Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate the effect of the nonglucocorticoid steroid U74006F in the pathogenesis of a murine traumatic shock model. Pentobarbital-anesthetized (40 mg/kg) rats were subjected to Noble-Collip drum trauma and developed a lethal shock state characterized by a decreased mean arterial blood pressure (MABP) to 67 +/- 2 mm Hg and survival time (1.5 +/- 0.2 h). In contrast, sham trauma rats exhibited a MABP of 122 +/- 4 mm Hg at 5 h postanesthesia. Administration of U74006F at doses of 22.5 mg/kg at 15 to 20 min following trauma significantly maintained a higher MABP and prolonged survival compared to those trauma rats receiving only the vehicle for U74006F (0.002 N HCl). U74006F at 15 and 22.5 mg/kg prolonged survival time to 2.6 +/- 0.3 (p less than 0.05) and 3.1 +/- 0.6 h (p less than 0.02), respectively. U74006F also significantly attenuated the plasma accumulation of cathepsin D (p less than 0.02 to p less than 0.01) and free amino-nitrogen compounds (p less than 0.01) compared to the rats receiving only vehicle. Additionally, U74006F at 15 and 22.5 mg/kg blunted the production of the cardiotoxic peptide, myocardial depressant factor (MDF) (p less than 0.01 to p less than 0.001). Moreover, U74006F is a steroid without significant glucocorticoid or mineralocorticoid activity. These results suggest that U74006F may be useful as a therapeutic agent in traumatic shock.
J Cardiovasc Pharmacol 1990 Feb
PMID:Protective effects of a novel nonglucocorticoid 21-aminosteroid (U74006F) during traumatic shock in rats. 168 14

We studied the effects of transforming growth factor-beta (TGF-beta), tissue plasminogen activator (tPA), and their combination in cats subjected to splanchnic artery occlusion (SAO) with reperfusion. Untreated anesthetized cats subjected to total occlusion of the celiac, superior, and inferior mesenteric arteries for 120 min, followed by reperfusion, uniformly died within 120 min after reperfusion. The mean survival time was 75 +/- 8 min. Plasma amino-nitrogen concentrations and cathepsin D and myocardial depressant factor (MDF) activities were markedly elevated following reperfusion. Superior mesenteric artery (SMA) rings isolated from cats subjected to SAO with reperfusion exhibited a significant loss of vasorelaxation to the endothelium-dependent dilators acetylcholine and A-23187. Administration of tPA (1 mg/kg) intravenously just before reperfusion did not prolong survival time (81 +/- 10 min) nor did it influence any biochemical or cardiovascular responses following reperfusion or ameliorate the depressed endothelium-dependent relaxation of SMA rings. In contrast, TGF-beta (50 micrograms/cat) ameliorated the SAO postreperfusion state in terms of survival rate and plasma MDF activity, and protected against depressed endothelium-dependent relaxation of SMA rings. TGF-beta alone slightly increased the survival time to 102 +/- 11 min. However, combined treatment with tPA (1 mg/kg) and TGF-beta (50 micrograms/cat) preserved endothelium-dependent relaxation and prevented increases in plasma amino-nitrogen more prominently than TGF-beta given alone and significantly increased the survival time to 118 +/- 3 min (p less than 0.01). These results indicate that TGF-beta exerts beneficial effects in SAO followed by reperfusion in cats, and tPA has an augmenting action on some of the beneficial effects of TGF-beta. These findings suggest that TGF-beta alone or in combination with tPA may be potentially useful therapeutic regimens in splanchnic ischemia shock by preserving splanchnic parenchymal and endothelial cells.
J Cardiovasc Pharmacol 1991 Jul
PMID:Beneficial effects of transforming growth factor-beta and tissue plasminogen activator in splanchnic artery occlusion and reperfusion in cats. 171 97

Cleavage sites of porcine big endothelin-1 (big ET-1, 1-39) by cathepsin D were examined and compared with those by other aspartic proteinases including pepsin. Cathepsin D cleaved not only the Trp21-Val22 bond, but also the Asp18-Ile19 bond of big ET-1[1-39]. The mature ET-1[1-21], generated by the cleavage between Trp21 and Val22, was subsequently degraded by removal of the C-terminal tripeptide (Ile19-Ile20-Trp21). On the other hand, pepsin cleaved the Trp21-Val22 bond of big ET-1[1-39] to produce ET-1[1-21], but did not degrade the generated ET-1[1-21]. These results indicate that aspartic proteinases such as cathepsin D and pepsin are capable of converting big ET-1[1-39] to ET-1[1-21], whereas the former proteinase is by no means specific for the Trp21-Val22 bond of big ET-1[1-39].
J Cardiovasc Pharmacol 1991
PMID:Mode of cleavage of porcine big endothelin-1 by aspartic proteinases. 172 36

We examined the effects of tiapamil, a Ca2+ antagonist, on infarct size, lymphatic enzyme release, and arrhythmias in reperfused, ischemic canine hearts. Three-hour reperfusion of the left anterior descending coronary artery, which had been ligated for 3 h, significantly increased cardiac lymphatic release of lactate dehydrogenase (LDH), cathepsin D and creatine phosphokinase (CPK), and the incidence of ventricular premature contractions (VPCs), the increases being markedly higher than those in ligation period. Tiapamil, at the i.v. dose of 3 mg/kg/h for 6 h during the ligation and reperfusion periods markedly reduced these increases in lymphatic levels of LDH and cathepsin D and in VPCs, and significantly decreased infarct size. Tiapamil treatment only during the ligation period had similar preserving effects, but tiapamil treatment only during reperfusion did not. These results suggest that blockade of the Ca2+ channel must be achieved during the early phase of an ischemic episode in order to prevent myocardial deterioration during reperfusion.
J Cardiovasc Pharmacol
PMID:Protection by the calcium antagonist tiapamil, against cardiac lymphatic enzyme leakage and arrhythmias in canine hearts during reperfusion. 241

Glomerular mesangial cells are contractile cells responsive to a variety of vasoactive substances. In addition, they are capable of synthesizing prostaglandins and renin-like enzyme(s) (RLE). We examined the identity of the RLE in cultured rat mesangial cells utilizing specific antibody raised to pure renal renin. Unlike cathepsin D, RLE is active at pH 7.4. One million mesangial cells contain 174 +/- 53 pg ANG I/h RLE intracellularly (ANG I, angiotensin I; n = 26). As evidenced by inhibition by renin-specific antibody, 52 +/- 3% RLE is due to immunoreactive renin. Mesangial immunoreactive renin activity is influenced by beta-adrenergic stimulation and increased extracellular calcium. Exposure to 1 microM isoproterenol at 37 degrees C for 1 h resulted in 103 +/- 53% increase in intracellular activity, i.e., 56 +/- 8 to 102 +/- 15 pg ANG I/h/10(6) cells (p less than 0.05, n = 7). Addition of calcium to culture media for 1 h resulted in an increase in intracellular renin activity. Addition of 1 mM (final concentration) calcium resulted in a ninefold increase in mesangial renin activity from 21 +/- 8 to 185 +/- 10 pg ANG I/h/10(5) cells (n = 4, p less than 0.001). Similarly, 4 mM calcium resulted in a sevenfold increase (n = 4, p less than 0.001). Thus, mesangial cells synthesize renin, which can be regulated by beta-adrenergic receptors and extracellular calcium. This intracellular renin may play an important role in the local regulation of contractile response and glomerular dynamics.
J Cardiovasc Pharmacol 1986
PMID:Cultured glomerular mesangial cells contain renin: influence of calcium and isoproterenol. 243 93

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.
J Cardiovasc Pharmacol 1988 Sep
PMID:Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock. 246 1

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using CV-6209, a specific antagonist of PAF. CV-6209, at a dose of 1 mg/kg (i.v.) given after trauma, significantly improved survival rate at 150 min and overall survival time. Furthermore, the plasma accumulation of the lysosomal hydrolase, cathepsin D, and a cardiotoxic peptide, myocardial depressant factor (MDF), were also attenuated by CV-6209 in traumatic shock. Combined treatment employing low doses of CV-6209 [0.2 mg/kg, i.v. and prostaglandin (PG) E1, 0.8 microgram/kg/min] in this shock model was also examined. CV-6209 (0.2 mg/kg) or PGE1 (0.8 microgram/kg/min) alone at these doses showed only minimal effects on survival, or plasma cathepsin D or MDF activities. However, combined treatment with CV-6209 (0.2 mg/kg, i.v.) and PGE1 (0.8 microgram/kg/min) significantly improved survival rate at 150 min, overall survival time, and decreased the accumulation of plasma MDF. These results suggest that PAF may play an important pathophysiologic role in traumatic shock in rats. Moreover, combination therapy using a PAF antagonist and PGE1 may be useful for the treatment of traumatic shock.
J Cardiovasc Pharmacol 1988
PMID:Protective effects of a platelet activating factor (PAF) antagonist and its combined treatment with prostaglandin (PG) E1 in traumatic shock. 246 48

CGP 38 560 is a low-molecular-weight (730) inhibitor of human renin that contains only one natural amino acid. In vitro, it is a potent inhibitor of human renin (Ki with tetradecapeptide, 0.4 X 10(-9) M). It has a high enzyme specificity (Ki values against human pepsin, gastricsin, and cathepsin D are 5 X 10(-6), 3 X 10(-6), and 0.6 X 10(-6) M) and is also species specific (IC50 values against human, marmoset, dog, and rat plasma renins are 7 X 10(-10), 7 X 10(-10), 7 X 10(-9), and 1 X 10(-6) M). In vivo, CGP 38 560 inhibits plasma renin activity (PRA) and lowers blood pressure (BP) after oral administration to conscious, normotensive, furosemide-pretreated marmosets. A dose of 10 mg/kg induces complete inhibition of PRA and a decrease in BP of 23 +/- 3 mm Hg (n = 4) after 30 min. These effects persist for up to 2 h. Blockade of the renin-angiotensin system appears to cause the hypotensive response since it is completely prevented by pretreatment with a converting-enzyme inhibitor. These findings demonstrate that the molecular size of renin inhibitors may be reduced to improve their oral activity without loss of potency or specificity.
J Cardiovasc Pharmacol 1989 Aug
PMID:CGP 38 560: orally active, low-molecular-weight renin inhibitor with high potency and specificity. 247 94

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as human renin inhibitors. ES-305, bis[(1-naphthyl)methyl]acetyl-histidyl-statine-2(S)-methylbutylami de, was found to be a highly potent human renin inhibitor that is species-specific and enzyme-specific. The replacement of the methylbutylamide of ES-305 with the leucyl-lysinol (ES-1005) showed similar high potency against human renin (Ki value of 2.4 x 10(-9) M) and monkey renin (Ki value of 7.9 x 10(-9) M) as ES-305. ES-1005 competitively inhibited human renin. The compound was about one order of magnitude less potent against pig, dog, and rabbit renins. It had moderate inhibitory potencies against cathepsin D and pepsin (IC50 of cathepsin D and pepsin of 1.6 x 10(-5) and 8.0 x 10(-6) M, respectively). ES-1005, a newly synthesized tripeptide derivative containing statine, is a highly potent inhibitor of not only primate renin but also a wide variety of nonprimate renins.
J Cardiovasc Pharmacol 1987
PMID:In vitro inhibition of human renin by statine-containing tripeptide renin inhibitor (ES-1005). 248 69

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.
J Cardiovasc Pharmacol
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


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