaneous administration of a novel prostacyclin agonist (ONO-1301) markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. The beneficial effects of ONO-1301 may occur through its long-lasting stimulation of cyclic adenosine 3', 5'-monophosphate and inhibition of thromboxane synthase.

Topics: Animals; Blood Pressure; Epoprostenol; Heart Rate; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Monocrotaline; Pyridines; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase

To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion.. Randomized, controlled trial.. Animal laboratory.. Twenty seven domestic pigs, weighing 24 to 31 kg.. All pigs were anesthetized and mechanically ventilated during the experiment. Eighteen pigs were subjected to an intracaval infusion of 10% allogeneic bone marrow suspension at a dose of 100 mg/kg over 5 mins. Nine pigs received only bone marrow suspension (fat embolism group). Nine pigs were given an intravenous bolus of aspirin (300 mg) 1 hr before the bone marrow suspension infusion. After the induction of fat embolism, intravenous aspirin was administered at a dose of 150 mg/hr for 2 hrs (aspirin-treated group). Nine pigs were infused with saline (control group).. In the fat embolism group, cardiac index decreased within 30 mins, while mean arterial pressure remained unchanged. Central venous pressure and pulmonary artery occlusion pressure remained relatively stable over time in the animals with fat embolism. Mean pulmonary arterial pressure and pulmonary vascular resistance increased immediately after the bone marrow suspension infusion from 23 +/- 0.8 (SEM) to 34 +/- 1.3 mm Hg and from 305 +/- 28 to 585 +/- 45 dyne x sec/cm5, respectively; these variables remained increased throughout the study period. Simultaneously, pulmonary shunt in the fat embolism group increased persistently from the baseline of 12.3 +/- 2.8%, and reached its maximum of 26.1 +/- 4.8% at the end of the experiment. Instant and gradual decreases in PaO2 (from 95 +/- 4 to 67 +/- 5 torr [12.6 +/- 0.5 to 8.9 +/- 0.7 kPa]), hemoglobin oxygen saturation (from 97.2 +/- 0.4 to 91.8 +/- 1.8%), and oxygen delivery (from 16.3 +/- 1.0 to 12.6 +/- 0.4 mL/min/kg) were observed in the fat embolism group. In the bone marrow suspension-infused animals, urine 2,3-dinor-6-ketoprostaglandin F1alpha excretion increased transiently from 451 +/- 63 up to 1466 +/- 499 pg/micromol creatinine, while urine 11-dehydrothromboxane B2 excretion increased transiently from 385 +/- 36 up to 2307 +/- 685 pg/micromol creatinine. In the aspirin-treated animals, urinary excretion of these prostanoid metabolites was reduced by 81% and 88%, respectively. The changes in mean pulmonary arterial pressure and PaO2 were ameliorated, and the alterations in pulmonary shunt and SaO2 were abolished in the animals with aspirin treatment.. Pulmonary hypertension, increased pulmonary vascular tone, and increased pulmonary shunt are hallmarks of the present fat embolism model. These hemodynamic responses may, at least partly, be related to the changed balance between prostacyclin and thromboxane A2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Cyclooxygenase Inhibitors; Embolism, Fat; Epoprostenol; Evaluation Studies as Topic; Hemodynamics; Hypertension, Pulmonary; Lung Diseases; Random Allocation; Swine; Thromboxane A2; Thromboxane B2

Chronic administration of prostacyclin (PGI2) improves hemodynamics in patients with primary pulmonary hypertension, but abrupt cessation of infusion can cause severe dyspnea of unknown etiology. We hypothesized that the discontinuation of PGI2 results in platelet activation, thromboxane A2 production, and increased pulmonary vascular tone. To test this, six sheep with indwelling catheters were monitored during infusion of PGI2 and after its cessation. Infusion of PGI2 caused a reduction in mean systemic arterial pressure (MAP) and systemic (SVR) and pulmonary vascular resistances (PVR), a rise in cardiac output (CO), and no change in pulmonary arterial or pulmonary capillary wedge pressure (PCWP). After discontinuation of PGI2, MAP and SVR rebounded to 30 and 67% above baseline, respectively, and PVR rose 26%. CO was depressed 23% within 10 min, and PCWP nearly doubled after stoppage of the drug. Concurrent treatment with a cyclooxygenase inhibitor did not attenuate these responses. 11-Dehydro-thromboxane B2 levels were not elevated during infusion or after cessation of PGI2. We conclude that the abrupt cessation of PGI2 infusion leads to systemic and pulmonary hypertension and transient cardiac dysfunction not mediated by cyclooxygenase metabolites of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Hypertension; Hypertension, Pulmonary; Infusions, Intravenous; Platelet Activation; Platelet Aggregation Inhibitors; Pulmonary Circulation; Sheep; Substance Withdrawal Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasodilation

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium.. We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls.. The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls.. An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Radioimmunoassay; Thromboxane A2; Thromboxane B2