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Biomedical subjects

D Shepro

Publications and source records attributed to D Shepro.

At least 109 records · Page 6Linked to original sources
PubMed1984

Antiinflammatory agents inhibit microvascular permeability induced by leukotrienes and by stimulated human neutrophils.

One pathologic change common to the inflammatory process is loss of microvessel membrane integrity which results in edema. Polymorphonuclear leukocytes (PMN) are primary contributors to the development of edema because they cause tissue injury which alters vascular permeability and hemodynamics. The aim of this study was to assess the influence of arachidonic acid metabolites generated by activation of human PMN on the in vivo microvascular preparation of the hamster cheek pouch. Fluorescein-labeled dextran MW: 150,000 was used to assess microvascular permeability. Human PMN were activated with arachidonic acid (AA) and the calcium ionophore A23187, and the supernatant retained for testing. Topical application of the PMN supernatant, purified LTD4 or LTB4 resulted in marked extravasation of macromolecules from post-capillary venules of control hamsters. The extravasation was reduced when hamsters were pretreated with indomethacin (5 mg/kg), imidazole (25 mg/kg), ketoconazole (10 mg/kg), 13-azaprostanoic acid (30 mg/kg), FPL 55712 (1 mg/kg) and dimethylthiourea (500 mg/kg). The interpretation of the results suggests that the increased vascular permeability induced by PMN secretions may be mediated in part by the thromboxane pathway.

Animals↗
PubMed1983

Binding, internalization, and degradation of [125I]insulin by cultured bovine aortic endothelial cells: effects of serotonin.

Cultured bovine aortic endothelial cells bind and internalize [125I]insulin and down regulate insulin receptors. Internalized insulin was not degraded significantly and diffused from the endothelial cells. Neither 5-hydroxytryptamine, methylamine, nor dansylcadaverine have any observable effect on insulin binding, internalization, metabolism, or down regulation of insulin receptors. Transglutaminase activity, however, is inhibited by 5-hydroxytryptamine and methylamine. These data indicate that transglutaminase is not required for insulin receptor-mediated endocytosis by bovine aortic endothelial cells in culture.

Animals↗
PubMed1983

Prostacyclin inhibits 5-hydroxytryptamine release but stimulates thromboxane synthesis during cardiopulmonary bypass.

The antiaggregating agent prostacyclin (PGI2) was infused into ten dogs during cardiopulmonary bypass (CPB) to minimize thrombocytopenia and platelet dysfunction. The animals were anesthetized, placed on mechanical ventilation and underwent thoracotomy. After heparinization with 300 u/kg, animals were assigned to control (n=5) or PGI2 treated groups (n=5). Thoracotomy and then CPB decreased platelet numbers to below 30,000/mm3 (p less than 0.05) and fibrinogen to less than 150 mg/dl (p less than 0.05). PGI2 at 100 ng/kg.min was infused for the 2 h period of CPB. PGI2 infusion did not prevent these changes, but did prevent platelet serotonin release. In the control group after CPB, platelet serotonin fell from the baseline value of 1.11 microgram/10(9) to 0.35 microgram/10(9) platelets (p less than 0.05). In contrast, PGI2 treatment resulted in a serotonin increase to 2.27 micrograms/10(9) platelets (p less than 0.05). Thromboxane B2 concentrations of platelets and plasma rose during CPB (p less than 0.05). Surprisingly, PGI2 infusion accentuated this rise in platelet and plasma thromboxane B2 (p less than 0.05). These data indicate that during CPB, an infusion of PGI2: 1) does not prevent thrombocytopenia; 2) increases platelet serotonin uptake despite, 3) an associated rise in platelet and plasma thromboxane B2.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Therapeutic benefits of 5-hydroxytryptamine inhibition following pulmonary embolism.

The smooth muscle-constricting, platelet amine, serotonin (5-hydroxytryptamine; 5-HT) is theorized to play an important role in the cardiopulmonary dysfunction that accompanies embolization. The present study was designed to examine this hypothesis. Autologous clot, 0.75 g/kg, was injected IV into 14 dogs. After 30 minutes, one half of the animals were randomly assigned to the treatment group and received a bolus infusion of 0.15 mg/kg ketanserin, a quinazoline derivative known to be a selective 5-HT receptor antagonist. Five minutes after embolization there were increases in mean pulmonary arterial pressure (MPAP) from 12 mm to 48 mmHg (p less than 0.001); pulmonary vascular resistance (PVR) from 2.2 mm to 12.2 mmHg X min/L (p less than 0.001); physiologic shunt (QS/QT) from 12% to 44% (p less than 0.01); and physiologic dead space (VD/VT), calculated from end tidal and arterial PCO2, from 8% to 39% (p less than 0.001). Within 15 minutes platelet counts decreased from 186,000/mm3 to 134,800/mm3 (p less than 0.05); 5-HT contained in circulating platelets fell from 1.71 micrograms/ to 1.44 micrograms/10(9) platelets (p less than 0.05). Five minutes after ketanserin, MPAP declined to 27 mmHg and was lower than the control value of 41 mmHg (p less than 0.05); PVR decreased to 6.2 mmHg X min/L, lower than 12 mmHg X min/L in controls (p less than 0.01); QS/QT fell to 26% in contrast to 47% in controls (p less than 0.05); and VD/VT declined moderately to 32% (p less than 0.05), although this value was not different from 38% in control animals. Cardiopulmonary function continued to improve in treated animals until termination of the experiment at four hours when pulmonary angiograms and perfusion scans demonstrated vascular recruitment compared with untreated embolized control dogs. These data demonstrate that the cardiopulmonary consequences of experimental embolization are primarily determined by the vasoconstrictive and bronchoconstrictive actions of 5-HT.

Animals↗
PubMed1983

Thromboxane mediation of cardiovascular dysfunction following aspiration.

Acid aspiration leads to an inflammatory response characterized by the activation and pulmonary entrapment of platelets and while blood cells (WBCs. We speculate that thromboxane (Tx) produced by these activated cells alters lung permeability and diminishes cardiac performance. The lungs of dogs were aspirated with 0.1N HCl (3 ml/Kg). Within 30 minutes in six untreated controls, cardiac index (CI) decreased from 121 to 104 ml/min . kg (P less than ).05), mean arterial pressure decreased from 142 to 120 mm Hg (P less than 0.05), Pao2 decreased from 91 to 73 mm Hg (P less than 0.05), and TxB2 levels increased from 70 to 130 pg/ml (P less than 0.05). Pulmonary WBC sequestration occurred after 2 hours, while at 21/2 hours edema fluid was noted in the endotracheal tube. Six dogs were treated with infusion of the imidazole derivative ketoconazole 1 hour after aspiration (2.5 mg/kg bolus followed by 10 mg/kg . hr for 2 hours). After 30 to 60 minutes of treatment, CI rose from 106 to 143 ml/min . kg (P less than 0.05), TxB2 decreased from 130 to 70 pg/ml (P less than 0.05). At 21/2 hours, plasma from treated animals used to incubate a papillary muscle led to developed tension 8% higher than that in controls (P less than 0.05). Sequestration of WBC was not observed. After 4 hours, 24 ml endotracheal edema fluid was collected in contrast to 127 ml in controls (P less than 0.05). A hamster cheek pouch used for bioassay of microvascular permeability yielded 78 leakage sites/cm2 with control edema fluid and 26/cm2 with fluid from treated animals (P less than 0.05). The importance of WBC Tx synthesis in the induction of permeability was tested by stimulation of isolated WBCs with ionophore in the presence or absence of ketoconazole (0.4 Microgram/ml). Ketoconazole reduced the number of leakage sites in the hamster cheek pouch from 196/cm2 noted in controls to 28/cm2 (P less than 0.05). These data support our hypothesis that Tx directly or indirectly lead to cardiac depression and WBC-mediated permeability.

Animals↗
PubMed1983

Ischemia of the limb stimulates thromboxane production and myocardial depression.

Thromboxane A2 is thought to be an important mediator of cardiopulmonary dysfunction, hence stimuli that effect synthesis of this prostanoid are of major interest. In this study, the thesis that ischemia of the limb is a significant stimulus to thromboxane A2 synthesis and the generation of a circulating negative inotrope is tested. Twelve healthy volunteers, taking no medications and ranging in age from 21 to 29 years, underwent inflation of an arm cuff to either 70 or 220 millimeters of mercury for ten minutes. Immediately after deflation of the cuff from 220 millimeters of mercury, the stable degradation product of thromboxane A2, thromboxane B2, rose from a base line plasma level of 34 +/- 6 picograms per milliliter (mean +/- SEM) to 70 +/- 18 picograms per milliliter. In contrast, deflation from a cuff pressure of 70 millimeters of mercury resulted in a lower thromboxane B2 level of 26 +/- 9 picograms per milliliter (p less than 0.05). Plasma obtained before and after inflation of the cuff to 220 millimeters of mercury was used to bathe a rat papillary muscle. Developed tension fell from a base line of 2.80 +/- 0.19 to 2.44 +/- 0.17 grams (p less than 0.01). There was no significant change in developed tension induced by plasma harvested after the cuff was inflated to 70 millimeters of mercury. The base line plasma level of 6-keto-prostaglandin F1 alpha, the hydrolysis product of prostacyclin, was 46 picograms per milliliter; the plasma serotonin, 51 nanograms per milliliter; the platelet serotonin, 1.02 micrograms per 10(9) platelets; platelet count, 220,000 per cubic millimeter, and white blood count, 6,094 per cubic millimeter. These values did not change significantly with cuff inflation to either 220 or 70 millimeters of mercury. The results show that ischemia of the limb leads to thromboxane A2 production. Possible adverse cardiac effects related to this event are suggested by the bioassay demonstrating that circulating plasma with high levels of thromboxane B2 is associated with the depression of tension of an isolated rat papillary muscle.

Adult↗
PubMed1982

Adverse effects of prostacyclin used to perfuse isolated lung lobes.

To test the hypothesis that preservation of circulating platelets would prolong the function of an isolated perfused canine lung lobe, prostacyclin (PGI2) was added to the perfusate. Platelet count in heparinized controls (n = 7) fell to 44,500 platelets/mm3, lower than 136,000 platelets/mm3 seen with 1 microgram/min PGI2 (n = 7, P less than 0.005). Surprisingly, with PGI2, thromboxane B2 (TXB2) the stable product of thromboxane A2 (TXA2), rose from 0.07 to 0.25 ng/ml, a level higher than controls (P less than 0.005). PGI2, in comparison to controls, also led to higher pulmonary arterial pressure, an increase in lobe weight, an increase in wet weight-dry weight ratio, an increase in physiological shunt, and a decrease in compliance (P less than 0.005). Further, with PGI2 there was hemorrhagic edema. Infusion of the PGI2 hydrolysis product 6-keto-prostaglandin F1 alpha (n = 2) led to results similar to controls. Adverse PGI2 effects were eliminated by pretreatment with ibuprofen (12.5 mg/kg, n = 5) or an antiplatelet antibody (n = 6). Infusion of PGI2 into a lobar pulmonary artery of an intact animal was without effect on the lung (n = 2). These results show that platelets exposed to a foreign surface will aggregate and be lost from the circulation. PGI2 prevents platelet loss but not the synthesis of TXA2. This vasoconstrictor is likely to be the cause of pulmonary hypertension and hemorrhagic pulmonary edema.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Thromboxane mediation of cardiopulmonary effects of embolism.

Humoral factors released from platelets during pulmonary embolism may be the cause of several attendant cardiopulmonary abnormalities. This study examines the role of thromboxanes (Tx) after experimental embolism induced with 0.5 g/kg autologous clot in four groups of five dogs: (a) untreated embolized controls; (b) pretreatment with the Tx synthetase inhibitor, imidazole 25 mg/kg . h i.v., starting 30 min before embolization; (c) pretreatment with the cyclooxygenase inhibitor indomethacin, 5 mg/kg, 12 h per os and 1 mg/kg, 1 h i.v. before the experiment; (d) treatment with prostacyclin (PGI(2)) 100 etag/kg . min i.v. for 1 h, 1 h after embolization. Within 30 min, embolization led to increases of 6-keto-PGF(1alpha), the stable hydrolysis product of PGI(2), from 0.11+/-0.08 etag/ml (mean+/-SD) to 0.33+/-0.10 etag/ml (P < 0.005) and TxB(2), the stable product of TxA(2), from 0.10+/-0.04 etag/ml to 0.38+/-0.06 etag/ml (P < 0.001). Increases were observed in total dead space (V(D)/V(T)) from 0.46+/-0.03 to 0.61+/-0.08 (P < 0.025, physiologic shunting (Q(S)/Q(T)) from 16+/-4% to 38+/-9% (P < 0.01), pulmonary vascular resistance (PVR) from 2.27+/-0.59 mm Hg.min/liter to 9.21+/-1.90 mm Hg.min/liter (P < 0.005) and mean pulmonary arterial pressure from 14+/-6 mm Hg to 34+/-1 mm Hg (P < 0.001). Cardiac index (CI) fell from 139+/-11 ml/kg.min to 95+/-17 ml/kg.min in 4 h (P < 0.025). Imidazole pretreatment prevented a rise of TxB(2), but not 6-keto-PGF(1alpha); indomethacin blocked both. Both agents maintained V(D)/V(T) at base line and limited increases in Q(S)/Q(T) and PVR. CI was higher after imidazole pretreatment compared with controls (P < 0.025). Indomethacin led to intermediate levels of CI. PGI(2) lowered TxB(2) (P < 0.025), V(D)/V(T) (P < 0.025), Q(S)/Q(T) (P < 0.025) and PVR (P < 0.05) within 30 min. During PGI(2) infusion, CI was higher than controls. Concentrations of TxB(2) correlated with V(D)/V(T), r = 0.79 and Q(S)/Q(T), r = 0.69 (P < 0.001). Treatment of three dogs with the imidazole derivative ketoconazole, 10 mg/kg IV, 30 min after 0.75 g/kg autologous clot resulted in a lowering of physiologic dead space, but no other improvement of cardiopulmonary function. These results show that a number of cardiopulmonary abnormalities induced by pulmonary embolism are related directly or indirectly to platelet secretions and that V(D)/V(T) is closely allied to TxA(2) levels.

Animals↗
PubMed1982

Depression of myocardial ATPase activity by plasma obtained during positive end-expiratory pressure.

Dogs treated with 15 cm H2O positive end-expiratory pressure (PEEP) invariably show a decrease in cardiac output (CO). Plasma that is obtained from PEEP-treated dogs and applied to an isometrically contracting rat papillary muscle results in a significant depression of the peak developed tension. The present study evaluates the nature of the circulating negative inotropic agent with respect to its action on the coupling of myocardial energy production and contraction. PEEP plasma was found to depress Ca++-ATPase activity (P less than 0.025) when incubated with cardiac subfractions obtained from dog and rat myofibrils, sarcolemma, and sarcoplasmic reticulum. No change in Mg++-ATPase activity was observed. The declines in Ca++-ATPase activity correlate significantly with decreases in left ventricular stroke work, stroke volume, and CO during PEEP treatment. The decrease in Ca++-ATPase with PEEP plasma also correlates with a decrease in developed tension of a rat papillary muscle bathed with PEEP plasma. There were no changes in CO in animals who were simply anesthetized; plasma from these animals did not alter developed tension or ATPase. These observations suggest that PEEP plasma and serum contain a negative inotropic agent(s) that may reduce contractility by Ca++-ATPase inhibition.

Adenosine Triphosphatases↗
PubMed1982

Circulating negative inotropic agent(s) following pulmonary embolism.

Pulmonary emboli may impair myocardial performance, causing declines in cardiac index (CI) and right and left ventricular stroke work (LVSW) because of mechanical events. We postulate that embolism also leads to the generation of a humoral factor(s) that may reduce cardiac contractility. Eleven mongrel dogs were infused with 0.5 gm/kg clot. Decreases in CI and LVSW were observed 1 hour after embolization. The stable metabolites of prostacyclin and thromboxane (Tx) A2--6-keto-PGF1 alpha and TxB2, respectively--increased within 30 minutes (P less than 0.005, P les than 0.001) and then decreased. These changes did not correlate with the declines in CI or LVSW. Plasma from embolized animals used to bathe an isolated rat papillary muscle reduced developed tension (Tpd) (P less than 0.001) and decreased calcium ATPase (Ca++-ATPase) activity of a myofibril preparation (P less than 0.001) obtained from rat cardiac muscle. The correlation between the reduction of TPd and myofibril Ca++-ATPase activity was 0.72 (P less than 0.001). The decline in Ca++-ATPase was also related to the decreases in CI (r = 0.59, P less than 0.001) and LVSW (r = 0.57, P less than 0.001). Five animals pretreated with indomethacin prior to embolization had no decrease in LVSW as compared with controls (P less than 0.001). Postembolism plasma did not depress papillary muscle Tpd and did not lower Ca++-ATPase activity of myofibrils. Anesthesia itself did not alter cardiopulmonary function. These results suggest that pulmonary emboli cause the release of a negative inotropic agent(s) into plasma that affects energy availability in the heart and reduces contractility. The production of this agent(s) is inhibited by indomethacin pretreatment.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Lung metabolism and systemic organ function.

In the past decade a variety of metabolic events have been described which occur in the lungs. These processes, such as the clearance of serotonin and norepinephrine, the inactivation of bradykinin and the activation of angiotensin II, and the synthesis of prostaglandins, may have a direct impact on systemic organ function. Under certain circumstances the lungs produce prostaglandins that may lead to severe hemodynamic instability and death. Pressure breathing with hyperinflation is a potent pulmonary metabolic stimulus. This commonly used therapeutic maneuver has been shown to increase fibrinolytic activity. The application of end-expiratory pressure will further enhance the fibrinolytic state by virtue of the pulmonary secretion of plasminogen activator. Positive end-expiratory pressure (PEEP) will also cause a lowering of the cardiac output, which is related at least in part to lung metabolism. Circulating factors are released during PEEP that have a negative inotropic effect. It is reasonable to view respiratory failure not only as a defect in gas exchange but also as a derangement in lung metabolism.

Angiotensin II↗
PubMed1982

Myocardial protection with prostacyclin after lethal endotoxemia.

A previous study of endotoxemia in dogs demonstrated that exogenous prostacyclin (PGI2), normally a product of vascular endothelium, restored the cardiac index to normal and improved survival. To account for these results, a study was undertaken to test whether PGI2 would alter isolated rat or dog cardiac mitochondrial function following incubation with plasma from endotoxemic animals. A group of five animals served as anesthetized controls. A second group of seven mongrel dogs was given 1.75 mg Escherichia coli endotoxin/kg and was observed for 5 hours without treatment. Anesthesia did not alter cardiopulmonary function; however, 30 minutes after endotoxin administration, the cardiac index decreased from 148 +/- 25 (mean +/- SD) to 111 +/- 12 ml/kg . min (P less than 0.05) and further decreased to 89 +/- 20 ml/kg . min after 4 hours. Dog plasma obtained 2 to 5 hours after endotoxin infusion, incubated with rat or dog myocardial mitochondria, decreased succinate dehydrogenase (SDH) activity (P less than 0.05) and depressed mitochondrial respiration in the presence of the substrate succinate and adenosine diphosphate (ADP) from 180 to 87 Natoms oxygen/mg protein . min (P less than 0.05). There was no change in oxygen consumption when substrate alone was present, nor did plasma alter the amount of ADP phosphorylation as a function of oxygen consumption. A third group of seven animals, 30 minutes after administration of 1.75 mg endotoxin/kg, was treated with 100 ng/kg . min PGI2 for 3 hours. PGI2 infusion in this group prevented the decrease in cardiac index. Plasma obtained during and after PGI2 infusion did not decrease mitochondrial SDH activity, which remained higher than that in controls (P less than 0.001); mitochondrial respiration was also not altered. A correlation was observed between cardiac index and SDH activity (r = 0.58, P less than 0.001) and between cardiac index and mitochondrial respiration (r = 0.61, P less than 0.001). In PGI2-treated dogs cardiac mitochondria were functionally and structurally normal in contrast to the depression and disruption produced by endotoxemia, as observed by enzymatic assay as well as electron microscopy. These results suggest that endotoxemia depresses cardiac mitochondrial respiration, an event related to the decrease in cardiac index. In contrast, cardiac function and mitochondrial respiration are maintained with PGI2 treatment.

Animals↗