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

---

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

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.
...
PMID:Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock. 246 1

The acid phosphatase and cathepsin D activities and cAMP and cGMP levels in isolated perfused rat heart were investigated during various periods of ischaemic myocardial injury and postischaemic reperfusion. The effect of phosphodiesterase inhibitor--caffeine was also studied. Free acid hydrolases activities and cyclic nucleotide content were increased under 40 and 60 min ischemia and 20 min postischaemic reperfusion. Addition of 50 microM caffeine to perfusion solution after 30 min of ischaemia resulted in increase of cAMP level, cAMP/cGMP ratio, lysosomal bound activities of acid hydrolase and decrease of free acid hydrolase activities. The obtained results suggested that defect in cAMP synthesis might be present in lysosomal membranes labilization in cardiomyocytes injured during ischaemic conditions. Addition of such agents, as caffeine, which increased heart cAMP level, may be effective in lysosomal membranes stabilization under reversible heart ischaemia and reperfusion.
...
PMID:[Acid hydrolase activity and cyclic nucleotide contents in the rat heart during myocardial ischemia and postischemic reperfusion]. 255 45

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.
...
PMID:Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock. 306 71

The role of platelet activating factor (PAF) in acute myocardial ischemia (MI), produced by the ligation of the left main coronary artery, was studied in anesthetized rats. A significant loss of cardiac amino-nitrogen concentration and cathepsin D activity was observed 6 hr after permanent occlusion MI or 10 min of MI followed by 6 hr of reperfusion in rats. A novel, potent, PAF antagonist, CV-6209 (160 nmol/kg or 1.6 mumol/kg) injected after the ligation, significantly retarded the loss of amino-nitrogen and cathepsin D activity in a dose-related manner. In another group of rats, CV-6209 (1.6 mumol/kg) significantly blocked the hypotension induced by repetitive injections of PAF (570 pmol/kg) with an apparent half-life of approximately 180 min. In isolated rat hearts perfused with Krebs-Henseleit solution, PAF (25 nmol/l) significantly increased coronary perfusion pressure by 15 +/- 2 mmHg and induced an increase in cardiac permeability using fluorescein isothiocyanate bovine albumin as a marker. Furthermore, the increase in cardiac permeability induced in isolated perfused rat hearts undergoing 15 min global ischemia followed by reperfusion was significantly attenuated by CV-6209 (250 nmol/l). These data indicate that PAF is an important mediator of ischemic damage in rat MI. Moreover, the extension of ischemic damage may be enhanced by the increase in cardiac permeability induced by PAF.
...
PMID:Role of platelet activating factor in propagation of cardiac damage during myocardial ischemia. 325 36

We studied the effects of human superoxide dismutase (h-SOD) in splanchnic artery occlusion (SAO) shock. Pentobarbital anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state usually resulting in a fatal outcome within 20 min after the release of the occlusion. h-SOD (10 mg/kg) was infused intravenously starting at reperfusion and lasting for 10 min. SAO shock rats treated with h-SOD maintained postreperfusion MABP at significantly higher values compared to rats receiving the vehicle (final MABP 84 +/- 6 vs 46 +/- 1 mm Hg, P less than 0.01, respectively). Treatment with h-SOD attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.01 from vehicle) as well as the activity of the lysosomal protease cathepsin D (P less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in h-SOD-treated rats than in SAO rats receiving only the vehicle (27 +/- 1 vs 64 +/- 3 U/ml, P less than 0.01). SAO shock rats treated with h-SOD also exhibited a significantly higher survival rate than the SAO shock +/- vehicle group (88% vs 11%, P less than 0.01, respectively). These results support the role of oxygen-derived radicals in the pathophysiology of SAO shock, and indicate that h-SOD effectively ameliorates the deleterious effects of oxygen radicals in this severe model of ischemia and reperfusion.
...
PMID:Anti-shock effects of human superoxide dismutase in splanchnic artery occlusion (SAO) shock. 339 43

Effect of diltiazem on subcellular distribution of lysosomal enzymes, high-energy phosphate metabolism and mechanical function in the ischemic heart was studied. Ischemia was induced by lowering the afterload pressure of the perfused working rat heart. The activities of cathepsin D, beta,N-acetylglucosaminidase and acid phosphatase were determined in the nonsedimentable and sedimentable fractions after centrifugation of the tissue extract to assess the subcellular distribution of lysosomal enzymes. After ischemia, decreases in the mechanical function and the tissue level of high-energy phosphates were observed. In addition, ischemia caused subcellular redistribution of lysosomal enzymes from the lysosomes to the cytoplasm. Reperfusion of the ischemic heart did not restore the mechanical function and the level of high-energy phosphates completely. Diltiazem (2.21 X 10(-6), 1.11 X 10(-5) and 2.21 X 10(-5) M) was provided for the heart 5 min before the onset of ischemia. Diltiazem preserved high-energy phosphates in the ischemic heart, and inhibited the subcellular redistribution of lysosomal enzymes being caused by ischemia, depending on its concentration. Reperfusion after ischemia with diltiazem recovered the mechanical function that had been decreased by ischemia. These results may indicate that diltiazem can protect the myocardium against ischemic damage.
...
PMID:Inhibition of ischemia-induced subcellular redistribution of lysosomal enzymes in the perfused rat heart by the calcium entry blocker, diltiazem. 365 10

The potential therapeutic value of the chemically stable carbacyclin analog ZK 36 374 was studied in acute myocardial ischemia (MI). In anesthetized cats, the left anterior descending coronary artery was ligated and 30 min later an i.v. infusion of ZK 36 374 (0.18 microgram/kg X min) on vehicle was initiated and continued for 4.5 hr. ZK 36 374 reduced the ST-segment elevation at 2 to 5 hr (P less than .01) when compared to vehicle-treated MI cats. ZK 36 374 completely prevented the loss of CK specific activities and the decrease in percentage of bound cathepsin D in the infarcted area of the myocardium (P less than .01), but had no influences on any of these parameters in shamoperated animals. In addition, ZK 36 374 reversed the MI-induced decrease in circulating platelet count toward the preinfarction levels, probably by dispersion of circulating platelet aggregates. ZK 36 374 prevented the ischemia-induced loss of myocardial catecholamines from adrenergic nerve terminals. ZK 36 374, at 0.18 microgram/kg X min, exerted a maximum antiplatelet effect, whereas a significant decrease in arterial blood pressure was seen at 1.79 microgram/kg X min (-30-40%). This indicates a considerable dissociation between antiplatelet and blood pressure-lowering activities of ZK 36 374 in this model. The data demonstrate a significant protective effect of ZK 36 374 in acute MI that might be associated with its platelet-stabilizing, antiadrenergic and myocardial cytoprotective activities.
...
PMID:Beneficial effects of a new carbacyclin derivative, ZK 36 374, in acute myocardial ischemia. 616 23

We studied the potential therapeutic value of the chemically stable carbacyclin analogue ZK 36 375 during acute myocardial ischemia and compared the cardiovascular and anti- and disaggregatory effects of the compound in vitro and ex vivo. In anesthetized cats the left anterior descending coronary artery was ligated, and 30 min later an intravenous infusion of ZK 36 375 (3.6 micrograms/kg X min) or vehicle was initiated and continued for 4.5 h. ZK 36 375 reduced the ST-segment elevation at 2-5 h (p less than 0.01) when compared to vehicle-treated cats. ZK 36 375 significantly inhibited both the loss of creatine phosphokinase--specific activity and the decrease in the percentage of bound cathepsin D in the infarcted area of the myocardium (p less than 0.05). ZK 36 375 did not reverse ischemia-induced formation of platelet aggregates in vivo and was found ex vivo to be two to three orders of magnitude less active in preventing platelet aggregation, redispersing platelet aggregates, and relaxing bovine coronary arteries than prostacyclin (PGI2) or its (5E) stereoisomer ZK 36 374. It is concluded that ZK 36 375 has a significant cardioprotective activity in acute myocardial ischemia of the cat that can be dissociated from antiplatelet effects in vivo.
...
PMID:Dissociation of antiplatelet effects from myocardial cytoprotective activity during acute myocardial ischemia in cats by a new carbacyclin derivative (ZK 36 375). 618 28

The effect of protizinic acid (PRT), a non-steroidal antiinflammatory drug, on the in vivo leukokinin (LK) generation system using feline acute ischemia model, in vitro LK generation system and the LK-induced contraction of the isolated smooth muscle was investigated. When 3 mg/kg PRT was injected twice intravenously to cats with acute cardiac ischemia, increased blood acid protease activity was inhibited and significant inhibitory action on the decrease of leukokininogen, the precursor of LK, was observed. Simultaneously, ST-segment elevation on the electrocardiogram tended to be suppressed and the lowered mean aortic blood pressure was significantly restored. On the LK generation induced by rabbit kininogen and acid protease derived from mouse L-1210 leukemic cells or rabbit polymorphonuclear leukocytes, PRT showed a dose-dependent inhibition while indomethacin (IM) and ibuprofen (IB) at a concentration of 3 X 10(-4) M showed no effect. However, potencies of the inhibitory actions of PRT, IM and IB on the LK generation induced by bovine spleen cathepsin D were almost the same at a concentration of 3 X 10(-4) M. Furthermore, PRT as well as IM showed antagonistic action on the isolated rat uterine contraction induced by LK. These results suggest that PRT not only inhibits the in vitro and in vivo generation of LK but also antagonizes to it on the receptor site of LK.
...
PMID:Effects of protizinic acid on leukokinin generation and its physiological action. 647 67

Intracellular accumulation of calcium is thought to play an integral role in the progression of ischemic injury and cell death. We infused the calcium entry blocker, nitrendipine (1.5 micrograms/kg per min), into cats in order to investigate the importance of extracellular Ca2+ influx during hemorrhagic shock. Nitrendipine proved to be a potent hypotensive agent in sham shock cats when infused over a 4 h period (156 +/- 9 to 90 +/- 5 mm Hg) (P less than 0.01). However, in hemorrhaged animals, nitrendipine treatment maintained the post-reinfusion MABP at a significantly higher (P less than 0.01) value than untreated controls (79 +/- 5 vs. 51 +/- 4 mm Hg, respectively). Superior mesenteric artery flow (SMAF) for hemorrhaged animals treated with nitrendipine was significantly higher (9.8 +/- 1.4 ml/min per kg) (P less than 0.01) than that for untreated cats (4.2 +/- 0.4 ml/min per kg), at 2 h post reinfusion. There was no significant increase in SMAF during oligemia in the nitrendipine-treated animals. Nitrendipine was also found to significantly retard the appearance of cathepsin D in the plasma of hemorrhaged cats as well as reduce plasma proteolysis to values not significantly different from sham shock animals. Furthermore, myocardial depressant factor (MDF) activity in the plasma of nitrendipine-treated shock cats was not significantly different from sham shock animals, while the plasma MDF activity for shock cats receiving vehicle increased 3-fold (P less than 0.001). The beneficial effects for nitrendipine in hemorrhagic shock are likely due to both its vasodilator function and its ability to reduce intracellular Ca2+ accumulation during ischemia, thereby reducing disruption of cell membrane systems.
...
PMID:Salutary effects of nitrendipine, a new calcium entry blocker, in hemorrhagic shock. 669 10


<< Previous 1 2 3 4 5 6 Next >>

---