Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased oxygen delivery and cellular hypoxia are important factors in the pathophysiology of hemorrhagic shock. We studied the effects of 100% oxygen at 1 and 3 ATA (atmosphere absolute) in a severe model of hemorrhagic shock induced by bleeding 50% of the total blood volume in rats. Post-treatment with 100% oxygen at 1 and 3 ATA maintained mean arterial blood pressure (MABP) in hemorrhaged rats at significantly higher values compared to untreated controls (P less than 0.01 at 1 and 3 ATA). Treatment with oxygen attenuated the increase in plasma activities of the lysosomal hydrolase cathepsin D (P less than 0.05 at 1 ATA; P less than 0.01 at 3 ATA). Oxygen at 3 ATA also attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.05). Furthermore, hyperoxia prevented the final increase in hematocrit (P less than 0.05 at 1 ATA; P less than 0.01 at 3 ATA). Hemorrhaged rats treated with oxygen also exhibited a significantly longer survival time (P less than 0.01 at both doses), and higher survival rates (50% at 1 ATA and 100% at 3 ATA; P less than 0.05 and P less than 0.01, respectively) than untreated shock rats. No significant effect on any of the above mentioned variables was found in hemorrhaged rats treated with 7% oxygen at 3 ATA (oxygen pressure 0.2 ATA), indicating that all salutary effects can be attributed to oxygen and not to the increased ambient pressure per se. Our results indicate that 100% oxygen in normobaric and hyperbaric conditions exerts important beneficial effects in hemorrhagic shock and may be a useful drug for the treatment of this condition.
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PMID:Oxygen therapy in hemorrhagic shock. 204 10

Prostacyclin (PGI2) and taprostene (CG-4203) were studied in a highly lethal model of splanchnic artery occlusion (SAO) shock in pentobarbital anesthetized rats. Total occlusion of the superior mesenteric and celiac arteries for 40 min resulted in a severe shock state often resulting in a fatal outcome within 2 h following release of the occlusion. PGI2 or taprostene was infused at a rate of 100 ng/kg/min commencing at occlusion of the celiac and superior mesenteric arteries. Taprostene significantly improved survival time and taprostene treated animals maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving taprostene vehicle (final MABP 96 +/- 3 vs 45 +/- 3.5 mmHg, p less than 0.001, respectively). In addition, taprostene significantly (p less than 0.05) attenuated the rise in hematocrit in SAO shock and the activity of plasma cathepsin D (p less than 0.005 from SAO vehicle). Taprostene also tended to decrease the accumulation of free amino-nitrogen compounds, but not significantly. In contrast, PGI2 neither improved survival time and the maintenance of post-reperfusion MABP, nor attenuated the rise in hematocrit, the plasma accumulation of free amino-nitrogen compounds, or plasma cathepsin D activity. These findings suggest that taprostene may possess greater cytoprotective properties than PGI2.
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PMID:Effects of prostacyclin and taprostene in splanchnic artery occlusion shock. 205 56

We studied the effects of BN 50739, a novel PAF antagonist, in a rat model of traumatic shock. Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma cathepsin D (4.2-fold), free amino-nitrogen (2.8-fold) and myocardial depressant factor (4.7-fold) activities and a survival time of 1.62 +/- 0.16 h. Treatment with BN 50739 (10 mg/kg, i.v.) 10 min post-trauma prolonged survival time to 3.14 +/- 0.44 h (p less than 0.01) and attenuated the accumulations of cathepsin D (5.8 vs. 12.5 U/ml, p less than 0.01), free amino-nitrogen (4.6 vs. 12.5 U/ml, p less than 0.001) and myocardial depressant factor (19.4 vs. 65.1 U/ml, p less than 0.001). Moreover, in washed rabbit platelets, BN 50739 inhibited PAF (1.85 nM)-induced aggregation (IC50: 50 nM) without affecting ADP (5 microM)-induced aggregation. In anesthetized rats, BN 50739 (10 mg/kg, i.v.) attenuated PAF (10-30 ng/kg, i.v.)-induced hypotension for longer than 5 h, without influencing acetylcholine (10 micrograms/kg, i.v.)-induced hypotension. These findings indicate that BN 50739 is a specific PAF receptor antagonist with a long duration of action in vivo. The beneficial effects of PAF antagonism on traumatic shock are significant in the present study, and are consistent with the concept that PAF is involved in the pathogenesis of traumatic shock.
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PMID:Beneficial actions of BN 50739, a new PAF receptor antagonist, in murine traumatic shock. 216 4

We studied the effects of nitric oxide (NO) solution and acidified sodium nitrite (NaNO2), which produces NO, in splanchnic artery occlusion (SAO) shock in cats. NO is thought to be endothelium-derived relaxing factor (EDRF), a labile substance having several potentially valuable biological effects. Anesthetized cats subjected to total occlusion of the celiac, superior mesenteric, and inferior mesenteric arteries for 120 min, followed by reperfusion, usually died approximately 60 min after reperfusion. NO infusion significantly improved survival time in SAO-shock cats compared with those receiving vehicle (P less than 0.005). Administration of NO also attenuated the increase in plasma activities of the lysosomal hydrolase cathepsin D (P less than 0.05), total amino-nitrogen (P less than 0.001), and of the cardiotoxic peptide, myocardial depressant factor (MDF) (P less than 0.001). SAO-shock cats treated with NaNO2 at pH 2.0 also exhibited lower plasma cathepsin D (P less than 0.001), amino-nitrogen (P less than 0.05), and MDF activities (P less than 0.01), and survival time was also significantly improved (P less than 0.02). The same dose of NaNO2 infused at pH 7.4 failed to exert any significant protective effect. These results indicate that NO exerts beneficial effects in SAO shock in cats and suggest that exogenously administered NO may be a potentially useful therapeutic agent in splanchnic ischemic shock, probably via a cytoprotective rather than a vasodilator effect.
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PMID:Beneficial effects of two forms of NO administration in feline splanchnic artery occlusion shock. 230 94

Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, increases in plasma cathepsin D (9.6-fold), free amino-nitrogen (4.0-fold), and myocardial depressant factor (5.2-fold) activities, and a survival time of 1.90 +/- 0.23 h. Following the induction of traumatic shock, plasma thromboxane B2 (TxB2) concentrations significantly increased from 3.12 +/- 0.68 to 6.78 +/- 0.27 pmol/ml. Treatment with the thromboxane receptor antagonist KW-3635 10 min post-trauma (2 mg/kg + 2 mg/kg per h, i.v.) prolonged survival time to 3.30 +/- 0.39 h (P less than 0.01) and attenuated the accumulation of cathepsin D compared to untreated trauma rats (6.6 +/- 1.1 and 13.6 +/- 1.3 U/ml, P less than 0.01), free amino-nitrogen (6.4 +/- 1.1 and 14.3 +/- 1.2 U/ml, P less than 0.01), and myocardial depressant factor (45 +/- 5 and 94 +/- 13 U/ml, P less than 0.02). However, KW-3635 did not prevent the increase in plasma TxB2 concentration, suggesting a lack of thromboxane synthetase inhibitory activity of this drug. The beneficial effects of thromboxane A2 (TxA2) antagonism in the present study are highly significant, and consistent with the concept that TxA2 is involved in the pathogenesis of traumatic shock.
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PMID:Protective effects of KW-3635, a novel thromboxane A2 antagonist, in murine traumatic shock. 240 10

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane-stabilizing agent that has been shown to exert beneficial effects in a variety of models of ischemia and circulatory shock. However, the use of PGI2 is limited by its instability and rapid biodegradation. We studied the effects of a novel, stable prostacyclin analog, CG-4203, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CG-4203 maintained postreinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (final MABP 101 +/- 3 vs. 75 +/- 5 mm Hg, p less than 0.01). CG-4203 was also found to attenuate the increase in plasma cathepsin D activity (p less than 0.01), as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in CG-4203-treated hemorrhaged rats than in rats receiving the vehicle (25 +/- 2 vs. 54 +/- 7 U/ml, p less than 0.01). In addition, CG-4203 exerted an anti-proteolytic action in pancreatic homogenates and inhibited platelet aggregation in platelet-rich plasma. However, CG-4203, at concentrations expected during treatment of shock, failed to have an immediate or delayed vasodilator effect in rat aortic rings, and thus vasodilation is not an important aspect of the antishock effects of CG-4203. Our results suggest that inhibition of platelet aggregation, as well as the antiproteolytic and membrane-stabilizing actions, could mediate the beneficial effects of CG-4203 in hemorrhagic shock.
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PMID:Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock. 246 1

The effects of R-68070 were studied in a well-characterized model of drum-induced traumatic shock in rats. R-68070 is a combination thromboxane A2 (TxA2) synthetase inhibitor-TxA2 receptor antagonist. Pentobarbital-anesthetized (50 mg/kg) rats subjected to Noble-Collip drum trauma developed a lethal circulatory shock state characterized by a marked decrease in mean arterial blood pressure (MABP) to about 75 mmHg, resulting in a survival time of 1.58 +/- 0.18 h. This compares with MABP of 120 +/- 4 mmHg 5 h after anesthetization in rats subjected to a sham traumatic shock protocol. Administration of R-68070 (1.5 mg/kg) significantly attenuated the plasma accumulation of the lysosomal protease, cathepsin D (p less than 0.05), as well as free amino-nitrogen concentration (p less than 0.05) and myocardial depressant factor activity (p less than 0.02). Additionally, R-68070 significantly prolonged survival time to 2.85 +/- 0.48 h (p less than 0.015) compared with traumatized rats given only the vehicle. These results suggest that TxA2 may be an important mediator in traumatic shock, and that R-68070 may prove to be a useful therapeutic agent in this situation if given early in the course of the shock state.
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PMID:Protective effects of a combination thromboxane synthesis inhibitor-receptor antagonist, R-68070, during murine traumatic shock. 253 78

Diets enriched with omega-3 unsaturated fatty acids are associated with decreased hypercholesterolemia and decreased risk of ischemic and atherosclerotic diseases. We studied the acute intravascular effects of some of these unsaturated fatty acids (i.e., eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) along with omega-6 unsaturated fatty acids, (i.e., linoleic and linolenic acid) in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes followed by reperfusion usually resulted in a fatal outcome 90-120 minutes after releasing the clamps. SAO shock rats treated with the omega-3 unsaturated fatty acid, EPA, exhibited an improved survival time and rate (p less than 0.05 from vehicle) compared to those receiving only vehicle (i.e., 50% ethanol). EPA and DHA treated SAO rats also exhibited lower plasma activities of the lysosomal protease, cathepsin D, free amino-nitrogen compounds, and the cardiotoxic peptide, myocardial depressant factor. These results indicate that omega-3 unsaturated fatty acids, especially EPA, have some acute beneficial effects in SAO shock in rats.
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PMID:Acute effects of unsaturated fatty acids in splanchnic artery occlusion shock. 255 Sep 71

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using WEB 2086, a specific antagonist of PAF. WEB 2086 (0.5 mg/kg) significantly reversed the decrease in mean arterial blood pressure (MABP) induced by PAF (0.3 micrograms/kg) in anesthetized rats. Anesthetized rats were subjected to Noble-Collip drum trauma. Traumatized rats treated with WEB 2086 (0.5 mg/kg bolus followed by infusion at 0.5 mg/kg/hr) maintained a higher MABP than those receiving only the vehicle (0.9% NaCl). Improvement in MABP paralleled a significant increase in overall survival time (p less than 0.01) in rats receiving WEB 2086 (0.5 mg/kg). WEB 2086 also significantly attenuated the plasma accumulation of the lysosomal hydrolase, cathepsin D and of free amino-nitrogen compounds, compared to shocked rats receiving only the vehicle. Furthermore, the production of the cardiotoxic peptide, myocardial depressant factor (MDF) was also blunted by WEB 2086. These results suggest that PAF may be an important mediator in the pathogenesis of traumatic shock in rats. Furthermore, PAF receptor antagonists may be useful as therapeutic agents when given early in the course of ischemic and shock states.
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PMID:Protective effects of a specific platelet activating factor (PAF) antagonist, WEB 2086, in traumatic shock. 271 50

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI2 release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 +/- 3 vs. 69 +/- 7 mm Hg, p less than 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p less than 0.02), and the plasma accumulation of free amino-nitrogen groups (p less than 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 +/- 4 vs. 61 +/- 8 U/ml, p less than 0.01). Moreover, plasma i6-keto-PGF1 alpha concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p less than 0.01 from vehicle), and augmented the release of i6-keto-PGF1 alpha, the stable metabolite of PGI2, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI2 release coupled with direct, or PGI2 mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.
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PMID:Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock. 306 71


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