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Biomedical subjects

D Shepro

Publications and source records attributed to D Shepro.

At least 91 records · Page 5Linked to original sources
PubMed1986

Cyclo-oxygenase products mediate hypoxic pulmonary hypertension.

High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 +/- 27 (mean +/- SD) to 35 +/- 13 mm HG (P less than .01). The mean arterial pressure (MAP) remained at 50 +/- 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 +/- 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 +/- 4 to 20 +/- 4 mm HG (P less than .01) whereas the PVR increased 70% (P less than .01). TxB2 rose from 147 +/- 85 to 271 +/- 154 pg/mL (P less than .05), and 6-keto-PGF1 alpha rose from 105 +/- 96 to 142 +/- 110 pg/mL. These substances are the hydrolysis products of TxA2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O2, values for MAP, CO, and PVR were similar to those of the nontreatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Heterogeneity of intimal and microvessel endothelial cell barriers in vitro.

We have compared the barriers provided by bovine aortic endothelial cells (AEC), cerebral microvessel endothelial cells (CMEC), and pulmonary microvessel endothelial cells (PMEC) cultured on microcarriers to the passage of trypan blue-bovine serum albumin (TB-BSA). AEC and PMEC barriers were quantitatively comparable, and significantly more permeable to TB-BSA than the CMEC barrier. Serotonin, norepinephrine, and histamine, shown to modulate the AEC barrier, had no effect on the CMEC barrier to TB-BSA. These results suggest that cultured endothelial cells (EC) retain region-specific phenotypic modifications of barrier function observed in vivo. Glutaraldehyde-fixed EC and EC kept at 4 degrees C to minimize transcytosis displayed TB-BSA passage that was reduced by less than 30%, which indicated that the bulk of tracer movement occurred via diffusion between EC. Treatment with cytochalasin B (5 micrograms/ml) resulted in significant AEC and CMEC barrier loss. These results suggest that microfilament bundles are involved in maintaining EC close junctional apposition. We have reported previously that exogenous serotonin and norepinephrine stimulate the EC barrier function in vivo and in vitro, and modulate EC motility, shape, and stress fiber assembly in vitro. In light of these data and the present results, we hypothesize that EC motility and shape change determine in part intercellular macromolecular diffusion by way of a dynamic system of pores of varying radii.

Analysis of Variance↗
PubMed1986

Reduction of polymorphonuclear leukocyte accumulations by inhibition of cyclooxygenase and thromboxane syntase in the rabbit.

Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.

Animals↗
PubMed1986

Nicotine stimulates pulmonary parenchymal thromboxane synthesis.

Smoking increases plasma levels of thromboxane (Tx) B2. Since intravenous nicotine is without effect on platelet TxB2 synthesis, it is likely that lung parenchyma is the site of metabolic importance. This study examines the TxB2 response and functional consequences to the lungs of intratracheal and intravenous instillations of nicotine tartrate. Rat lungs perfused with Krebs-Henseleit (K-H) solution without recirculation were used. After hemodynamic stabilization, the perfusate was either left unaltered or switched to 5 X 10(-4) M nicotine. After 20 minutes of K-H perfusion, effluent levels of TxB2 fell from 41 +/- 6 pg/ml (mean +/- standard error) to 16 +/- 5 pg/ml. A similar decline was noted with nicotine perfusion. K-H perfusion was used throughout the second set of experiments. The lungs were instilled with either saline solution (1 ml/kg body weight) or 5 X 10(-4) M nicotine in saline solution. In the nicotine group, TxB2 levels rose to 86 +/- 5 pg/ml versus 22 +/- 3 pg/ml in saline-instilled controls (p less than 0.05). In addition, pulmonary edema developed in nicotine-instilled lungs. Pretreatment with the Tx synthase inhibitor OKY-046 prevented the rise in TxB2 concentration after nicotine instillation and led to a wet weight/dry weight ratio of 4.0 +/- 0.4 versus 7.5 +/- 1.5 in untreated control lungs (p less than 0.05). Pretreatment with the lipoxygenase inhibitor diethylcarbamazine increased TxB2 levels to 235 +/- 34 pg/ml (p less than 0.05). Diethylcarbamazine also lowered pulmonary artery pressure from 18 +/- 1 mm Hg to 6.1 +/- 0.7 mm Hg in control lungs (p less than 0.05) but did not reduce edema formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Pulmonary and systemic consequences of localized acid aspiration.

Acid aspiration may recruit a generalized inflammatory reaction that can potentiate the local injury. After surgical isolation of bronchi in a group of 15 dogs, 1 milliliter per kilogram of 0.37 normal hydrochloric acid was instilled into either side. After five minutes, platelet and white blood cell counts fell to 10,000 and 1,000 per cubic millimeter (p less than 0.05). Platelet aggregates were noted in blood smears. 111Indium-platelet activity doubled over both the aspirated and nonaspirated lung (p less than 0.05). Physiologic dead space rose from 18 to 67 per cent and to 46 per cent in the aspirated and nonaspirated lung (p less than 0.05). Physiologic shunt increased from 12 to 47 per cent and to 43 per cent (p less than 0.05) on the two sides. Plasma thromboxane B2 levels at 30 minutes rose from 0.28 to 0.93 nanograms per milliliter (p less than 0.05). Edema fluid from the aspirated lung had thromboxane B2 values of 2.87 nanograms per milliliter, indicating pulmonary synthesis. Within five minutes of aspiration, systemic effects were prominent; mean arterial pressure fell from 114 to 46 milliliters of mercury (p less than 0.05), and the cardiac index fell 24 per cent from 106 to 81 milliliters per kilogram per minute (p less than 0.05) along with an 18 per cent decrease in contractility of a rat papillary muscle bathed in plasma from the aspirated dog. Mean pulmonary arterial pressure rose from 12 to 18 millimeters of mercury (p less than 0.05). Despite fluid infusion at 36 milliliters per kilogram per hour to keep wedge pressure constant at 5.5 millimeters of mercury, and sampling of one-third the blood volume, hemoglobin concentration rose 0.9 grams per cent (p less than 0.05) indicating increased microvascular permeability. At autopsy, the aspirated and nonaspirated lung were indistinguishable with congestion, interstitial hemorrhage, and white blood cell infiltrates. Systemic organs showed vascular congestion and edema. These data demonstrate that local aspiration leads to generalized inflammatory sequelae with cardiopulmonary failure.

Animals↗
PubMed1985

Vasoactive amines modulate actin cables (stress fibers) and surface area in cultured bovine endothelium.

Cultured bovine aortic endothelial cells were fixed and stained with NBD-phallicidin and quantitated with a digital image analyzer for changes in actin cables and surface area. Serotonin (5-HT), norepinephrine (NE), dopamine and histamine (all at 10(-4)M concentrations) were tested for their ability to induce cytoskeletal changes. Only 5-HT and NE increased actin cables significantly (p less than 0.01), 80.7% and 97.9%, respectively. Dopamine and histamine treated cells showed a 67.4% and 80.8% decrease in actin cables respectively (p less than 0.01). Stimulated increases of actin cables by 5-HT were inhibited by Ketanserin, and propranolol inhibited NE stimulation of actin cables. Treatment of cells with these blockers alone also decreased actin cables below control values (p less than 0.01). Pretreatment of cells with diphenhydramine, but not cimetidine, inhibited histamine-induced decreases in actin cables. Stimulation of surface area by 5-HT and NE was also observed, with 40.8% and 80.7% increases respectively, when compared with controls (p less than 0.01). The increases in actin cables were associated with a lack of ruffled edges that are indicative of motile cells. In contrast, induced decreases in actin cables resulted in cells with ruffled edges. Exogenous 5-HT and NE have been shown to prevent the increased permeability visible as extravasation of red blood cells from postcapillary venules in thrombocytopenic animals. The present data suggest that 5-HT and NE may be involved in maintaining the endothelial barrier function by a receptor-mediated stimulation of actin cables. Also, histamine-induced decreases in actin cables may be correlated with the amine's action in vivo as a mediator of increased inflammatory permeability.

Actins↗
PubMed1985

Eicosanoid modulation of stress fibers in cultured bovine aortic endothelial cells.

Leukotrienes (LT) B4, LTD4, and thromboxanes (TX) are cytotoxic, and increase microvascular permeability. Because endothelial stress fibers are theorized to be part of the cytoskeletal mechanism by which microvessels maintain their barrier function, the effect of these eicosanoids on stress fibers in bovine aortic endothelial cells was tested. LTB4, LTD4, and TXB2 each decreased stress fiber numbers by 93%, 62%, and 66%, respectively, when compared to controls (P less than 0.01). In contrast, endothelial cells treated with prostacyclin (PGI2) at 10(-7) M, produced a significant increase (P greater than 0.01) in stress fiber numbers, 211% to that of controls. Azaprostanoic acid (13-APA) and FPL55712, receptor antagonists to TX and slow-reacting substance of anaphylaxis (SRS) receptors, respectively, the cyclooxygenase inhibitor ibuprofen, and the TX synthase inhibitors imidazole and ketoconazole were used to test for possible endothelial cell receptor mediation and de novo prostanoid synthesis associated with inflammatory eicosanoid-induced disassembly of stress fibers. Each pharmacologic agent inhibited the LTD4- and TXB2-induced decreases in stress fibers; LTB4-stimulated stress fiber decreases were inhibited only by pretreatment with TX synthase blockers. These data suggest that increased permeability associated with inflammatory eicosanoid metabolites may have as a common target stress fiber disassembly, and the mechanism may be receptor-mediated. That cyclooxygenase and TX synthase blockers inhibited the eicosanoid action suggests that endogenous TX synthesis may be a step in the mechanism. PGI2 enhancement of the microvascular barrier may be related to the effect of PGI2 on promoting stress fiber assembly. In summary, endothelial cell synthesized autocoids derived from arachidonic acid may help to regulate microvascular permeability by way of their action on stress fiber assembly/disassembly, and unbalanced prostanoid secretion by way of LT stimulation may result in a loss of the microvascular barrier and increased permeability.

Actin Cytoskeleton↗
PubMed1985

Thromboxane A2 moderates permeability after limb ischemia.

Reperfusion after limb ischemia results in muscle edema as well as excess secretion of thromboxane A2 (TxA2), an agent associated with permeability increase in other settings. This study tests whether TxA2 moderates the permeability following limb ischemia. A tourniquet inflated to 300 mmHg was applied for 2 hours around the hind limb of four groups of dogs. In untreated animals (N = 25), 2 hours following tourniquet release, plasma TxB2 values rose from 320 pg/ml to 2416 pg/ml (p less than 0.001), and popliteal lymph values rose from 378 pg/ml to 1046 pg/ml (p less than 0.001). Platelet TxB2 was unaltered and plasma 6-keto-PGF1 alpha levels did not vary. Following ischemia, lymph flow (QL) increased from 0.07 to 0.37 ml/h (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged at 0.41. These measurements indicate increased permeability since increase in hydrostatic pressure in a second group by tourniquet inflation to 50 mmHg (N = 7) led to a rise in QL from 0.07 to 0.22 ml/h, but a fall in the L/P ratio to 0.32, a value lower than the ischemic group (p less than 0.05). Pretreatment with the imidazole derivative ketoconazole (N = 11) reduced platelet Tx synthesis from 42 ng to 2 ng/10(9) platelets, but lymph TxB2 levels rose to 1703 pg/ml after ischemia, indicating an extravascular or vessel wall site of synthesis not inhibited by ketoconazole. Pretreatment with a lower molecular weight imidazole derivative OKY 046 (N = 9) inhibited all Tx synthesis after ischemia. Prior to tourniquet inflation, both OKY 046 and ketoconazole lowered plasma TxB2 levels as well as the L/P ratio (p less than 0.05). After ischemia, OKY 046, but not ketoconazole, maintained the L/P ratio at 0.33, a value below that of untreated animals (p less than 0.05). These results indicate that nonplatelet-derived TxA2 modulates both baseline and ischemia-induced increases in microvascular permeability in the dog hind limb.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Serotonin, histamine, and norepinephrine mediation of endothelial and vascular smooth muscle cell movement.

The effects of serotonin (5-HT), histamine (H), and norepinephrine (NE) on bovine aortic endothelial cell (BAE) and vascular smooth muscle cell (VSM) movement were quantitated using a phagokinetic tracking assay. BAE movement was significantly reduced by 5-HT (31%), H (48%), and NE (62%) at concentrations ranging from 10(-10) to 10(-4) M (P less than 0.01). VSM motility was significantly enhanced by 5-HT (17%) and H (25%) at concentrations of 10(-8) and 10(-4)M, respectively (P less than 0.01). NE (10(-4)M) reduced VSM motility by 63% (P less than 0.01). Ketanserin (1 microM) reduced the 5-HT-associated inhibition of BAE movement by 75% (P less than 0.01). Diphenhydramine (1 microM) reduced the H-associated inhibition of BAE movement by 66% (P less than 0.01). Propranolol (1 microM) reduced NE-associated inhibition of BAE movement by 50% (P less than 0.01) and 5-HT-associated inhibition by 45% (P less than 0.05), but phenoxybenzamine had no significant effect. The results suggest 1) BAE and VSM are affected qualitatively in opposite ways by 5-HT and H; 2) the H-associated inhibition of BAE movement appears to be at least partially mediated by H1 receptors; 3) the 5-HT-associated inhibition of BAE movement may be mediated directly by a 5-HT binding component but indirectly by beta-adrenergic receptors; and 4) the NE-associated inhibition of BAE movement appears to be mediated by beta-adrenergic receptors.

Animals↗
PubMed1985

Endothelial serotonin uptake and mediation of prostanoid secretion and stress fiber formation.

The kinetics of serotonin (5-hydroxytryptamine [5-HT] ) uptake by intimal and microvessel endothelial cells (ECs), in culture and in suspension, were investigated. The data suggest that although the amine is cleared rapidly by all types of ECs, the mode of uptake varies according to endothelial source. Confluent cultured aortic ECs clear exogenous 5-HT by a nonsaturable mechanism. Cardiac microvessel ECs also clear 5-HT by nonmediated diffusion, unlike pulmonary and adipose microvascular ECs, where a carrier-mediated mechanism exists. The action of 5-HT on prostanoid secretion and prostacyclin (prostaglandin I2 [PGI2] ) on 5-HT uptake by primary cultures of confluent aortic ECs was assayed. In vitro 5-HT concentrations from 10(-3) to 10(-12) M have no effect on PGI2 and thromboxane (TxA2) synthesis by cultured primary aortic ECs. Exogenous PGI2, however, inhibits 5-HT uptake by cultured primary aortic ECs. Last, 5-HT stimulates stress fibers as much as 80%, and increases surface area by 40% in cultured ECs. The agonistic action of 5-HT appears to be receptor mediated in that it can be blocked by pretreating the ECs with ketanserin, a 5-HT2 receptor blocker. Prostanoids also mediate stress fiber numbers, and substances known to increase permeability such as TxA2 also cause a disassembly of stress fibers. We hypothesize that 5-HT and PGI2, by some mechanism yet to be explained, directly and/or indirectly help to maintain endothelial structural integrity by promoting stress fiber formation.

Animals↗
PubMed1985

Prostacyclin and thromboxane A2 moderate postischemic renal failure.

Since prostacyclin (PGI2) is known to regulate renal cortical blood flow and since ischemia stimulates thromboxane (Tx) A2 synthesis, the role of these prostanoids in moderating the response to renal ischemia was studied in the rat. At baseline, plasma TxB2 concentration in untreated animals (n = 13) was 357 pg/ml. The left renal pedicle was clamped for 45 minutes after a right nephrectomy (n = 16), which led after 5 minutes of reperfusion to a rise in TxB2 to 2825 pg/ml (p less than 0.001), but there was no change in 6-keto-PGF1 alpha. After 24 hours creatinine levels rose from 0.4 to 3.0 mg/dl (p less than 0.001), and left renal weight rose from 94% to 117% (p less than 0.001) relative to the weight of the right kidney. In nephrectomized but nonischemic sham control rats (n = 7), creatinine level was 0.9 mg/dl and kidney weight 91% after 24 hours. Pretreatment with OKY 046 (n = 13) (2 mg/kg administered intravenously) blocked ischemia-induced TxB2 synthesis, while 6-keto-PGF1 alpha levels rose from 96 to 302 pg/ml (p less than 0.001). There was no increase in creatinine levels or kidney weight relative to the sham group. Pretreatment with ibuprofen (n = 10) (12 mg/kg) or OKY 046 and ibuprofen (n = 9) inhibited TxB2 and 6-keto-PGF1 alpha synthesis, but creatinine levels and renal weight rose (p less than 0.001). Renal histology in OKY 046-pretreated animals was equal to that in nephrectomized controls, while all other ischemic groups showed tubular necrosis. Results indicate that a high PGI2/TxA2 ratio protects against renal ischemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Vasoactive agonists prevent erythrocyte extravasation in thrombocytopenic hamsters.

The mediating action of selected vasoactive amines and their respective antagonists on vascular fragility, visible as cutaneous petechiae, was assayed with thrombocytopenic (TCP) hamsters. Serotonin (5-HT), norepinephrine (NE), epinephrine, dopamine and isoproterenol administered IP reduced petechiae significantly within 10 min; phenylephrine had no effect. Of the natural amines, 5-HT and NE were most effective in reducing petechial sensitivity to values obtained with untreated, normal animals; hence these two amines only were tested pharmacologically. Pretreatment of TCP animals with Ketanserin or propranolol, administered IP or IV, abolished any petechial inhibitory action of 5-HT and NE respectively; pretreatment with phenoxybenzamine reduced significantly the NE inhibition of petechiae, but to a lesser degree than propranolol. In contrast, atenolol, prazosin and yohimbine had no significant effect. Ketanserin abolished the action of NE, but adrenoceptor blockers had no effect on 5-HT-treated TCP hamsters. The results suggest that 5-HT and NE inhibition of petechiae may be receptor-mediated and that there may be receptor interaction. This was supported by the observation that non-additive subthreshold doses of 5-HT and NE, which individually did not prevent petechial formation in TCP hamsters, when combined totally inhibited petechiae. The theorized importance of endogenous 5-HT and NE to maintain postcapillary venule junctional integrity (site of petechial hemorrhaging) was also demonstrated by treating normal hamsters with drugs known to block or antagonize either 5-HT or NE uptake. In every instance petechial sensitivity rapidly occurred, and the loss of microvascular integrity in Ketanserin-treated hamsters mimicked quantitatively the petechial sensitivity observed with TCP animals.

Animals↗
PubMed1984

Leukotriene induction of TxB2 in cultured bovine aortic endothelial cells.

The leukotrienes (LT) are potent mediators of inflammation, capable of inducing plasma leakage from postcapillary venules and vasoconstriction of terminal arterioles. Some microvascular effects may be attributable to LT stimulation of thromboxane (Tx) synthesis. Incubation of primary cultures of bovine aortic endothelial cells with buffer, LTB4 (10(-8) M) or LTD4 (10(-8)M), resulted in TxA2 production in pg/10(5) cells to the extent of: 67 +/- 20, 571 +/- 180, and 333 +/- 60 respectively, as measured by radioimmunoassay of the stable metabolite TxB2. Endothelial pretreatment with the LTD4 receptor antagonist FPL55712 (10(-5)M) significantly blocked any LTB4- or LTD4-stimulated TxA2 synthesis. Pretreatment with the TxA2 synthetase inhibitor ketoconazole (10(-6)M) also prevented LTB4 of LTD4 stimulation of TxA2. Preincubation with DMTU (10(-5)M), an hydroxyl radical scavenger, decreased LTB4-induced release of TxA2 (405 +/- 40 and 366 +/- 20, respectively). These findings suggest that LT may mediate their inflammatory actions in vascular beds by stimulation of Tx release from endothelial cells.

Animals↗
PubMed1984

Determinants of cardiovascular stability during abdominal aortic aneurysmectomy (AAA).

Patients undergoing abdominal aortic aneurysmectomy (AAA) develop depressed cardiac function during aortic clamping. The importance of volume status and thromboxane (Tx) mediated declines in cardiac contractility in determining this event was studied. In a blinded fashion, patients received the cyclo-oxygenase inhibitor ibuprofen 12 mg/kg by mouth (n = 11) or a placebo (n = 15), 1.5 hours prior to surgery. In the placebo group levels of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin (PGI2) rose from 20 +/- 10 to 1170 +/- 80 pg/ml (p less than 0.05) soon after incision. Concentrations of TxB2, the stable hydrolysis product of TxA2, were unchanged until 30 minutes after the aorta was clamped when arterial TxB2 concentrations rose from 90 +/- 20 to 230 +/- 30 pg/ml (mean +/- SEM) (p less than 0.05). A pulmonary source for PGI2 and TxA2 was indicated by the observation that arterial 6-keto-PGF1 alpha and TxB2 levels exceeded those in pulmonary arterial blood by 180 +/- 50 and 110 +/- 30 pg/ml, respectively (p less than 0.05). Levels of TxB2 in circulating platelets remained unchanged from baseline in the placebo group. During aortic clamping, cardiac index (CI) fell 0.7 +/- 0.2 1/min X m2 (p less than 0.05) in placebo treated patients, and there was a 6% decline in plasma contractility as bioassayed with a rat papillary muscle (p less than 0.05). Placebo patients entered surgery with a PAWP greater than or equal to 10 mmHg (mean 13 mm). Ibuprofen suppressed production of TxB2, such that 30 minutes after aortic clamping TxB2 was 70 +/- 30 pg/ml, a value lower than control patients (p less than 0.05). Further, plasma no longer depressed contractility of the papillary muscle. Five patients given ibuprofen had an initial pulmonary arterial wedge pressure (PAWP) of 10 mmHg or greater (mean 12 mmHg). During aortic clamping there was an insignificant decrease in CI of 0.2 +/- 0.1 1/min X m2. This was in contrast to the CI decrease in six other ibuprofen treated patients of 0.9 +/- 0.2 1/min X m2 whose PAWP at the start of surgery was less than 10 mmHg (mean 6 mmHg) (p less than 0.05), and to placebo patients whose initial PAWP was greater than or equal to 10 (p less than 0.05). Platelet counts fell from 185,000 to 121,000/mm3 in placebo patients (p less than 0.05), but did not fall when ibuprofen was given. Creatinine concentrations were unaffected by ibuprofen. Blood replacement in placebo and ibuprofen patients was similar, 1.90 +/- 0.20 and 0.65 +/- 0.15 1, respectively. Results indicate that CI will not decrease during AAA if sufficient volume is given before surgery to increase PAWP above 10 mmHg, and secondly, if TxB2 synthesis is inhibited.

Aged↗
PubMed1984

Role of serotonin in patients with acute respiratory failure.

An early event in the evolution of acute respiratory failure (ARF) is thought to be the activation of platelets, their pulmonary entrapment and subsequent release of the smooth muscle constrictor serotonin (5HT). This study tests the thesis that inhibition of 5HT will improve lung function. The etiology of ARF in the 18 study patients was sepsis (N = 10), aspiration (N = 3), pancreatitis (N = 1), embolism (N = 2), and abdominal aortic aneurysm surgery (N = 2). Patients were divided into two groups determined by whether their period of endotracheal intubation was less than or equal to 4 days (early ARF, N = 12) or greater than 4 days (late ARF, N = 6). Transpulmonary platelet counts in the early group showed entrapment of 26,300 +/- 5900 platelets/mm3 in contrast to the late group where there was no entrapment (p less than 0.05). The platelet 5HT levels in the early group were 55 +/- 5 ng/10(9) platelets, values lower than 95 +/- 15 ng/10(9) platelets in the late ARF group (p less than 0.05), and 290 +/- 70 ng/10(9) platelets in normals. The selective 5HT receptor antagonist, ketanserin was given as an intravenous bolus over 3 minutes in a dose of 0.1 mg/kg, followed by a 30-minute infusion of 0.08 mg/kg. During this period mean arterial pressure (MAP) fell from 87 +/- 5 to 74 +/- 6 mmHg (mean +/- SEM) (p less than 0.05). One and one-half hours following the start of therapy, MAP returned to baseline. At this time, patients with early ARF showed decreases in: physiologic shunt (Qs/QT) from 26 +/- 3 to 19 +/- 3 (p less than 0.05); peak inspiratory pressure from 35 +/- 2 to 32 +/- 2 cmH2O (p less than 0.05) and in mean pulmonary arterial pressure from 32 +/- 2 to 29 +/- 1 mmHg (p less than 0.05). At 4 hours all changes returned to baseline levels. In early ARF ketanserin did not alter pretreatment values of: pulmonary arterial wedge pressure, 17 +/- 3 mmHg; cardiac index, 2.8 +/- 0.3 L/min X m2; platelet count, 219,000 +/- 45,000/mm3; platelet 5HT, 55 +/- 5 ng/10(9) platelets; plasma 5HT, 142 +/- 21 ng/ml; plasma thromboxane B2, 190 +/- 30 pg/ml; or plasma 6-keto-PGF1 alpha, 40 +/- 10 pg/ml. Ketanserin infusion in patients with late ARF yielded no benefit. In both ARF groups the decreases in QS/QT were inversely related to the duration of intubation (r = 0.70; p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Inhibition of ischemia-induced thromboxane synthesis in man.

The ability of the imidazole derivative, ketoconazole, to inhibit thromboxane (Tx)A2 synthesis in response to ischemia was tested in ten volunteers. Two hours after taking placebo or ketoconazole 400 mg by mouth, plasma levels of the stable degradation product of TxA2, TxB2, were 300 +/- 129 pg/ml (mean +/- SEM) and 297 +/- 80 pg/ml, respectively. Arm ischemia for 10 min induced by inflation of a cuff to 220 mm Hg led to a rise in TxB2 levels to 657 +/- 157 pg/ml after placebo (p less than 0.05) and 337 +/- 81 pg/ml after ketoconazole. One hour after cuff deflation, TxB2 returned to pre-ischemia levels in both groups. Platelet TxB2 concentrations were 27 +/- 6 ng in the placebo and 35 +/- 6 ng/10(9) platelets in the ketoconazole group, and were unchanged by cuff inflation. The fact that plasma and platelet TxB2 values were not lower 2 hr after ketoconazole treatment was explored in another group of four nonstressed volunteers who received 400 mg of drug. After 2 hr, TxB2 values had fallen from 170 +/- 30 pg to 120 +/- 10 pg; at 4 hr, 6 hr, and 8 hr they were 30 +/- 20 pg, 5 +/- 5 pg, and 5 +/- 5 pg/ml, respectively. These results indicate that tourniquet ischemia provokes TxA2 synthesis, and that the source of this prostanoid is likely to be ischemic tissue and not platelets. Finally, ketoconazole can profoundly inhibit both background and stimulated TxA2 synthesis.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Arachidonic acid metabolites mediate early burn edema.

Standard burns were sequentially produced on the backs of Sprague-Dawley rats at 0, 1, 2, and 2 1/2 hr, followed by the IV injection of Evans blue dye. All animals were killed at 3 hr, and burns evaluated by wet/dry weight ratios, and Evans blue extravasation scored 1-4 by two observers. Five groups of rats were compared to controls. Rats made neutropenic by exposure to 137cesium showed no significant difference in wet/dry weight ratio or Evans blue extravasation compared to controls. At 1 1/2 hr four other groups were treated with various inhibitors of arachidonic acid metabolism including ibuprofen, a cyclo-oxygenase inhibitor; FPL 55712, a leukotriene (LT) receptor antagonist; ketoconazole, an inhibitor of thromboxane (Tx) synthetase; and lodoxamide, a calcium channel inhibitor. All treated groups showed significant reduction of Evans blue dye extravasation. Wet/dry weight ratios were significantly reduced in rats treated with FPL 55712 and ketoconazole before or after burning. These data support the postulate that oxygenation products of arachidonic acid, particularly Tx and LT, are important mediators in early burn edema.

Animals↗