Pulmonary prostacyclin production with increased flow and sympathetic stimulation

We evaluated the effects of an abrupt increase in flow and of a subsequent sympathetic nerve stimulation on the pulmonary production of prostacyclin (PGI2) and thromboxane A2 (TXA2) in canine isolated left lower lobes perfused in situ with pulsatile flow. When flow was abruptly increased from 50 +/- 3 to 288 +/- 2 ml/min, mean pulmonary arterial pressure (Ppa) increased by 15 +/- 2 Torr and then declined by 2.4 Torr over the next 5 min. This secondary decrease in Ppa was associated with a significant 0.26 +/- 0.11 ng/ml increase in the pulmonary venous concentration of the stable PGI2 hydrolysis product 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) as determined by radioimmunoassay. Stimulation of the left stellate ganglion usually resulted in an increase in Ppa which peaked at 1.1 +/- 0.6 Torr above its prestimulus level and then declined over the next 5 min. Associated with this decline was a 0.24 +/- 0.11 ng/ml increase in 6-keto-PGF1 alpha at 1 min. We suggest that the decline in Ppa is due to the synthesis and release of PGI2 by the endothelial cells in response to an increase in perfusion pressure.     

The concentrations of 6-keto-PGF1 alpha and TXB2 in plasma samples from patients with benign and malignant tumours of the breast

Peripheral plasma concentrations of 6-keto-PGF1 alpha and TXB2 were measured in patients with benign and malignant tumours of the breast, in patients with non-gynecological diseases, and in healthy female controls. The values were significantly higher in female patients with malignant tumours of the breast than in healthy controls (146 +/- 28 vs 13 +/- 2.5 pg/ml for 6-keto-PGF1 alpha p less than 0.01 and 78 +/- 17 vs 11 +/- 2 pg/ml for TXB2, p less than 0.01). Benign tumours of the breast were also associated with significantly raised plasma levels of 6-keto-PGF1 alpha and TXB2 compared to normal controls (52 +/- 5 vs 13 +/- 2.5 pg/ml for 6-keto-PGF1 alpha, p less than 0.01 and 26 +/- 5 vs 11 +/- 2 pg/ml for TXB2, p less than 0.05). The high levels of 6-keto-PGF1 alpha and TXB2 were not found to be correlated with clinical and histopathological data. The surgical removal of the primary tumour has apparently no effect on the plasma concentrations of 6-keto-PGF1 alpha and TXB2 over a follow-up period of 9 days after operation. The lack of alterations in the ratio of TXB2:6-keto-PGF1 alpha in the cancer patients and other subjects studied before and after surgery is indicative of the regulatory power of metabolic systems to preserve the homeostatic balance.     

Plasma thromboxane and prostacyclin: comparison during normal pregnancy and pregnancy complicated by hypertension

Plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolites of two prostanoids with opposing biological effects, TXA2 and prostacyclin, were measured by radioimmunoassay in normal pregnancy (controls) and pregnancy complicated by hypertension (PIH) from 32 to 36 (Period 1; P1) and from 36 to 40 (Period 2; P2) weeks of gestation. The plasma concentration of each compound in the control subjects was 265.6 +/- 58.4 (TXB2), 132.4 +/- 16.5 (6-keto-PGF1 alpha) for P1 (n = 10) and 142.6 +/- 11.8 (TXB2), 68.5 +/- 5.2 (6-keto-PGF1 alpha) for P2 (n = 10) respectively (pg/ml, mean +/- s.e). In the patients with PIH, TXB2 concentrations increased moderately for P1 (419.2 +/- 21.2; n = 7) and significantly (p less than 0.005) for P2 (452.8 +/- 31.0; n = 7) respectively (pg/ml, mean +/- s.e), while the plasma levels of 6-keto-PGF1 alpha revealed a slight to moderate decrease both for P1 (84.5 +/- 4.0; n = 7) and P2 (59.7 +/- 8.1; n = 7) respectively (pg/ml, mean +/- s.e). The physiological balance of TXB2 to 6-keto-PGF1 alpha was significantly greater (p less than 0.005) in the patients with PIH, where the TXB2/6-keto-PGF1 alpha ratio was 5.2 +/- 0.7 for P1 and 9.4 +/- 2.3 for P2 respectively (mean +/- s.e) compared with that of the controls, where it was 2.4 +/- 0.4 for P1 and 2.0 +/- 0.2 for P2 respectively (mean +/- s.e).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Comparison of plasma prostanoid levels in the human cord artery in normal and fetal distressed deliveries

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2; as a stable metabolite of TXA2), prostaglandin F2 alpha (PGF2 alpha) and 6-keto-PGF1 alpha (as a stable end product of prostacyclin) have been measured by using specific radioimmunoassay in the plasma of the cord artery immediately after delivery before the cord was clamped. Plasma prostanoid concentrations in normal deliveries (n = 8, as controls) were 24.8 +/- 2.6 (PGE2), 246.8 +/- 37.0 (TXB2), 122.2 +/- 13.3 (PGF2 alpha) and 82.1 +/- 7.7 (6-keto-PGF1 alpha) respectively (pg/ml, mean +/- s.e). On the other hand, in fetal distressed deliveries showing continuous bradycardia (n = 6), they increased significantly to 275.4 +/- 20.1 (PGE2), 948.6 +/- 102.5 (TXB2), 218.0 +/- 21.4 (PGF2 alpha) and 1498.6 +/- 298.4 (6-keto-PGF1 alpha) respectively (pg/ml, mean +/- s.e, p less than 0.005). However, both PGF2 alpha/PGE2 and TXB2/6-keto-PGF1 alpha ratios declined significantly from 4.70 +/- 0.33 to 0.68 +/- 0.05 and from 3.07 +/- 0.37 to 0.68 +/- 0.12 respectively (mean +/- s.e, p less than 0.005) in the fetal distressed group compared with those of the controls. From these results, it may be concluded that the cord artery, which is known as the patent source for the production of PGE2 and prostacyclin, did exert a sufficiently strong reaction to overcome the undesirable haemodynamic changes to maintain the fetal well-being in utero.     

Relevance of vasoactive mediators for the blood pressure effects of intravenous arachidonic acid injection in rats.

Vasopressor response and release of eicosanoids following intravenous injection of arachidonic acid (AA) were examined in normotensive rats. AA administration caused a rapid initial fall of arterial pressure followed by a brief rise and a subsequent prolonged fall in anesthetized rats. Immediately after AA injection the blood levels of TXB2 and 6-keto-PGF1 alpha, the stable metabolites of TXA2 and prostacyclin, rose, from 1.52 +/- 0.23 ng/ml to 176.4 +/- 42.6 ng/ml and from 4.05 +/- 0.67 ng/ml to 171.4 +/- 31.2 ng/ml, respectively. Blood pressure behaviour and eicosanoid blood level were influenced by different inhibitors and antagonists of vasoactive mediators. The cyclooxygenase inhibitor acetylsalicylic acid completely eliminated the second blood pressure depression after AA injection and simultaneously diminished TXB2 and 6-keto-PGF1 alpha formation in murine blood, whereas the TXA2 receptor antagonist BM 13.177 prevented the return of the blood pressure to preinjection level after the initial brief fall in arterial pressure. Although the TXA2 synthase inhibitor HOE 944 markedly inhibited TXB2 formation, no influence on AA-induced blood pressure changes could be registered. The receptor antagonist of platelet activating factor BN 52021 and the serotonin and histamine receptor antagonist cyproheptadine also reduced TXB2 amounts, in murine blood without any effects on blood pressure behaviour.     

水钠负荷对血,肾脏前列环素,血栓素A2的影响及...

For evaluating the role of prostacyclin (PGI2) and thromboxane A2 (TXA2) in the metabolism of salt and water, the metabolic products of PGI2 and TXA2 (6-keto-PGF1 alpha and TXB2 respectively) were measured by radioimmunoassay in salt-loaded rabbits. 36 normal rabbits were randomly divided into 3 groups: 1. normal control group; 2. 3h salt-loading group (3 h group); 3. 24 h salt-loading group (24 h group). Both the 3 h and 24 h groups were given 0.9% NaCl solution by subcutaneous injection to the hind legs. The kidneys were dissected into 4 slices: outer cortex, inner cortex, outer medulla and inner medulla. The plasma 6-keto-PGF1 alpha in the 3 h group was increased from the control value of 46.61 +/- 19.04 pg/ml to 111.63 +/- 58.36 pg/ml (P less than 0.01). All of the dissected renal slices also showed significant increase of 6-keto-PGF1 alpha synthesis in both the 3 h and the 24 h groups (P less than 0.001 vs. normal). The urinary sodium concentrations have a good correlation with 6-keto-PGF1 alpha in plasma or in kidney tissues. Plasma TXB2 in normal group was 499.27 +/- 197.86 pg/ml, but no significant change was found in the 3h group. However, in the 24 h group it decreased significantly to 218.76 +/- 114.54 pg/ml (P less than 0.05 vs. normal group). Although the TXB2 increment was significant only in inner medulla, all other dissected renal slices showed some increase of TXB2 synthesis too. It is concluded that salt-loading can cause increase of PGI1 and TXA2 synthesis in normal renal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leukotrienes increase levels of prostanoids in cerebrospinal fluid in piglets

We investigated effects of exogenous leukotrienes (C4, D4, or E4) on levels of prostanoids in cerebrospinal fluid in newborn pigs (1-5 days). A "closed" cranial window was placed over the parietal cortex. Pial arterial diameter was measured with a microscope and electronic micrometer system. Levels in cerebrospinal fluid (CSF) of 6-keto-Prostaglandin F1 alpha (6-keto-PGF1 alpha), Thromboxane B2 (TXB2), and Prostaglandin E2 (PGE2) were measured by radioimmunoassay. Topical application of leukotrienes C4, D4, or E4 (5,000 ng/ml) similarly constricted pial arteries by 15 +/- 2% (n = 14) (mean +/- SEM). In addition, leukotrienes increased levels of 6-keto-PGF1 alpha from 806 +/- 136 to 1,612 +/- 304 pg/ml (n = 13), TXB2 from 161 +/- 31 to 392 +/- 81 pg/ml (n = 10), and PGE2 from 2,271 +/- 342 to 4,636 +/- 740 pg/ml (n = 13). Each type of leukotriene had similar effects on prostanoid synthesis. In other experiments (n = 5), we found that 2.0 ng/ml PGE2 in CSF dilated pial arteries by 24 +/- 8% and that 1.0 ng/ml PGI2 dilated pial arteries by 15 +/- 6%. These results indicate that leukotrienes are able to increase levels of prostanoids in cerebral cortex.     

Effects of arachidonic acid and prostaglandin F2 alpha in isolated rat lungs

Isolated rat lungs were ventilated and perfused by saline-Ficoll perfusate at a constant flow. The baseline perfusion pressure (PAP) correlated with the concentration of 6-keto-PGF1 alpha the stable metabolite of PGI2 (r = 0.83) and with the 6-keto-PGF1 alpha/TXB2 ratio (r = 0.82). A bolus of 10 micrograms exogenous arachidonic acid (AA) injected into the arterial cannula of the isolated lungs caused significant decrease in pulmonary vascular resistance (PVR) which was followed by a progressive increase of PVR and edema formation. Changes in perfusion pressure induced by AA injection also correlated with concentrations of the stable metabolites (6-keto-PGF1 alpha: r = -0.77, TxB2: -0.76), and their ratio: (6-keto-PGF1 alpha/TXB2: r = -0.73). Injection of 10 and 100 micrograms of PGF2 alpha into the pulmonary artery stimulated the dose-dependent production of TXB2 and 6-keto-PGF1 alpha. No significant correlations were found between the perfusion pressure (PAP) which was increased by the PGF2 alpha and the concentrations of the former stable metabolites. The results show that AA has a biphasic effect on the isolated lung vasculature even in low dose. The most potent vasoactive metabolites of cyclooxygenase, prostacyclin and thromboxane A2 influence substantially not only the basal but also the increased tone of the pulmonary vessels.     

Vascular resistance and Kf in normal and PMA-injured rabbit lungs: effects of adenosine

The effects of adenosine (ADO) on pulmonary vascular resistance (PVR) distribution, vascular compliance (C), and permeability were determined in normal and PMA-injured isolated rabbit lungs perfused with a 1:1 mixture of 6% albumin in Krebs-Henseleit buffer and autologous blood. ADO or vehicle was continuously infused into the reservoir at 1,4, or 5 mumol/min after a 1-mumol bolus of ADO or vehicle. The capillary filtration coefficient (Kf) and arterial, venous, and double occlusion pressures were measured at baseline and 30 min after phorbol myristate acetate (PMA; 4 x 10(-8) M) or vehicle. Perfusate differential and total leukocyte counts as well as adenine nucleotides, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) concentrations were determined at each measurement period. ADO was recovered as hypoxanthine and inosine in the perfusate. ADO alone did not alter PVR, C, Kf, or TxB2 but reduced 6-keto-PGF1 alpha levels. PMA induced an increase in Kf (0.024 +/- 0.002 to 0.040 +/- 0.006 g.cmH2O-1.min-1, P less than 0.05) that was completely blocked by 4 or 5 mumol/min ADO. PVR increased by 63 +/- 11% after PMA, primarily in the arteries and arterial and venous microvessels. The postcapillary resistance increase was blunted by 4 mumol/min ADO; 5 mumol/min ADO prevented the PVR increase in all segments. ADO did not affect the initial adherence of neutrophils in the lung or the PMA-induced 87 +/- 2% decrease in circulating leukocytes (greater than 98% lymphocytes) or threefold increase in TxB2 levels. These results suggest that protection by ADO is not mediated by the altering of cyclooxygenase products or by leukocyte adherence.     

Effects of nitrogen dioxide exposure on the contents of prostaglandins and thromboxane B2 in broncho alveolar lavage

Effects of 10 ppm nitrogen dioxide (NO2) exposure on the contents of prostaglandins (PGs) and thromboxane (TX) B2 in bronchoalveolar lavage (BAL) of rats were studied. In the BAL of normal rats, the amounts of PGs and TXB2 in the whole lavage were 6-keto-PGF1 alpha (38.0 +/- 6.4 ng) greater than TXB2 (11.8 +/- 4.0 ng) greater than PGF2 alpha (5.7 +/- 1.6 ng) much greater than PGE (0.5 +/- 0.3 ng). Rats were exposed to NO2 for 1,3,5,7 and 14 days. The NO2 exposure decreased in the level of 6-keto-PGF1 alpha by about 35% throughout the exposure. The level of TXB2 was higher in the day 5 exposure group (155%). The contents of PGF2 alpha and PGE first, decreased and then transiently increased on days 3 and 5. PG 15-hydroxy-dehydrogenase activity of lung homogenate decreased correspondingly on day 3 and 5. Then the contents PGF2 alpha and PGE decreased on day 7 and 14. 6-keto-PGF1 alpha and TXB2 are stable metabolites of PGI2, a strong bronchorelaxant and TXA2, a strong bronchoconstrictor respectively. Therefore the results suggested that the decrease in 6-keto-PGF1 alpha, a major prostanoid in the BAL and the increase in TXB2 may correlate with broncho constriction by NO2 exposure.     

Pulmonary microvascular response to LTB4: effects of perfusate composition

We examined the effects of leukotriene B4 (LTB4) on pulmonary hemodynamics and vascular permeability using isolated perfused guinea pig lungs and cultured monolayers of pulmonary arterial endothelial cells. In lungs perfused with Ringer solution, containing 0.5 g/100 ml albumin (R-alb), LTB4 (4 micrograms) transiently increased pulmonary arterial pressure (Ppa) and capillary pressure (Pcap). Pulmonary edema developed within 70 min after LTB4 injection despite a normal Pcap. The LTB4 metabolite, 20-COOH-LTB4 (4 micrograms), did not induce hemodynamic and lung weight changes. In lungs perfused with autologous blood hematocrit = 12 +/- 1%; protein concentration = 1.5 +/- 0.2 g/100 ml), the increases in Ppa and Pcap were greater, and both pressures remained elevated. The lung weight did not increase in blood-perfused lungs. In lungs perfused with R-alb (1.5 g/100 ml albumin) to match the blood perfusate protein concentration, LTB4 induced similar hemodynamic changes as R-alb (0.5 g/100 ml) perfusate, but the additional albumin prevented the pulmonary edema. LTB4 (10(-11)-10(-6) M) with or without the addition of neutrophils to the monolayer did not increase endothelial 125I-albumin permeability. Therefore LTB4 induces pulmonary edema when the perfusate contains a low albumin concentration, but increasing the albumin concentration or adding blood cells prevents the edema. The edema is not due to increased endothelial permeability to protein and is independent of hemodynamic alterations. Protection at higher protein-concentration may be the result of LTB4 binding to albumin.     

Effect of dipyridamole on prostanoid production in rat isolated atria.

The effect of 0.01 microM dipyridamole on prostanoid production was studied in atria from normal, acute diabetic and insulin-treated diabetic rats. Diabetes was induced by i.v. administration of 65 mg/kg of streptozotocin (STZ) and the rats were killed 5 days later. Atria were incubated during 60 min in Krebs solution. The prostanoids 6-keto-prostaglandin (PG) F1alpha (6-keto-PGF1alpha) and thromboxane (TX) B2, stable metabolites of prostacyclin and TXA2, respectively, as well as PGE2 were measured by reversed phase high-performance liquid chromatography-UV. In diabetic atria, 6-keto-PGF1alpha production was reduced by 50% whereas TXB2 release was increased two-fold compared to the controls, with a significant decrease in the 6-keto-PGF1alpha/TXB2 ratio. The preincubation with 0.01 microM dipyridamole for 30 min increased 6-keto-PGF1alpha production in control, diabetic and insulin-treated diabetic atria whereas TXB2 release was not modified. This effects provoked an significant increase in the 6-keto-PGF1alpha/TXB2 ratio. In conclusion, STZ diabetes reduces the 6-keto-PGF1alpha/TXB2 ratio impairing the functional status of the atria. Dipyridamole increased this ratio in atria from diabetic and insulin-treated diabetic rats, thus opposing the effects of STZ diabetes. This fact suggests the possibility of a participation of the drug in pathologies characterized by an imbalance in the production of vasodilator and vasoconstrictor prostanoids.     

Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs

The effect of acute cyclooxygenase (CYO) inhibition on the cardiopulmonary adjustments at birth was examined in chronically instrumented, unanesthetized, term lambs before, during, and after cesarean section (spontaneous respiration). One of three infusions was started 20 min before birth: saline control (C, n = 6), indomethacin (I, n = 6), or meclofenamate (M, n = 3). The stable metabolite of prostacyclin, plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, aorta), was measured by radioimmunoassay as an index of CYO activity. Indomethacin blocked the rise of 6-keto-PGF1 alpha observed in control lambs after birth and indomethacin-treated lambs exhibited an attenuation of the postnatal decrease in mean pulmonary arterial pressure. Pulmonary arterial pressure (Ppa) was 53 +/- 2 and 47 +/- 2 Torr (mean +/- SE) at 15 min and 40 +/- 3 and 34 +/- 2 Torr at 120 min in I and C groups, respectively. There were no serial or group differences in cardiac output and cardiac right to left shunt (indicator dilution) from 15 to 120 min after birth. Arterial PO2 (PaO2) was not different between groups: 37 +/- 4 Torr at 15 min and 47 +/- 5 min at 120 min after birth (control lambs). The results for I and M were similar for all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-, cycle- and topographic dependency of human myometrial prostaglandin (6-keto-PGF1 alpha, PGF2 alpha)-synthesis in vitro

Specimens of human myometrium (isthmus and fundus) freshly obtained at hysterectomy were immediately transferred in ice cold Tyrode solution and placed in superfusion chambers. Spontaneous contractions were recorded, the effluent of the myometrium was analyzed for PGF2 alpha and 6-keto-PGF1 alpha by use of specific radioimmunoassay systems. Dating of the menstrual cycle was achieved by histological evaluation of the endometrium. The PG release rates expressed as ng/min/g wet weight were correlated to the patients age and to the phase of the menstrual cycle. The production rates of 6-keto-PGF1 alpha were negatively correlated to the age of the patients and declined in fundus specimens from 2.89 +/- 0.35 ng/min/g wet weight in 39-42 years old patients to 0.52 +/- 0.17 ng/min/g wet weight in 48-52 years old women during the secretory phase (p less than 0.001). Similar significant correlations were found in specimens obtained from the isthmus uteri. During the proliferative phase fundus specimens produced on average 1.61 +/- 0.67 ng/min/g wet weight in 39-42 years old patients and 0.49 +/- 0.12 ng/min/g wet weight 6-keto-PGF1 alpha in 48-52 years old women respectively (p les than 0.001). The PGF2 alpha synthesis in myometrial specimens of fundus or isthmus origin was significantly lower than 6-keto-PGF1 alpha and did not correlate to the age of the patients during the proliferative phase. However, PGF2 alpha release rates during the secretory phase were significantly (p less than 0.001) higher in younger women. These results suggest an age-, cycle- and topographic dependency of PGI2 synthesis in human myometrial tissue.     

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.     

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.     

Fluid balance in sheep lungs before and after extracorporeal perfusion

Lung fluid balance was studied in sheep under the following conditions: 1) unanesthetized, standing in a metabolic cage; 2) anesthetized, in a supine position; 3) 1 h after extracorporeal perfusion; and 4) either 4-6 h after extracorporeal perfusion (i.e., control experiments) or 1.5 h after left atrial pressure was increased by 15 cmH2O. Lung lymph flow rate (QL), plasma and lymph concentrations for nine protein fractions, urea permeability-surface area product (PS), urea effective diffusivity (D1/2S), and extravascular lung water (VE) were measured under each condition. Bloodless wet and dry lung weights were measured at the end of each experiment. QL increased and lymph-to-plasma concentration ratio for total proteins (L/P) decreased after the sheep were anesthetized and placed in a supine position. This possibly resulted from an increase in microvascular pressure induced by anesthesia and/or reorientation of the lungs. PS, D1/2S, and VE decreased, indicating a decrease in perfused surface area associated with a decreased cardiac output or alteration in lung orientation. After 90 min of extracorporeal perfusion, no significant differences were found in QL, PS, and D1/2S compared with those measured during the anesthetized period. No changes in PS or D1/2S could be detected after an average of 4.2 h of extracorporeal perfusion. The average bloodless wet-to-dry lung weight ratio [(W-D)/D] was 3.77 +/- 0.12, well within the range for normal sheep lungs. An increase in venous pressure of 15 cmH2O produced a response similar to that observed in the unanesthetized sheep lung lymph preparation: QL increased, L/P decreased, PS and D1/2S did not increase, and VE and (W-D)/D increased slightly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of morphology and malignancy of three new human melanoma cell lines on the cyclooxygenase pathway

Three newly established human melanoma cell lines (WU-BI, PN-JC, MJ-ZJ) of different morphology and different stage of malignancy were incubated with ionophore A23187 (2.5 to 40 microM) or arachidonic acid (AA, 6.25 to 100 microM). PGF2 alpha, 6-keto-PGF1 alpha, PGE2, TXB2 and 2,3-dinor-TXB2 from isolated cells and supernatants were measured by negative ion chemical ionization gas chromatography/mass spectrometry (GC/MS). PGE2 decreased in the fibroblastoid MJ-ZJ cells from 36.7 ng/mg cell protein about 70% (A23187) and about 20% (AA), respectively. However, in the cell supernatant PGE2 increased up to 295.4 +/- 66.5 ng/mg cell protein. Production of PGF2 alpha and PGE2 increased up to 5.7 +/- 1.2 ng/mg cell protein for polydendritic WU-BI cells and spindle shaped PN-JC cells. Up to 9.3 +/- 4.3 ng PGF2 alpha and 13.4 +/- 4.7 ng PGE2 was measured for WU-BI and PN-JC in the cell supernatants. All three melanoma cell lines completely lacked formation of 6-keto-PGF1 alpha, TXB2, and 2,3-dinor-TXB2.     

Effects of bopindolol on platelet function in hypertension at rest and during exercise

The effects of bopindolol, a new nonselective beta-blocking agent, on platelet function have been studied in 10 male hypertensive patients given the drug (1 mg/day) in turn for eight weeks. Bopindolol significantly (p less than 0.01) decreased the bicycle exercise- (1.5 W/kg body weight for 6 minutes) induced increase in platelet aggregation. During bopindolol-treatment both the slope and the height of the platelet aggregation response curve were moderately decreased at rest before exercise and significantly (p less than 0.05) decreased at rest after exercise. During exercise the slope amounted to 75.4 +/- 44 degrees before and to 70.8 +/- 5.3 degrees after therapy (p less than 0.01), the height to 64.0 +/- 11.9% before and to 58.1 +/- 14.7% (p less than 0.05) after therapy. Furthermore, bopindolol significantly increased the exercise-induced decrease in platelet sensitivity to PGI2 (p less than 0.05; IC-50-value: 2.10 +/- 0.47 vs 1.88 +/- 0.31 ng/ml) and PGD2 (p less than 0.05; IC-50-value: (19.88 +/- 2.10 vs 18.57 +/- 1.63 ng/ml). Bopindolol also significantly (p less than 0.05) decreased the exercise-induced elevation in serum-TXB2 (244.9 +/- 35.2 vs 237.3 +/- 27.2 ng/ml) and plasma-TXB2 (15.7 +/- 6.3 vs 13.1 +/- 3.7 pg/ml). The platelet count, the plasma levels of 6-oxo-PGF1 alpha, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were not affected by bopindolol. It is concluded that bopindolol favourably affects platelet function, in that it lowers exercise-induced platelet aggregation and TXB2-formation in therapeutical doses and increases platelet sensitivity to antiaggregatory prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)