Concentration Of 6-ketoprostaglandin F1 Alpha Research Articles

Panax Notoginseng Saponins Combined with Dual Antiplatelet Drugs Potentiates Anti-Thrombotic Effect with Alleviated Gastric Injury in A Carotid Artery Thrombosis Rat Model

ObjectiveTo observe the combination effects of Panax notoginseng saponins (PNS)and dual antiplatelet drugs (DAPT), and to explore the mechanism via cyclooxygenase /prostaglandin pathway. MethodsRight carotid artery thrombosis was induced in Wistar rats by infiltration with 70% FeCl3, and the animals were randomly divided into sham group, model group, DAPT group and PNS + DAPT group, intragastrically treated for 4 weeks. The cerebral pia mater microcirculation was observed in vivo after anesthetizing by anatomical microscope. The wet weight of carotid artery thrombosis was measured. Gastric mucosal injury was observed by hematoxylin and eosin staining. Platelet aggregation rate was detected with adenosine diphosphate -induced turbidimetry. Platelet CD62p expression was detected by flow cytometry. Concentrations of 6-Ketoprostaglandin F1 alpha, prostaglandin E2 in gastric mucosa and thromboxane B2, 6-Ketoprostaglandin F1 alpha, tissue plasminogen activator, plasminogen activator inhibitor, and fibrin fragment D in the plasma were measured by radioimmunoassay. ResultsPNS and DAPT increased the blood flow volume of cerebral pia mater and decreased erythrocyte aggregation and leukocyte adhesion of model rats. Compared to DAPT, PNS and DAPT further reduced the weight of carotid artery thrombosis with enhanced inhibition of platelet aggregation, increased tissue plasminogen activator levels and decreased fibrin fragment D levels. PNS and DAPT alleviated gastric injury induced by dual antiplatelet drugs and upregulated the expression of 6-Ketoprostaglandin F1 alpha in the gastric mucosa compared with DAPT. ConclusionsPNS combined with DAPT increased anti-thrombosis effects of DAPT and mitigated DAPT-related gastric injury. The underlying mechanisms may be associated with enhanced antiplatelet aggregation and activation of the fibrinolytic system and up-regulation of 6-Ketoprostaglandin F1 alpha expression in gastric mucosa.

Determination of Prostacyclin in Plasma through a Bioluminescent Immunoassay for 6-Keto-prostaglandin F1α: Implication of Dosage in Patients with Primary Pulmonary Hypertension

This work describes a solid-phase immunoassay for 6-keto-prostaglandin F1alpha, the stable hydrolysis product of prostacyclin (prostaglandin I2). Prostacyclin, a potent vasodilator with antiplatelet and antiproliferative properties is an effective treatment for primary pulmonary hypertension and pulmonary arterial hypertension associated with scleroderma and scleroderma-like syndrome. Levels of 6-keto-prostaglandin F1alpha can be directly correlated with levels of prostacyclin. Therefore, 6-keto-prostaglandin F1alpha, has become the indicator of choice to measure prostacyclin levels. The single-step immunoassay for 6-keto-prostaglandin F1alpha reported here was developed using the bioluminescent protein aequorin as a label. Analyte-label conjugates were constructed by linking the carboxyl group of 6-keto-prostaglandin F1alpha and lysine residues of aequorin by chemical conjugation methods. The binding properties of 6-keto-prostaglandin F1alpha toward its antibody and the bioluminescent properties of aequorin were retained in the conjugate, which was then used to generate a dose-response curve for the analyte in a convenient microtiter plate format. The concentration of 6-keto-prostaglandin F1alpha after extraction from plasma showed good correlation with the concentration of 6-ketoprostaglandin F1alpha obtained without prior extraction of the same plasma sample. This measurement demonstrated that the assay allows the measurement of 6-keto-prostaglandin F1alpha directly in plasma without any pretreatment of the samples, which results in a much simpler method with a faster assay time.

Changes in cerebral venous prostanoids during midazolam-induced cerebrovascular hypotension in newborn piglets.

We hypothesized that the effects of midazolam are associated with altered prostanoid synthesis in the newborn piglet during continuous infusion. To test this hypothesis, we examined the effect of midazolam on prostanoid production in the carotid artery and sagittal sinus vein before and during midazolam infusion. Prospective, randomized, controlled, experimental study. Research laboratory at Long Beach Memorial Medical Center. Fourteen newborn piglets (1-3 days old, 1-1.5 kg) randomly assigned to receive either midazolam or vehicle (5% dextrose) infusion for 6 hrs. Two groups of animals received either a) a loading dose of 300 microg/kg of midazolam over 15 mins, followed by a continuous intravenous infusion of 100 microg/kg/hr (n = 6), or b) equivalent volume bolus and intravenous infusions of 5% dextrose (control, n = 8). Changes in systemic and cerebral venous hemodynamics, blood gases, and prostanoid (prostaglandin E2, 6-ketoprostaglandin F1 alpha, thromboxane B2) production were measured at baseline, postbolus, and at 0.5, 2, 4, and 6 hrs. Systemic and cerebral venous midazolam concentrations were measured at 0.5, 1, 2, 3, 4, 5, and 6 hrs. Midazolam infusion did not affect systemic hemodynamics or blood gases. In contrast, midazolam infusion significantly reduced sagittal sinus vein blood pressure, PO2, oxygen saturation, and oxygen content. Cerebral fractional oxygen extraction increased and was positively correlated with cerebral fractional midazolam extraction. Concurrently, systemic and sagittal sinus vein plasma prostaglandin E2 concentrations decreased, whereas 6-ketoprostaglandin F1 alpha concentrations increased with midazolam infusion. Thromboxane B2 concentrations increased transiently in the systemic plasma. Midazolam infusion preceded by a high bolus dose in newborn piglets alters systemic and sagittal sinus vein prostanoid production. It is also associated with changes in sagittal sinus vein blood pressure and cerebral fractional oxygen extraction. These changes may reflect decreased brain perfusion and metabolism during midazolam infusion.

Anticoagulation with prostacyclin and heparin during continuous venovenous hemofiltration

To investigate anticoagulation with prostacyclin (prostaglandin I2 [PGI2]) and/or heparin during continuous venovenous hemofiltration, and the role of in vitro tests of primary hemostasis in controlling anticoagulation. Prospective, randomized, controlled trial. Intensive care unit. Forty-six consecutive, critically ill, mechanically ventilated patients with postoperative acute renal failure. Anticoagulation of the patient's blood was accomplished using heparin (6.0 +/- 0.3 IU/kg/hr for group 1), PGI2 (7.7 +/- 0.7 ng/kg/min for group 2), or both PGI2 and heparin (6.4 +/- 0.3 ng/kg/min, 5.0 +/- 0.4 IU/kg/hr, respectively, for group 3), administered into the extracorporeal line before the hemofilter during continuous venovenous hemofiltration. After Ethics Committee approval and informed consent were obtained, tests of primary and secondary hemostasis, plasma concentrations of 6-ketoprostaglandin F1 alpha (by radioimmunoassay), and hemodynamic measurements were performed before hemofiltration and 24 hrs after hemofiltration. In groups 1 and 3, hemodynamic parameters remained stable, whereas in group 2 (the PGI2 group), there were significant reductions in systemic and pulmonary vascular resistances and mean arterial pressure. Platelet function was unchanged in group 1, and was inhibited in groups 2 and 3. Corresponding with the prolongation of in vitro bleeding time, the 6-ketoprostaglandin F1 alpha concentration was increased, indicating an effective inhibition of platelet aggregation within the hemofilter. Platelet counts remained stable in all patients. Plasma coagulation tests were stable in groups 2 and 3, and were prolonged in group 1. In all patients, no major bleeding complications were observed and there was no clinically important bleeding. Mean hemofilter duration lasted longest in group 3. Blood urea nitrogen and circulating creatinine concentrations decreased significantly in groups 2 and 3 within the study period. Patients receiving both PGI2 and heparin showed better hemodynamic profiles and enhanced hemofilter duration compared with the other groups and no bleeding complications were observed. Therefore, we recommend anticoagulation with PGI2 and heparin during continuous venovenous hemofiltration with close monitoring of platelet function, coagulation profile, and overall hemodynamics.

Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheep

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)

Light/dye microvascular injury selectively eliminates hypercapnia-induced pial arteriolar dilation in newborn pigs.

Cerebral vasodilation in response to hypercapnia involves prostanoids in newborn pigs. This study examines the hypothesis that endothelial injury in vivo inhibits cerebral vasodilation and prostacyclin synthesis in response to hypercapnia, thus suggesting prostacyclin is a primary endothelium-derived vasodilating factor in newborn pig cerebral circulation. Anesthetized piglets with closed cranial windows were studied before and after injury caused by light/dye or before and after dye-only sham control. Light/dye injury was produced by injecting sodium fluorescein intravenously and passing filtered light from a mercury arc lamp through the cranial window. Ultrastructural changes to endothelium of pial vessels were produced that were characterized by surface pits, vacuolar cytoplasmic inclusions, and mitochondrial injury. After the light/dye injury, dilation to hypercapnia was absent while dilations to iloprost, isoproterenol, and sodium nitroprusside and constrictions to norepinephrine and acetylcholine were retained. Before light/dye treatment, hypercapnia increased cortical periarachnoid 6-keto prostaglandin F1 alpha concentration approximately threefold. However, after treatment, 6-keto-prostaglandin F1 alpha was not increased significantly in response to hypercapnia. These findings are consistent with the hypothesis that endothelial prostacyclin synthesis induced by hypercapnia participates in dilation of adjacent smooth muscle.

Prostanoid cascade inhibition prevents cardiovascular and adrenocorticotropic responses to mineral acid infusion.

Mineral acid infusion is used to investigate the effects of acidemia on the cardiovascular and respiratory systems. Previous studies have shown that small infusions of HCl increase mean arterial pressure (MAP), adrenocorticotropic hormone (ACTH), and cortisol without producing acidemia. We infused 1 meq/min of 1 N HCl intravenously into chronically catheterized conscious sheep with or without pretreatment with 1.1 mg/kg flunixin-N-methylglucamine, a cyclooxygenase inhibitor (n = 6). Acid infusion resulted in significant increases in heart rate (83 +/- 5 to 94 +/- 7 beats/min), MAP (84 +/- 3 to 104 +/- 6 mmHg), ACTH (97 +/- 23 to 285 +/- 101 pg/ml), cortisol (20 +/- 3 to 37 +/- 16 ng/ml), sodium (149.5 +/- 0.8 to 150.6 +/- 1.3 meq/l), potassium (3.96 +/- 0.09 to 4.31 +/- 0.19 meq/l), and thromboxane (Tx) B2 (stable metabolite of TxA2) (147 +/- 78 to 2,304 +/- 1,213 pg/ml), whereas these changes were prevented by flunixin. Plasma concentrations of 6-ketoprostaglandin F1 alpha (stable metabolite of prostacyclin), prostaglandin E2, interleukin-1 alpha, and hematocrit did not change in either group. Arterial pH decreased, whereas arterial partial pressure of CO2 increased significantly in both groups. Arterial partial pressure of O2 declined in both groups, but the decrease was significantly greater in the group not receiving flunixin. We conclude that a cyclooxygenase metabolite, most likely TxA2, mediates the MAP, heart rate, ACTH, and cortisol responses to mineral acid infusion.

Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid.

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)

Topical arachidonic acid restores pial arteriolar dilation to hypercapnia of postischemic newborn pig brain.

In the newborn pig, cerebral vasodilator responses to hypercapnia are lost after cerebral ischemia. We examined the effect of topical application of arachidonic acid (30 micrograms/ml, 20 min) to the postischemic piglet brain on subsequent pial arteriolar dilated in response to hypercapnia (10% CO2 ventilation) and topical isoproterenol (10(-6), 10(-7) M). After 20 min cerebral ischemia, pial arterioles did not dilate to hypercapnia but responded to isoproterenol in a fashion similar to before ischemia. Treatment with arachidonic acid after ischemia restored pial arteriolar dilation to hypercapnia. Hypercapnia caused an increase in cortical periarachnoid concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) before but not after ischemia. After postischemic treatment with arachidonic acid, the increase in cortical periarachnoid fluid 6-keto-PGF1 alpha during hypercapnia was restored. Therefore, topical application of arachidonic acid to cerebral vessels restores cerebral prostanoid synthesis and pial arteriolar dilation in response to hypercapnia that has been abolished by ischemia.

Effects of endothelin-1 and conversion of big endothelin-1 in the isolated perfused rabbit lung.

We examined the effects of endothelin-1 (ET-1) on pulmonary hemodynamic and transvascular fluid filtration and the conversion of big endothelin-1 (big ET-1), a precursor of ET-1, in isolated perfused rabbit lungs at constant vascular and airway pressures. Furthermore we examined whether ET-1 contributes to cyclooxygenase metabolism. The perfusate flow decreased significantly after bolus administration of 1 or 0.1 nmol of ET-1. Lung weight did not increase throughout the experimental period. Big ET-1- (1 nmol) induced decrease in the flow was slow in developing, although the maximum response was comparable to that induced by the same dose of ET-1. The concentration of bit ET-1 in the perfusate progressively decreased, while that of ET-1 increased in a time-dependent manner. Phosphoramidon, an inhibitor of metalloproteinase, suppressed the pressor effect of big ET-1 (P less than 0.01) and the increase in the concentration of ET-1 in the perfusate (P less than 0.05). The present findings provide the first evidence suggesting that the potent vasocontractile effect of big ET-1 in pulmonary circulation can be attributed to the production of ET-1 by the conversion from big ET-1 in the vascular bed. ET-1-induced perfusate flow changes were not affected by indomethacin, and the concentration of 6-ketoprostaglandin F1 alpha, a metabolite of prostacyclin, did not increase after ET-1 administration.

Effects of endothelin-1 on endothelial cells in the porcine coronary artery.

The effects of endothelin-1 (ET-1) on endothelial cells from the porcine coronary artery were investigated using cascade bioassay and radioimmunoassay methods. For comparison, endothelial cells from the rabbit abdominal aorta were also used. Freshly isolated endothelial cells were perfused with Krebs' solution. Liberation of vasodilatory substances was detected under bioassay conditions by measuring the relaxing activity of the perfusate on endothelium-denuded strips of the porcine coronary artery contracted with ET-1. The perfusate in the absence of ET-1 slightly inhibited the contraction, suggesting that endothelial cells spontaneously release vasorelaxing substances. After application of ET-1, the perfusate-induced relaxation drastically increased. Oxyhemoglobin completely abolished the relaxation induced by perfusate from endothelial cells of the rabbit abdominal aorta but only marginally attenuated the relaxation induced by perfusate from endothelial cells of the porcine coronary artery. In contrast, indomethacin significantly attenuated the relaxation induced by perfusate from the endothelial cells of the porcine coronary artery. In endothelium-intact strips of the porcine coronary artery, ET-1 significantly increased the concentration of 6-ketoprostaglandin F1 alpha but did not modify the cellular concentration of either cAMP or cGMP. It is concluded that ET-1 augments the release of vasorelaxing factors from endothelial cells both in the porcine coronary artery and in the rabbit abdominal aorta and that the major vasorelaxing substance derived from endothelial cells may be different in these two blood vessels. Prostaglandin I2 in the former and nitric oxide in the latter are suggested as possible candidates. The vasorelaxation induced by prostaglandin I2 may not be mediated by cAMP-dependent mechanisms in the porcine coronary artery.

Effects of endothelin on coronary flow, mechanical performance, oxygen uptake, and formation of purines and on outflow of prostacyclin in the isolated rabbit heart.

Endothelin is a 21-residue peptide formed during incubation of isolated porcine endothelial cells. Due to its pronounced vasoconstrictor activity, endothelin has been proposed to play a role in the regulation of vascular tone. We studied the effects of synthetic endothelin (0.1-10 nM) on coronary flow, mechanical performance, myocardial oxygen uptake, and formation of purines, and outflow of 6-ketoprostaglandin F1 alpha (metabolite of prostacyclin) in rabbit hearts perfused with saline by the Langendorff method. Endothelin dose-dependently decreased the coronary flow, at 10 nM, by about 75%. Heart rate, ventricular contractility, myocardial oxygen uptake, and purine release were affected by endothelin no more than by a corresponding mechanical reduction of the coronary flow. In contrast, the diastolic relaxation appeared to be directly diminished by endothelin. The concentration of 6-ketoprostaglandin F1 alpha in the cardiac effluent was dose-dependently elevated by about 14 times by endothelin (10 nM) (p less than 0.001). A corresponding mechanical restriction of the coronary flow insignificantly affected the effluent concentration of 6-ketoprostaglandin F1 alpha. The calcium channel blocker nifedipine (1 microM) completely abolished the decrease in diastolic relaxation induced by endothelin and markedly counteracted the peptide-induced increase in effluent concentration of 6-ketoprostaglandin F1 alpha, but did not affect the vasoconstrictor activity. These data demonstrate that endothelin induces vasoconstriction and facilitates the outflow of prostacyclin in the rabbit heart. In addition, the peptide appears to affect diastolic relaxation in this organ.

Spontaneous injury in isolated sheep lungs: role of perfusate leukocytes and platelets.

Perfusion of isolated sheep lungs with blood causes spontaneous edema and hypertension preceded by decreases in perfusate concentrations of leukocytes (WBC) and platelets (PLT). To determine whether these decreases were caused by pulmonary sequestration, we continuously measured blood flow and collected pulmonary arterial and left atrial blood for cell concentration measurements in six lungs early in perfusion. Significant sequestration occurred in the lung, but not in the extracorporeal circuit. To determine the contribution of these cells to spontaneous injury in this model, lungs perfused in situ with a constant flow (100 ml.kg-1.min-1) of homologous leukopenic (WBC = 540 mm-3, n = 8) or thrombocytopenic blood (PLT = 10,000 mm-3, n = 6) were compared with control lungs perfused with untreated homologous blood (WBC = 5,320, PLT = 422,000, n = 8). Perfusion of control lungs caused a rapid fall in WBC and PLT followed by transient increases in pulmonary arterial pressure, lung lymph flow, and perfusate concentrations of 6-ketoprostaglandin F1 alpha and thromboxane B2. The negative value of reservoir weight (delta W) was measured as an index of fluid entry into the lung extravascular space during perfusion. delta W increased rapidly for 60 min and then more gradually to 242 g at 180 min. This was accompanied by a rise in the lymph-to-plasma oncotic pressure ratio (pi L/pi P). Relative to control, leukopenic perfusion decreased the ratio of wet weight to dry weight, the intra- plus extravascular blood weight, and the incidence of bloody lymph. Thrombocytopenic perfusion increased lung lymph flow and the rate of delta W, decreased pi L/pi P and perfusate thromboxane B2, and delayed the peak pulmonary arterial pressure. These results suggest that perfusate leukocytes sequestered in the lung and contributed to hemorrhage but were not necessary for hypertension and edema. Platelets were an important source of thromboxane but protected against edema by an unknown mechanism.

Effects of dibutyryl cAMP on pulmonary air embolism-induced lung injury in awake sheep.

To assess the role of intracellular adenosine 3',5'-cyclic monophosphate (cAMP), we tested the effects of dibutyryl cAMP (DBcAMP), an analogue of cAMP, on lung injury induced by pulmonary air embolism in awake sheep with chronic lung lymph fistula. We infused air (1.23 ml/min) in the pulmonary artery for 2 h in untreated control sheep. In DBcAMP-pretreated sheep DBcAMP was infused (1 mg/kg bolus and 0.02 mg.kg-1.min-1 constantly for 5 h); after 1 h from beginning of DBcAMP administration the air infusion was started. After the air infusion, pulmonary arterial pressure (Ppa) and lung lymph flow rate (Qlym) significantly increased in both groups. DBcAMP-pretreated sheep showed significantly lower responses in Qlym (2.7 X base line) compared with untreated control sheep (4.6 X base line); however, Ppa, left atrial pressure, and lung lymph-to-plasma protein concentration ratio were not significantly different between the two groups. Although plasma and lung lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations increased significantly during the air infusion, DBcAMP-pretreated sheep showed significantly lower responses. Thus DBcAMP infusion attenuated pulmonary microvascular permeability induced by air embolism. We conclude that pulmonary vascular permeability is in part controlled by the intracellular cAMP level.

Effect of Indomethacin on Gastric Mucosal Prostaglandins in Humans: Correlation With Mucosal Damage

We evaluated in healthy human beings the effect of indomethacin on gastric mucosal prostaglandin concentration and on gastric mucosal damage in a placebo-controlled study. Prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha concentrations of gastric mucosal biopsy specimens, obtained endoscopically, were measured by radioimmunoassay. Mean prostaglandin concentration of the antrum and fundus was similar. In both regions there was considerable intersubject variability in prostaglandin concentration. Repeated 50-mg oral doses of indomethacin for 4 days reduced mean prostaglandin F2 alpha and E2 concentration by 50.2% and 69.4%, respectively, in the fundus and by 40.0% and 49.7% in the antrum, but this led to no significant mucosal damage when assessed endoscopically or histologically. A single 100-mg oral dose of indomethacin reduced mean prostaglandin F2 alpha and prostaglandin E2 concentration by 81.4% and 60.9% in the fundus and by 64.2% and 57.5% in the antrum and also induced significant mucosal injury in both regions when assessed endoscopically. However, there was no correlation between degree of suppression of prostaglandin concentration by indomethacin and endoscopic evidence of mucosal damage.

Effects of indomethacin on estradiol-induced attenuation of hypoxic vasoconstriction in lamb lungs.

To determine whether cyclooxygenase products mediated the attenuation of hypoxic pulmonary vasoconstriction induced by estradiol, we measured pulmonary arterial pressure at a flow of 50 ml X min-1 X kg-1 (Ppa50) during steady-state exposures to inspired O2 tensions (PIO2) between 0 and 200 Torr in isolated lungs of juvenile ewes. Intramuscular estradiol (10 mg) 44-60 h before study significantly decreased perfusate concentrations of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator, prostacyclin, but did not significantly affect the stimulus-response relationship between PIO2 and Ppa50. Estradiol (20 mg) 3-5 days before study increased 6-keto-PGF1 alpha concentrations and decreased Ppa50 at PIO2 of 10, 30, and 50 Torr. Indomethacin added to the perfusate of these lungs reduced 6-keto-PGF1 alpha to undetectable levels and altered the estradiol-induced attenuation, increasing Ppa50 at PIO2 of 10 and 30 Torr, but decreasing Ppa50 at PIO2 of 200 Torr. Despite these effects, Ppa50 remained lower than the values measured in lungs not treated with estradiol. These results suggest that the estradiol-induced attenuation of the hypoxic stimulus-response relationship was mediated only in part by cyclooxygenase products, the net effects of which were vasodilation at PIO2 of 10 and 30 Torr, but vasoconstriction at PIO2 of 200 Torr.

Hyperventilation, alkalosis, prostaglandins, and pulmonary circulation of the newborn.

This study was designed to determine whether the effects of hyperventilation on the pulmonary circulation of the newborn lamb were 1) due to mechanical factors or to respiratory alkalosis; and 2) mediated by prostaglandins. Six control lambs were studied during normal ventilation and during hyperventilation with, and without, decreased carbon dioxide (CO2). Five lambs were given indomethacin and studied similarly. In control lambs, hyperventilation with decreased CO2 decreased pulmonary arterial pressure from 26 +/- 2.2 to 18 +/- 1.0 (SE) Torr (P less than or equal to 0.005) and pulmonary vascular resistance from 0.099 +/- 0.035 to 0.070 +/- 0.011 Torr X kg-1 X min-1 (P less than or equal to 0.015). Hyperventilation with normal CO2 did not affect the pulmonary circulation. Hyperventilation with decreased CO2 increased pulmonary arterial concentrations of 6-ketoprostaglandin F1 alpha, a major metabolite of prostacyclin, in control lambs but not in the indomethacin-treated lambs. However, it affected the pulmonary circulation of the control- and indomethacin-treated lambs similarly. In conclusion, hyperventilation affected the pulmonary circulation by respiratory alkalosis not by mechanical factors and prostaglandins did not mediate its effects.

Peptide 6A, a fibrin(ogen) degradation product, increases coronary blood flow.

The coronary hemodynamic effects of intracoronary administration of a fibrin(ogen)-derived pentapeptide, Ala-Arg-Pro-Ala-Lys (peptide 6A), were evaluated in open-chest anesthetized dogs. With administration of peptide 6A (2.5-30 mumol), coronary blood flow increased and coronary vascular resistance decreased promptly in a dose-related manner. Increase in coronary blood flow was independent of any change in indexes of myocardial O2 demand, indicating the peptide 6A exerts direct effects on coronary arterial tone. Systemic arterial and left ventricular end-diastolic pressures remained unchanged with smaller doses but decreased when higher doses of peptide 6A (greater than or equal to 20 mumol) were administered. Plasma concentrations of 6-ketoprostaglandin F1 alpha, stable hydrolysis product of prostacyclin, increased in coronary sinus blood samples in conjunction with increase in coronary blood flow. Administration of indomethacin (5 mg/kg iv) inhibited peptide 6A-induced release of prostacyclin and significantly attenuated the effects of peptide 6A on coronary hemodynamics. Pretreatment of animals with H2-receptor blocker cimetidine (500 mg iv) or with H1-and H2-receptor blocker diphenhydramine (50 mg iv) had no significant effects on peptide 6A-induced increase in coronary blood flow. This study suggests that this fibrin(ogen)-derived peptide has potent vasodilator effects on the coronary vascular bed of the dog, and these effects are in part mediated by stimulation of prostacyclin release.

Maternal plasma prostacyclin concentration in pre-eclampsia and other pregnancy complications.

To study the involvement of antiaggregatory and vasodilatory prostacyclin (PGI2) in various pregnancy complications, we measured the concentrations of 6-ketoprostaglandin F1 alpha, a stable hydration product of PGI2, using a specific radioimmunoassay, in plasma samples from 123 women between 22 and 41 weeks of complicated or normal pregnancy. The levels of 6-keto-PGF1 alpha (mean +/- SE) in pre-eclampsia (267.0 +/- 26.6 pg/ml, n = 22), diabetic pregnancy (266.6 +/- 19.2 pg/ml, n =21), twin pregnancy (310.7 +/- 28.2 pg/ml, n = 10), threatened premature labour (285.9 +/- 23.2 pg/ml, n = 26), placenta praevia or placental abruption (248.9 +/- 24.5 pg/ml, n = 6), hepatosis gravidarum (249.3 +/- 15.0 pg/ml, n = 3) or in pregnancies complicated by intrauterine fetal growth retardation (296.9 +/- 34.2 pg/ml, n = 14) or fetal death (267.5 +/- 20.9 pg/ml, n = 6) did not differ from each other or from the 6-keto-PGF1 alpha levels in normal pregnancy (266.4 +/- 15.0 pg/ml, n = 22). Furthermore, the 6-keto-PGF1 alpha levels bore no relation to the gestational age, maternal drug use (insulin, glucocorticoids, antihypertensive drugs) or to the sex, birth weight or condition of the newborn infant, or to the placenta weight.