Polyglactin 910/polydioxanone bicomponent totally resorbable vascular prostheses

Previous studies from our laboratory have shown that bioresorbable vascular prostheses woven from lactide-glycolide copolymers and implanted into arteries of several animal models become replaced by cellular tissues; the rate of replacement parallels the kinetics of prosthetic resorption. This study evaluates the efficacy of bicomponent resorbable prostheses as a method of augmenting resistance to dilatation during the resorption period of the more rapidly resorbed component. Bicomponent prostheses (n = 37) were woven from compound yarns containing 74% polyglactin 910 (PG910) and 26% polydioxanone (PDS) and were interposed into adult white New Zealand rabbit infrarenal aortas. Resultant prosthesis-tissue complexes were harvested after 2 weeks to 12 months. Specimens were photographed and sectioned for light, scanning, and transmission electron microscopy. Randomly selected fresh explants at 1 and 3 months and control aortic segments from the same rabbits were simultaneously perfused with culture media (37 degrees C, 100/80 mm Hg, 60 ml/min) and perfusates assayed by means of tritiated radioimmunoassay techniques for the stable prostacyclin metabolite 6-keto-PGF1 alpha before and after the addition of sodium arachidonate (10 micrograms/ml) to the media. Results showed 100% patency, no aneurysms, and stenosis in 1 of 37 prostheses (3%). PG910 was totally resorbed by 2 months and PDS by 6 months. By 1 month inner capsule thickness was 303 +/- 30 microns. In contrast to previous reports this was significantly thicker than that within 100% PDS (230 +/- 40 microns) and significantly less thick than in 100% PG910 (530 +/- 62 microns). Inner capsules in all three groups stabilized at similar thicknesses (417 to 502 microns).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostacyclin production by blood-contacting surfaces of endothelialized vascular prostheses

This study examines prostacyclin production by blood-contacting surfaces within woven vascular prostheses of polydioxanone (PDS), polyglactin 910 (PG910), or Dacron interposed into rabbit infrarenal aortas. Grafts and normal aortic segments were explanted after 1, 3, and 6 months for pulsatile perfusion with Medium-199 for 60 minutes. Aliquots were removed serially for 6-keto-PGF1 alpha assay. After 30 minutes sodium arachidonate (10 micrograms/ml) was added. Specimens were studied by light microscopy, SEM and TEM. Patency in all three groups exceeded 90%. All three showed re-endothelialization at one month. Normal aorta produced low basal 6-keto-PGF1 alpha with a marked evanescent post arachidonate increase. Dacron did not differ from normal aorta. PG910 and PDS both produced significantly less 6-keto-PGF1 alpha post arachidonate at one month but both increased to normal by three months.     

Arterial regeneration over polydioxanone prostheses in the rabbit

We analyzed histologic, ultrastructural, and functional characteristics of rabbit aortic conduits regenerated over absorbable polydioxanone prostheses. Twenty-eight polydioxanone-elicited prosthesis/tissue complexes harvested two weeks to 12 months following implantation were analyzed grossly; photographed; sectioned for light, scanning, and transmission electron microscopy; and studied for compliance, bursting strength, and prostacyclin and thromboxane metabolite contents. No aortic-related deaths or hemorrhages occurred. Smooth regenerated conduits without stenoses were seen in 27 of 28 specimens, with one small aneurysm. Transprosthetic myofibroblast migration and proliferation paralleled the kinetics of macrophage-mediated prosthetic dissolution, which was consequently delayed compared with polyglycolic acid prostheses. Confluent endothelial-like luminal surfaces were present after two weeks. Progressive inner capsular thickening ended after three months at 420 micron. Ex vivo compliance curves resembled arterial elasticity. Regenerated tissue withstood 1200 mm Hg of systolic pressure, and 6-keto-prostaglandin F1 alpha to thromboxane B2 ratios did not differ from normal control specimens.     

Comparison of static incubation versus physiologic perfusion techniques for quantitation of luminal release of prostacyclin and thromboxane in canine arteries and veins

Intraluminal release of 6-keto-PGF1 alpha and TxB2 in ex vivo canine arteries and veins was assessed during five consecutive 15-min periods using static incubation and physiologic perfusion techniques. Arterial segments were perfused with 90 ml/min pulsatile flow at 100 mm Hg and vein segments with 90 ml/min nonpulsatile flow at 7 mm Hg. During the final 15-min period vessels were stimulated with arachidonic acid (AAS). Perfusion of vein segments caused a higher release of 6-keto-PGF1 alpha during the first 30 min (P less than 0.05) and following AAS (P less than 0.05) than did static incubation. Perfused arterial segments exhibited a higher release than did incubated segments of 6-keto-PGF1 alpha for 45 min (P less than 0.01) as well as following AAS (P less than 0.01). TxB2 release was higher during the entire observation period in perfused arteries and veins compared to incubated vessels (P less than 0.01 and less than 0.05, respectively). There was no correlation between the amounts of 6-keto-PGF1 alpha or TxB2 released when comparing values obtained by one technique to values obtained by the other (P greater than 0.1). These data suggest that flow related shear stress alters vascular prostanoid production, and that such should be accounted for when interpreting results of studies on prostacyclin and thromboxane release from intact vessels.     

Angiotensin II stimulation of prostaglandin E2 and 6-keto-F1 alpha formation by isolated human glomeruli

The intrinsic in vitro production of prostaglandins (PGs) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) and the conversion of exogenous substrate to PGs and TxB2 by isolated human glomeruli was demonstrated, 6-keto-PGF1 alpha was the major product. This was observed under basal conditions and following incubation with exogenous substrate. Indomethacin (Indo; 10(-4 M) inhibited the conversion of arachidonic acid to PGs and the release of [1-14C]-labeled products from human glomeruli by about 80%. The addition of angiotensin II (AII) to the isolated glomeruli produced, under basal conditions, an almost selective stimulation of 6-keto-PGF1 alpha. Following the prelabeling of glomeruli with 1-14C-arachidonic acid, the increase of glomerular PG formation after AII was added was also only significant for 6-keto-PGF1 alpha. When glomeruli were preincubated with large amounts of non-radiolabeled substrate. AII stimulated PGE2 and 6-keto-PGF1 alpha formation significantly. The data demonstrate PG formation in isolated human glomeruli and show an interaction between AII and the prostaglandin system in this tissue. This interrelationship might have physiologic consequences in the regulation of glomerular hemodynamics.     

Prostaglandin synthesis associated with renal allograft rejection in the dog

Vasospasm and intrarenal thrombosis are characteristics of acute renal allograft rejection. A possible mediator of these phenomena is thromboxane A2. Single kidneys were exchanged between nonimmunosuppressed mongrel dogs. At intervals after transplantation, rejecting and normal kidneys were removed and slices of cortex and medulla were prepared for incubation. The in vitro release of thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1a (6-keto-PGF1 alpha) into the incubation media was measured by radioimmunoassay. Within 72 hr of transplantation the cortex of rejecting kidneys synthesized 10 to 30 times as much PGE2 and TxB2 as normal controls. A similar increase was not observed for 6-keto-PGF1 alpha synthesis. In the medulla there was a selective reduction in 6-keto-PGF1 alpha production within five days of transplantation. In both cortex and medulla there was a significant increase in the ratio of TxB2 to 6-keto-PGF1 alpha production. Reversal of the normal TxB2:6-keto-PGF1 alpha ratio could induce the widespread intrarenal thrombosis and vasospasm that characterizes acute renal allograft rejection.     

Arterial regeneration over absorbable prostheses

Small-vessel arterial replacement by a prosthetic material elicits inflammatory and regenerative reactions that alter the patency rate of the resultant prosthesis-tissue complex. Woven absorbable polyglycolic acid prostheses, 24 mm in length, were implanted into adult rabbit aortas and followed for 7 1/2 months. At the time the animals were killed, 45 specimens were studied grossly and by arteriography, light and electron microscopy, immunohistology, and bursting-strength determinations. No rabbit died of aortic-related complications. Mild dilation occurred in 11% (five specimens), and intimal hyperplasia occurred in 13% (six specimens), with 76% (34 specimens) displaying parallel walls at the original 3- to 4-mm diameter. Microscopy showed that the prostheses were replaced by regenerating endothelialized vessels containing smooth musclelike myofibroblasts and dense fibroplasia, without thrombosis or infection. All withstood saline solution infusion at three to five times the systolic pressure. Results of these studies demonstrate conditions that permit arterial regeneration over absorbable scaffolds.     

Partially bioresorbable vascular grafts in dogs.

Previous studies have shown the effectiveness of partially resorbable arterial prostheses in the rabbit. This study compares these same compound prostheses with commercial graft materials in the dog. Conduits 4 mm inner diameter X 50 mm in length were woven from composite yarns containing 69% polyglactin 910 (PG910)/31% polypropylene or containing 70% polydioxanone/30% polypropylene. Nonresorbable controls were woven Dacron and expanded polytetrafluoroethylene (ePTFE). Baseline platelet aggregometry to 10(-5) mol/L adenosine diphosphate was performed. Seventy prostheses were implanted into the aorto-ilac positions, and the prosthesis/tissue complexes were harvested serially from 2 weeks to 1 year. Explanted specimens were photographed and fixed for light microscopy and for scanning and transmission electron microscopy. Results showed no aneurysms or perigraft hematomas. Overall patency for the PG910/polypropylene grafts was 18 of 20 (90%) and for polydioxanone/polypropylene was 19 of 22 (86%). For Dacron and ePTFE, 13 of 19 (68%) and 6 of 11 (54%) remained patent at time of explantation. The partially resorbable grafts, as a group, had significantly greater patency than the control grafts (p less than 0.03). Platelet aggregometry was not predictive of graft patency. Histologic analysis of the partially bioresorbable groups showed inner capsules (IC) composed of myofibroblasts and collagen beneath confluent endothelialized surfaces by 1 month. Kinetics of IC formation paralleled the rates of resorption of the resorbable components. IC cellularity and thickness were greater than those within Dacron or ePTFE. This study suggests an enhanced transinterstitial endothelial cell and myofibroblast ingrowth into the ICs of partially resorbable grafts and shows the effectiveness of these prostheses in the dog.     

Prostacyclin and thromboxane in acute hemorrhagic pancreatitis in dogs

To study the role of the vasodilatory, antiaggregatory prostacyclin (PGI2) and its endogenous antagonist thromboxane A2 (TxA2) in acute pancreatitis, we measured serum thromboxane B2 (TxB2, which indicates platelet TxA2 production) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, which indicates systemic PGI2 production) from sequential blood samples in trypsin and taurocholate induced acute canine hemorrhagic pancreatitis (AHP). In addition the effect of a prostaglandin synthesis inhibitor, ibuprofen, was studied and systemic (MAP) and pulmonary artery pressure (MPAP) were recorded for 4.5 hr. The animals were divided into a sham-operated group, an AHP group, an ibuprofen prophylaxis group, and an ibuprofen therapy group. In the sham group the parameters remained stable throughout the experiment. In the AHP group MAP decreased steadily and 6-keto-PGF1 alpha rose significantly from 80.0 +/- 7.8 to 956.0 +/- 287.0 pg/ml (P less than 0.001), whereas serum TxB2 and MPAP remained unchanged. Ibuprofen prophylaxis eliminated the initial fall in MAP and the rise of 6-keto-PGF1 alpha. Ibuprofen therapy normalized the initially decreased MAP and depressed the level of 6-keto-PGF1 alpha. We conclude that PGI2 may at least partly mediate the initial hypotension in canine AHP, whereas platelet TxA2 production obviously has a negligible role in the development of hemodynamic changes in AHP.     

Biocompatibility of Hemoglobin Solutions. I. Reactions of Vascular Endothelial Cells to Pure and Impure Hemoglobins

Hemoglobin (Hb) solutions can cause vasoconstriction and activation of intravascular coagulation. Because the endothelium plays a major role in the regulation of vascular tone and hemostasis, a study was conducted of human umbilical vein endothelial cells (EC) incubated with various Hbs. Cell injury was evaluated by electron microscopy and the release of lactic dehydrogenase, H2O2, and procoagulant "tissue factor." Cell reaction was assessed by the measurement of 6-keto-prostaglandin F (PGF)1 alpha (metabolite of prostacyclin) and thromboxane B2 (metabolite of thromboxane A2). Incubation with unmodified bovine hemoglobin for 24 h caused no cell injury and a reaction characterized by 48.4 +/- 8.2% increase in 6-keto-PGF1 alpha production, accompanied by 40.2 +/- 9.4% reduction in thromboxane (Tx)B2 (compared with a control group of EC incubated with saline solution). Incubation with a nonpure Hb solution (Hb plus red blood cell membrane aminophospholipids; a-PLs) caused cell injury with significant release of tissue factor, plus a reaction characterized by 97.5 +/- 12.5% increase in TxB2 production accompanied by 25.3 +/- 3% reduction in 6-keto-PGF1 alpha. A second nonpure Hb [Hb plus bacterial environmental endotoxin (E)] caused cell injury, the release of tissue factor, and increased production of both prostaglandins, with greater release of TxB2 (197 +/- 17%) than of 6-keto-PGF1 alpha (112 +/- 8.3%). These data indicate that the endothelium reacts differently to pure and nonpure hemoglobins. The biocompatibility of Hb solutions, with regard to vasoconstriction and activation of intravascular coagulation, depends on the absence of stromal a-PLs and bacterial E.     

Prostaglandin and thromboxane synthesis by rat glomerular epithelial cells

Isolated rat glomeruli have been shown to synthesize prostaglandin (PG) and thromboxane (Tx). In this study, we evaluated, by radioimmunoassay and radiochromatographic methods, PG and Tx synthesis by glomerular cells in culture. Transmission and scanning electron microscopy showed polygonal cells, attached by desmosomes, with surface microvilli. These features are typical of glomerular epithelial cells. Incubation of these glomerular epithelial cells with arachidonic acid (C20:4) resulted in an array of endproducts with concentrations of PGE2 greater than TxB2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha . Addition of angiotensin II (AII) to the cultured glomerular cell produced almost exclusive stimulation of PGE2 with PGE2 much much greater than PGF2 alpha greater than TxB2 = 6-keto-PGF1 alpha . AII and AIII (100 micrometer to 1 micrometer ) stimulated PGE2 in glomerular epithelial cells, and the increments of PGE2, as a function of the concentration of AII or AIII, were similar. The sar1-thr8-AII analog inhibited both AII- and AIII-stimulated PGE2 synthesis. The divalent cation ionophore A23187 in concentrations of 0.2 to 2.0 micrometer increased primarily PGE2 and TxB2 synthesis with smaller increases of PGF2 alpha and 6-keto-PGF1 alpha . The relative concentrations of PG and Tx produced by rat glomerular epithelial cells, incubated with C20:4 or A23187, were similar. Our results demonstrate that: (1) the predominant cell grown in culture from the rat glomerulus, after 9 days, is the epithelial cell; (2) this cell is capable of PG and Tx synthesis; (3) stimulation of PG by AII and AIII may be mediated by the same cellular receptor, AII and AIII increase primarily the synthesis of a vasodilatory PG, PGE2; (4) exogenous substrate C20:4 or release of endogenous C20:4 by the divalent cation ionophore A23187 not only stimulates PGE2 but also the vasoconstrictor TxA2; and (5) the PG and Tx endproducts synthesized by epithelial cells may be determined by an intracellular coupling of the specific synthetic enzymes with different pools of C20:4.     

Assessment of prostacyclin and thromboxane A2 release during reperfusion after global ischemia induced by crystalloid cardioplegia--comparison between warm and cold ischemia

The metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), 6-keto-PGF1 alpha and thromboxane B2 (TxB2), were investigated during reperfusion (RP) following warm (37 degrees C, 60 min, n = 9) or cold (15 degrees C, 120 min, n = 11) ischemia induced by cold (4 degrees C) or normothermic (30 degrees C) K+ cardioplegia (CP) in isolated canine hearts subjected to global ischemia and RP. 6-Keto-PGF1 alpha flux was significantly higher (p less than 0.025) in the warm group at 1, 5, and 10 min of RP (4,202 +/- 1,412, 2,475 +/- 1,875, and 1,255 +/- 633 pg/g.min, mean +/- SD) compared to those in the cold group (1,504 +/- 1,245, 434 +/- 641, and 370 +/- 329 pg/g.min). TxB2 flux was small in amount compared to 6-keto-PGF1 alpha in both groups. Regarding the coronary hemodynamics, the cold group alone showed statistically significant relationships of coronary sinus blood flow to TxB2 level and TxB2/6-keto-PGF1 alpha ratio in coronary sinus blood. Also, coronary vascular resistance showed linear relations to these two parameters of the metabolites. In a supplementary experiment only with cold ischemia for 180 min, 6-keto-PGF1 alpha was released at each coronary flush-out by CP and the incremental amount showed a gradual increase during ischemia. These results indicated that significant production and release of PGI2 occurred during ischemia and RP following CP arrest and these related to the degree of myocardial damage while the response of TxA2 seemed less significant. The role of PGI2 release during RP following cardioplegic arrest was discussed.     

Pulmonary dysfunction secondary to soft-tissue endotoxin

Our purpose was to determine whether peripheral soft tissues produce and release prostanoids in response to local sepsis, and whether this mediator release can produce pulmonary dysfunction. Escherichia coli endotoxin (2 micrograms/kg in 100 mL of saline) was injected below the hide of the flank in seven unanesthetized sheep. In three additional sheep, ibuprofen (12.5 mg/kg of body weight) was injected with the endotoxin. Thromboxane B2 and 6-keto-PGF1 alpha (prostacyclin) levels were measured in tissue lymph draining the flank, lung lymph, pulmonary artery (Ppa), and aortic plasma. One hour after endotoxin administration, mean PaO2 decreased from 90 to 74 mm Hg and Ppa increased from 22 to 35 mm Hg. Lung lymph flow (QL) increased only 50% with QL being protein poor. No increase in lung or peripheral soft-tissue vascular permeability was noted. Tissue lymph (TxB2) increased from 220 +/- 114 to greater than 10,000 pg/mL with levels in Ppa plasma increasing from 300 +/- 128 to 595 +/- 124 pg/mL and aortic plasma from 270 +/- 141 to 410 +/- 104 pg/mL. Lung lymph TxB2 paralleled aortic values. Peak levels of 6-keto-PGF1 alpha in systemic lymph exceeded 2,000 pg/mL while levels in lung lymph remained relatively constant. The pulmonary injury and the increase in TxB2 was prevented by ibuprofen. We conclude that the response of soft tissue to local endotoxin is to release thromboxane in quantities sufficient to raise plasma levels and to produce hypoxia and pulmonary hypertension. The lung dysfunction is not produced by an increase in lung water or vascular permeability.     

Prolonged hemorrhagic shock decreases splanchnic prostacyclin synthesis

The effect of increasing time of hemorrhage-induced hypotension on basal splanchnic prostanoid (PG) release was examined. Male Sprague-Dawley rats were anesthetized and hemorrhaged to 30 mm Hg for 30, 60, or 120 min (SK-30, SK-60, SK-120 groups). Following shock, the superior mesenteric artery and its end organ intestine (SV + SI) was cannulated and perfused in vitro with Krebs buffer at 3 ml/min. Basal SV + SI release of 6-keto-PGF1 alpha (6-keto), PGE2, and thromboxane B2 (TxB2) was measured in the SK groups by radioimmunoassay after 15, 30, 60, 90, and 120 min of perfusion and compared to sham-operated controls (SM-30, SM-60, and SM-120 groups). 6-Keto was the major PG released from the sham SV + SI groups and was two- to sixfold higher than PGE2 or TxB2 release. Acute shock for 30 min increased SV + SI 6-keto release threefold or higher than the SM-30 group after 15-90 min of perfusion. Acute shock for 60 or 120 min lowered all PG release below SM-60 and SM-120 levels. These data confirmed our earlier study which showed that the SV + SI attempted to compensate for acute hemorrhagic shock for 30 min by increased release of prostacyclin, a potent endogenous vasodilator. The present study showed that the capacity of the SV + SI to increase endogenous prostacyclin release following hemorrhagic shock was limited by the time duration of the hypotension.     

Renal prostaglandin production is increased during abdominal sepsis in the rat and unaffected by the infusion of different amino acid formulations

Renal prostaglandin (PG) production was studied in 32 laparotomized (control) and 33 septic rats (cecal ligation and puncture). Control and septic rats were infused for 18 hr with 5% glucose or 5% glucose and one of three amino acid formulations containing 22, 35, or 45% branched chain amino acids. When comparing renal PG production from endogenous precursors in septic versus control rats, significant increases (P less than 0.01) could be detected for PGE2, 6-keto-PGF1 alpha, and TxB2. The infusion of either 5% glucose alone or 5% glucose with 4.25% of any of the three amino acid formulations tested did not change renal PG production in either control or septic rats.     

Vasodilating prostaglandins attenuate ischemic renal injury only if thromboxane is inhibited.

Ischemia-induced renal injury is prevented by inhibition of thromboxane (Tx) synthesis. This protection was believed to be secondary to a high prostaglandin (PG)/TxA2 ratio. This study tests whether increasing the PG/Tx ratio by administration of vasodilating PGs protects the reperfused ischemic kidney. Anesthetized rats underwent right nephrectomy and 45 minutes of left renal pedicle clamping. Beginning 10 minutes before clamp release, animals were treated intravenously with the following: saline placebo (n = 10); the cyclooxygenase inhibitor ibuprofen (Ibu), 12.5 mg/Kg in a bolus (n = 8); a stable analogue of prostacyclin (PGI2), 500 ng/kg/minute for 2 hours (n = 9); PGE1, 400 ng/kg/minute for 2 hours (n = 8); the combination Ibu and PGI2 (n = 8) or PGE1 (n = 8). In saline treated ischemic controls, 5 minutes after reperfusion plasma, thromboxane (TxB2) and 6-keto-PGF1 levels were 2537 and 317 pg/ml, respectively--higher than the TxB2 and 6-keto-PGF1 levels of 750 and 80 pg/ml, respectively, in nephrectomized but nonischemic sham controls (n = 7) (p less than 0.05). In ischemic control animals at 24 hours, creatinine levels were 4.6 mg/dl, relative to 0.9 ml/dl in sham animals (p less than 0.05); the weight of the left (L) ischemic kidney relative to the right (R) normal kidney was 118%, compared with 99% in sham animals (p less than 0.05); and renal histology of ischemic control animals at 24 hours showed acute tubular necrosis (ATN) relative to normal findings in sham animals. Pretreatment with Ibu led to: TxB2 and 6-keto-PGF1 levels of 116 and 40 pg/ml, lower than those of sham animals (p less than 0.05); creatinine levels of 4.6 mg/dl, L/R renal weight of 119%; and ATN similar to that of ischemic controls. Treatment with a PGI2 analogue or PGE1 was not protective and led to increases in TxB2, 6-keto-PGF1, creatinine, L/R renal weight, and ATN similar to that of ischemic controls. The combination of Ibu and either PGI2 or PGE1 led to: reduced levels of TxB2 and 6-keto-PGF1 (p less than 0.05); attenuated increases in creatinine to 2.2 and 2.3 mg/dl, respectively (p less than 0.05); and limited ATN (p less than 0.05). These data indicate that the vasodilating PG protect the ischemic reperfused kidney only when Tx is inhibited.     

Effects of sex hormones on rabbit gallbladder prostaglandin biosynthesis

The influence of sex hormones on female and male rabbit gallbladder prostaglandin biosynthesis was examined by radiochromatographic analysis of microsomal membrane fractions. Normal male rabbit total cyclooxygenase activity was modest, producing small amounts of PGE2, PGF2 alpha and 6-keto-PGF1 alpha (breakdown product of PGI2). The normal female gallbladder (GB) microsomes demonstrated an increase in total cyclooxygenase activity when compared to the normal male rabbit gallbladder microsomes. The major prostaglandin (PG) products produced were 6-keto-PGF1 alpha, PGE2 (fivefold higher activity than the male), and PGF2 alpha. The effect of exogenous sex hormones was studied by comparing GB PG biosynthesis in male rabbits treated with exogenous estrogen (50 micrograms/kg sub Q X 5 days) and female rabbits treated with exogenous testosterone (2.5 mg/kg sub Q X 5 days). Exogenous estrogen significantly increased total cyclooxygenase activity in the male rabbit GB microsomes with a significant increase in 6-keto-PGF1 alpha production when compared to the normal male. Exogenous testosterone significantly decreased female rabbit GB total cyclooxygenase activity with a significant decrease in PGE2 biosynthesis and a substantial lowering in 6-keto-PGF1 alpha production. These data suggest that the major sex hormones, estrogen and testosterone, have potent but opposite effects on rabbit GB PG biosynthesis. Both sex hormones may contribute to the sex differences found in our original studies in rabbit GB biosynthesis.     

Renal excretion of prostanoids and cyclic AMP in chronic partial ureteral obstruction of the rabbit

The renal excretion of prostaglandins E2 and 6-keto-F1 alpha, thromboxane B2 and cyclic adenosine 3', 5'-monophosphate was measured in a solitary kidney model of chronic ureteral obstruction in rabbits. The presence of obstruction was confirmed by intravenous pyelography. Growth rate of the animals and furosemide-stimulated diethylenetriaminepentaacetic acid renography were used to grade the obstruction. As correlated to urinary creatinine concentration the excretion of 6-keto-PGF1 alpha dominated in nephrectomized, unobstructed control animals. With the degree of ureteral obstruction becoming more severe, the output of PGE2 increased, while that of 6-keto-PGF1 alpha and TxB2 decreased. As a result the ratios PGE2/6-keto-PGF1 alpha and PGE2/TxB2 were three times as high in severely obstructed rabbits as in control animals. The renal output of cyclic AMP was unaffected by chronic obstruction. We conclude that the renal metabolism of prostanoids is affected in a unique way in chronic partial obstruction of the ureter.     

Effects of ibuprofen on a pig Pseudomonas ARDS model

The effects of ibuprofen (I) were studied in the Pseudomonas (P) porcine ARDS model. Pigs, 14-26 kg (5 in each group), were anesthetized and ventilated with 0.5 FiO2 and 5 cm H2O PEEP. A control (C) group received saline only, a second group was given P, 1 X 10(8) org/ml at 0.3 cc/20 kg/min, and a third group was given P followed by 12.5 mg I at 20 and 120 min. Pulmonary arterial (PAP), wedge (PWP) and systemic arterial pressures, cardiac output (CO), and thermal-cardiogreen extravascular lung water (EVLW), thromboxane (TxB2), 6-keto-PGF1 alpha, PaO2, PaCO2 were determined every 30 min. Albumin flux was measured with scintigraphic determination of lung:heart radioactivity ratios versus time, called slope index (SI). At 3 hr, P produced marked (P less than 0.05) increases in PAP (18 +/- 7 to 37 +/- 2 mm Hg), TxB2 (471 +/- 513 to 9216 +/- 3615 pg/ml), 6-keto-PGF1 alpha, EVLW (6.4 +/- 1.4 to 14.6 +/- 5.7 mg/kg), and SI (0.4 +/- 0.2 to 1.7 +/- 0.5 X 10(-3) U/min) with decreases in PaO2 (214 +/- 47 to 101 +/- 41 torr), CO and SAP. Ibuprofen caused a rapid clearing of TxB2 and 6-keto-PGF1 alpha associated with a transient decrease in PAP; PaO2 was considerably improved compared to P; however, CO, SAP, EVLW, and SI were unaffected. Prostaglandin blockage temporarily ameliorated the pulmonary hypertension and markedly improved oxygenation in this porcine septic ARDS model, but failed to alter increased permeability, confirming other studies that the increased pulmonary shunt in ARDS is not only dependent upon capillary leak.     

Prostaglandin and thromboxane formation in glomeruli from rats with reduced renal mass

In vitro formation of prostaglandins (PG) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) by glomeruli from rats with reduced renal mass (RRM) were evaluated by radioimmunoassay. Four weeks following ablation of renal mass, PGE2, PGF2 alpha, and TxB2 production by glomeruli from RRM rats was significantly greater, when compared with glomerular PG and TxB2 production of sham-operated control (C) rats. The effect of cyclooxygenase inhibition with indomethacin and the selective inhibition of thromboxane formation with UK 38485 on glomerular filtration rate (GFR) was investigated in experiments in vivo. In RRM rats indomethacin reduced GFR from 212 +/- 17 to 138 +/- 14 microliter/100 g/body weight (p less than 0.05) without effect on C rats. Thromboxane synthesis inhibition with UK 38485, however, increased GFR significantly in RRM rats (221 +/- 26 to 303 +/- 21; p less than 0.05). The data suggest that vasodilatory PGs and TxB2 modulate GFR in rats with ablation of renal mass.