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Biomedical subjects

D Shepro

Publications and source records attributed to D Shepro.

At least 127 records · Page 7Linked to original sources
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↗
PubMed1982

Prostaglandin mediation of unstable hemodynamics during lung perfusion.

Positive end-expiratory pressure (PEEP) leads to a fall in both mean arterial blood pressure (MAP) and cardiac output (CO). This study tests the hypothesis that humoral factors, particularly prostanoids, are important mediators of these events. A support dog was used for ex vivo perfusion of an isolated left lung lobe (LLL) at a fixed flow. In group I (n = 10) an isolated, isovolumetrically contracting dog heart was placed in circuit between the support dog and LLL. Indomethacin (5 mg/kg) was used to pretreat the support dogs and LLL donors of group II (n = 9); support dogs of group III (n = 5); and LLL donors of group IV (n = 4). This cyclooxygenase inhibitor was not used for groups I or V (n = 14). The last two groups were similar except that a heart was not included in the circuit of group V. In group V lobe perfusion during simple inspiratory mechanical ventilation led to decreases in support dog MAP from 141 +/- 3 to 118 +/- 15 mm Hg (P less than 0.01) and CO from 4.0 +/- 0.9 to 2.8 +/- 0.8 L/min (P less than 0.01). Application of PEEP further reduced MAP and CO (P less than 0.01). In the perfused isolated hearts of group I, Starling curves were shifted downward during PEEP at five of six left ventricular balloon volumes tested. In groups II and III MAP and CO were unchanged with mechanical ventilation or PEEP and were higher than groups I or V (P less than 0.05). Radioimmunoassay of the stable degradation products of prostacyclin and thromboxane (Tx) A2 demonstrated low concentrations of these prostanoids in support dogs of group III as compared with group V (P less than 0.05). Blocking the LLL donor dog (group IV) produced hemodynamic results and prostanoid concentrations intermediate between groups I and V. The results show that mechanical ventilation and PEEP can cause a circulating agent(s) to be released that results in a decline in MAP and CO. This is prevented with indomethacin.

Animals↗
PubMed1982

Inhibition of permeability edema with imidazole.

Acute respiratory failure (ARF) with permeability edema and increased physiologic shunting (QS/QT) occurs after complement activation. Leukocytes aggregate, become entrapped in the lungs, and release vasotoxic agents. This study of 31 sheep infused with zymosan-activated plasma (ZAP) tests the hypothesis tha thromboxane (Tx) A2, a proaggregator and bronchoconstrictor, is an intermediate in complement-induced ARF. Group I animals (n = 11) were untreated controls. An imidazole infusion, 25 mg/kg . hr was started 1 hour before a ZAP infusion in group II (n = 10). Prostacyclin (PGi2) was given to group III sheep (n = 10) in a dose of 100 ng/kg . min 3- minutes before the ZAP infusion. Within 5 minutes ZAP led to a decrease in the leukocyte count to 2900/mm3 (P less than 0.001), a rise in plasma TxB2 concentration (the stable degradation product of TxA2) from 14 to 246 pg/ml (P less than 0.001), a rise in lymph TxB2 from 24 to 609 pg/ml (P less than 0.001), a rise in QS/QT from 13% to 31% (P less than 0.01), and a rise in mean pulmonary arterial pressure from 17 to 43 mm Hg. Both imidazole and PGI2 prevented the increase in TxB2 and QS/QT and limited the increases in MPAP to 25 and 30 mm Hg, respectively--values below those of untreated controls (P less than 0.05). Imidazole, but not PGI2, prevented the increase in lymph flow, which in controls increased from 2.8 +/- 8.5 ml/30 min (P less than 0.01), and lymph albumin clearance, which increased from 2.2 to 6.0 ml/30 min (P less than 0.01). The high lymph concentrations of TxA2 suggest a pulmonary site of production, and its bronchoconstrictive action may account for the increase in QS/QT. However, TxA2 is only partially responsible for the pulmonary hypertension and is apparently unrelated to changes in permeability. The protective action of infused imidazole against increased permeability appears to be independent of its inhibition of Tx synthetase.

Animals↗
PubMed1981

Maintenance of cardiodynamics with aspirin during abdominal aortic aneurysmectomy (AAA).

The importance of prostacyclin (PGI2) and thromboxane (Tx) medication of depressed cardiac performance during abdominal aortic aneurysm operative surgery was studied by contrasting the effects of 650 mg aspirin administered 12 hours before operation to that of a placebo. In 11 patients who received a placebo, the stable metabolite of PGI2, 6-keto-PGF1 alpha rose from 0.050 +/- 0.032 eta grams/ml to 0.419 +/- 0.257 eta grams/ml (p less than 0.01) 30 minutes after the skin incision. The stable metabolite of TxA2, TxB2 did not increase until the aorta was clamped when TxB2 rose from 0.089 +/- 0.054 eta grams/ml to 0.193 +/- 0.138 eta grams/ml (p less than 0.05); this was prior to blood transfusion. During aortic clamping cardiac output decreased 27% (p less than 0.001). In vitro testing of patient plasma showed: 1) depressed developed tension (Tpd) of a rat papillary muscle by 16% (p less than 0.05); 3) reduction of Ca++-ATPase and Mg++-ATPase activity in a rat myocardial subfraction of sarcoplasmic reticulum (p less than 0.05); 3) reduction of Ca++-ATPase in a rat myocardial subfraction of myofibrils (p less than 0.01). Aspirin administered to 11 patients produced no measurable changes in blood loss or fluid requirements. Aspirin lowered preoperative 6-keto-PGF1 alpha and TxB2 levels (p less than 0.01) and prevented an increase of either agent during operation. The low Tx levels were associated with a stable cardiac output during aortic clamping. Further, plasma obtained from aspirin-treated patients did not depress papillary muscle contractility nor decrease ATPase activity of either myocardial subfraction. The observation that TxB2 when added to a papillary muscle or myocardial subfractions, did not decrease Tpd or ATPase suggests that TxB2 plays an indirect role in altering cardiac muscle activity. The results indicate that Txs modulate cardiac depression, which can be prevented with 650 mg aspirin before operation.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Inhibition of thrombocytopenic petechiae by exogenous serotonin administration.

The effect of serotonin on vascular fragility, visible as petechiae, was examined in antiplatelet serum-induced thrombocytopenic hamsters. Serotonin was administered intravenously or intraperitoneally, and following a single injection of 0.5 mg/100 g body weight, a temporary inhibition of petechial formation for approximately 1 h was observed. Repeated serotonin injections maintained animals free of petechiae for the 4-hour period of administration. Plasma levels of serotonin and the effect of serotonin on cutaneous perfusion were not significant factors in the observed inhibition of petechiae. The data suggest that in normal animals platelet serotonin may contribute more to maintaining microvascular structural integrity than platelet adhesion.

Animals↗
PubMed1981

Prostacyclin reversal of lethal endotoxemia in dogs.

Severe endotoxemia, a condition where microembolization and intravascular coagulation are thought to play important roles, was treated experimentally with prostacyclin (PGI(2)). In a study of 24 dogs, 8 control animals injected with 1.75 mg.kg(-1) of endotoxin died within 24 h. Six animals given intravenous aspirin 100 mg/kg, 30 min after endotoxin died. 9 of 10 dogs infused with 100 ng PGI(2).kg(-1).min(-1) for 3 h, given 30 min after the injection of endotoxin survived 24 h (P < 0.025). Injection of endotoxin resulted in a: (a) maximal 62% fall in mean arterial pressure (P < 0.001); (b) transient doubling of mean pulmonary arterial pressure (P < 0.001); (c) initial 70% drop in cardiac index (P < 0.001); (d) decline in blood platelets from 213,700 to 13,700/mm(3) (P < 0.001), and leukocytes from 7,719 to < 750/mm(3) (P < 0.001); (e) depressed urine output (P < 0.001); (f) 34% decrease in blood fibrinogen (P < 0.01) and an increase in fibrin degradation products > 50 mug/ml (P < 0.001); (g) fivefold increase in circulating cathepsin D titer (P < 0.005) and (h) increase in blood norepinephrine (P < 0.005), dopamine (P < 0.005), and epinephrine (P < 0.001). Aspirin treatment led to an increase in mean arterial pressure (P < 0.001) and mean pulmonary arterial pressure (P < 0.005), but cardiac index, urine flow, platelets, leukocytes, fibrin degradation products, and cathepsin D levels remained similar to untreated controls. After infusion of PGI(2) there was a: (a) prompt increase of cardiac index to base-line levels; (b) late increase in mean arterial pressure (P < 0.005) after the discontinuation of PGI(2) treatment (c) restoration of urine output; (d) increase in circulating platelets to levels still below base line but above untreated control animals (P < 0.05); (e) no effect on circulating leukocyte levels; (f) fall in fibrin degradation products to 11.2 mug/ml (P < 0.05); (g) decline in cathepsin D levels to values 60% lower than the untreated controls (P < 0.025); and (h) reduction in plasma norepinephrine levels to base line at 4 h (P < 0.005). Although the mode of PGI(2) action is not clear, it is effective in the treatment of experimental endotoxemia.

Animals↗
PubMed1981

Serotonin uptake by isolated adipose capillary endothelium.

The uptake of serotinin (5-hydroxytryptamine, 5-HT) by endothelial cells was studied in freshly isolated capillary and other microvessel (< 50 micrometers, inner diameter) endothelium obtained from rat epididymal fat pads. Endothelial cells incubated with [3H]-5-HT removed 60 pmol of [3H]-5-HT per mg of protein at 1 hr, an apparent Km of 3 X 10(-7) M and a Vmax of 20 pmol/mg of protein, measured at 15 min, were obtained. Uptake of 5-HT (10(-6) of M) was inhibited by ouabain, selected metabolic inhibitors (iodoacetate, 2--4 dinitrophenol and sodium azide), 4 degrees C, tryptamine (10(-5) M and the 5-HT antagonists, fluoxetine and imipramine (10(-5) M and 10(-4) M, respectively). At concentrations of 5-HT greater than Km value, uptake appears to be principally by nonfacilitative diffusion rather than by carrier-mediated transport.

Adipose Tissue↗