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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enhanced platelet function and a decrease in fibrinolytic activity have been reported in patients with mild hypertension after treatment with various nonselective beta-blockers. Until now, such changes have not been reported during treatment with beta 1-selective drugs or with agents that have intrinsic sympathomimetic activity. The impact of angiotensin-converting enzyme inhibitors and diuretics on platelet function and fibrinolytic activity has not been fully elucidated. Calcium antagonists of various types, however, are known to decrease platelet release in vivo whereas their effects on platelet aggregation and fibrinolytic activity are less clear. The new dihydropyridine calcium antagonist isradipine, when tested in a group of patients with mild hypertension, resulted in a decrease in platelet aggregation, a shortened euglobulin clot-lysis time, and a dramatic increase in t-PA (tissue-plasminogen activator) activity after 14 days of treatment. These changes remained stable throughout the 1-year study period. The fact that antihypertensive therapy does not always result in the hoped-for prolongation of life, despite satisfactory blood pressure reduction, may be in part due to an unfavorable impact on various components of the blood-clotting system.
J Cardiovasc Pharmacol 1992
PMID:Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence? 137 29

Retinoic acid induces tissue-type plasminogen activator (t-PA) but not plasminogen activator inhibitor-1 (PAI-1) expression in cultured human umbilical vein endothelial cells (HUVEC). To further investigate the relation between the structure of the retinoids and their ability to induce t-PA synthesis in vitro, 11 analogues were studied in HUVEC culture. The retinoid analogues were classified into one of three groups according to their t-PA-inducing potential. Group 1 showed little induction (0.9- to 1.9-fold after 48 h) at concentrations between 10(-8) and 10(-6) M. Group 2, which includes all-trans-retinoic acid, induced t-PA threefold to fivefold at 10(-6) M but had little effect at 10(-8) M (less than threefold). Group 3, which comprises arotinoid acid (RO-13-7410) and RO-13-6307, induced t-PA antigen secretion fivefold at 10(-8) M. The retinoids of groups 2 and 3 had a terminal carboxyl group and alkyl substitution of the lipophylic head of the retinoid skeleton. The group 3 retinoids also contained an aromatic ring. The t-PA-inducing activity of these third-generation retinoids correlates to some extent with other activities, including regression of papilloma, keratinization in vivo, and clonal inhibition of tumor cell lines in vitro. Some of the retinoids caused a small but significant (up to 1.5-fold at 24 h) increase in PAI-1 antigen secretion. The group 3 retinoids appear to be sufficiently potent inducers of t-PA secretion to warrant further investigation in in vivo animal models.
J Cardiovasc Pharmacol 1992 Apr
PMID:Stimulation by retinoids of tissue-type plasminogen activator secretion in cultured human endothelial cells: relations of structure to effect. 138 May 92

Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.
Cardiovasc Drugs Ther 1992 Apr
PMID:Advances in thrombolytic therapy. 139 Mar 21

The current risk of disease transmission through homologous blood transfusion has lead to a revival in the use of autologous blood. The development of a coagulopathy increases the usage of blood and blood products and therefore the risk of disease transmission. Blood salvaged at operation is subjected to physical and humoral activating factors. The potential systems to be activated are located either in the plasma or non red cell cellular elements. Homologous blood and blood salvaged at operation before and after washing was examined for activation of the plasma and cellular systems by measuring the presence of fibrin degradation products (xDP's), activated complement (C3a) and plasminogen activator and inhibitor activity from the plasma systems; and elastase, serotonin, lysophospholipids, leukotriene B4, lysoplatelet factor and phospholipase A2 from the cellular systems. The plasma systems were activated in the salvaged blood which had elevated levels of xDP's and C3a compared to the patient's blood (p less than 0.05). The products of cellular activation were also elevated in operatively salvaged blood (p less than 0.01 for all the above products). The levels xDP's were normal but the levels of C3a increased in stored blood. The levels of the cellular systems, elastase, serotonin and lysoplatelet activating factor, increased with the duration of storage of bank blood. Unwashed and aged stored blood contains potentially harmful products. Consideration should be given to removal of non red cell elements in blood stored for surgery.
J Cardiovasc Surg (Torino)
PMID:The quality of blood used for transfusion. 154 6

The pharmacokinetics and thrombolytic properties of two variants of recombinant human tissue-type plasminogen activator (rt-PA) were studied in dogs with a copper coil induced thrombosis of the left anterior descending coronary artery. The first variant, rt-PA-delta FEK1-Gln184, lacked amino acids 6 to 173 [comprising the fibronectin finger-like (F), the epidermal growth factor-like (E), and the first kringle (K1) domains] and had the glycosylated Asn184 mutagenized to Gln. The second variant, rt-PA-delta FEK1-Gln184, Val277, had in addition Lys277 mutagenized to Val. Injection of 0.25, 0.50, or 1.0 mg/kg of rt-PA in groups of three dogs caused reflow in six of nine dogs, within 18 +/- 15 min (mean +/- SD), but was associated with reocclusion within 2 h in all animals. Injection of 0.125, 0.25, or 0.50 mg/kg of rt-PA-delta FEK1-Gln184 caused reflow in all of nine dogs, within 17 +/- 23 min, with persistent patency in four animals (p = 0.02 vs. rt-PA). Bolus injection of 4:1 mixtures of rt-PA-delta FEK1-Gln184 and rt-PA in total amounts of 0.125, 0.25, or 0.50 mg/kg resulted in reflow in eight of nine dogs within 25 +/- 21 min with persistent patency in seven (p = 0.003 vs. rt-PA, p = 0.25 vs. rt-PA-delta FEK1-Gln184 alone). Injection of 0.25, 0.50, or 1.0 mg/kg of rt-PA-delta FEK1-Gln184, Val277 produced reperfusion in six of nine dogs, within 27 +/- 26 min, with persistent patency in three (p = 0.59 vs. rt-PA and p = 0.23 vs. rt-PA-delta FEK1-Gln184).(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990 Aug
PMID:Pharmacokinetics and coronary thrombolytic properties of two human tissue-type plasminogen activator variants lacking the finger-like, growth factor-like, and first kringle domains (amino acids 6-173) in a canine model. 169 74

Thrombolytic effects of tissue-type plasminogen activator (t-PA) are limited by in vivo platelet activation and dynamic coronary vasoconstriction. To examine if the concurrent administration of a fibrin(ogen)-degradation product, pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) with t-PA would improve the thrombolytic effects of t-PA, dogs with electrically induced coronary thrombus were given t-PA alone or with peptide 6A. In dogs given t-PA alone (0.75 mg/kg over 20 min), coronary blood flow was restored in 69% of animals (9 of 13 dogs), with a mean time to reflow of 21 +/- 10 min and duration of reflow of 35 +/- 18 min. Reocclusion occurred in 77% of dogs (7 of 9 dogs). With concurrent administration of peptide 6A (200 mumol), coronary venous 6-keto-PGF1 alpha concentrations increased from 221 +/- 71 to 422 +/- 161 pg/ml (p less than 0.05), but not with t-PA given alone. Coronary blood flow was restored in 7 of 11 dogs (reperfusion rate 64%), with mean time to reflow of 17 +/- 7 min and duration of reflow of 35 +/- 15 min. The coronary reocclusion rate was 86%. All these indices of thrombolysis were similar to those in dogs given t-PA alone. In ex vivo experiments, we also demonstrated release of endothelium-derived relaxing factor from canine coronary artery rings in response to peptide 6A. To further examine the role of prostacyclin (PGI2) in thrombolytic response to t-PA, eight other dogs were given t-PA with a PGI2 analog iloprost (100 ng/kg/min for 40 min).(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1991 Aug
PMID:Combined thrombolytic effects of tissue-plasminogen activator and a fibrinogen-degradation product peptide 6A or iloprost. 171 84

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 +/- 6 vs. 18 +/- 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1-6.6 ml/min/kg for BM 06.022 and of 12.6-42.3 ml/min/kg for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1991 Jul
PMID:Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model. 171 79

The effects on fibrinolytic components of pentoxifylline (Trental), of its first metabolite BL 194 (penthydroxyfylline), and of its analogue HWA 448 (torbafylline) were studied in rats. BL 194, though not pentoxifylline and HWA 448, significantly enhanced the induced release by platelet-activating factor (PAF) of tissue-type plasminogen activator (tPA) from isolated perfused rat hindlegs. In contrast, the simultaneously induced release of von Willebrane factor (vWF) was reduced by BL 194. The effect of BL 194 on PAF-induced release of tPA and vWF could be mimicked by isobutyl-methylxanthine (IBMX), an inhibitor of phosphodiesterases. In vivo, BL 194 and pentoxifylline did not affect baseline levels of plasma tPA and PA inhibitor activity, nor did these compounds affect the in vivo induction of tPA release by PAF. Similarly, the induction by endotoxin of PA inhibitor activity was not influenced by pentoxifylline or BL 194. By its opposite effects on tPA and vWF release. BL 194 might favrorably influence the thrombotic balance.
J Cardiovasc Pharmacol 1991 Jul
PMID:The effect of pentoxifylline (Trental) and two analogues, BL 194 and HWA 448, on the release of plasminogen activators and von Willebrand factor in rats. 171 89

Fibrinolytic activity was measured in a 14-day placebo-controlled study of propranolol and the calcium antagonist isradipine in 20 mildly hypertensive patients (diastolic blood pressure 95-115 mm Hg) compared with 24 healthy volunteers. The parameters under study included euglobulin clot-lysis time, and tissue-plasminogen activator activity and its inhibitor (PAI). The two drugs exerted equal antihypertensive effects in the patients who had raised blood pressure, but had markedly different actions on the fibrinolytic system. Propranolol substantially reduced the fibrinolytic activity in both the hypertensive and healthy control groups. Isradipine, on the other hand, had no effect on fibrinolytic activity in the controls, but augmented the activity in the hypertensive subjects. The possible mechanisms for the different actions of the two agents may be related to the vascular endothelium.
J Cardiovasc Pharmacol 1991
PMID:Does antihypertensive therapy affect the natural protection against thrombosis? 172 Apr 83

Platelet function was investigated in healthy volunteers and patients with essential hypertension by measurement of thresholds for ADP and adrenaline-induced aggregation and plasma concentrations of platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) after administration of antihypertensive drugs. Fibrinolytic activity was investigated by the euglobulin clot lysis time (ECLT) and tissue plasminogen activator (t-PA) activity. Compared to normotensive controls, patients with essential hypertension showed increased aggregation as evidenced by a decrease in ADP thresholds for ex vivo platelet aggregation. ECLT was significantly prolonged and t-PA significantly lowered, indicating impaired fibrinolytic activity in mild hypertension. In different studies, we have shown that various antihypertensive drug regimens differ in their effects on platelet function and fibrinolytic activity when given to healthy volunteers or patients with mild-to-moderate essential hypertension. In normal volunteers, treatment with the calcium antagonists verapamil, nifedipine, and felodipine lowered plasma concentrations of PF-4 and beta-TG, indicating a reduced platelet activity in vivo. Fibrinolytic activity was not influenced by calcium antagonist treatment in the normal volunteers. Interestingly, however, t-PA increased significantly in the hypertensive group. When compared to placebo or beta 1-selective blockers, propranolol, a non-selective beta-adrenergic blocker without partial agonist activity, reduced ADP and adrenaline threshold values for ex vivo platelet aggregation in hypertensive subjects and impaired fibrinolytic activity in the normal volunteers as well as in the hypertensive groups by increasing ECLT and reducing t-PA. Hypothetically, the effects of antihypertensive drugs on platelet function and fibrinolytic activity could be of importance for their proposed actions on cardiovascular morbidity and mortality.
J Cardiovasc Pharmacol 1991
PMID:Platelet function and fibrinolytic activity in hypertension: differential effects of calcium antagonists and beta-adrenergic receptor blockers. 172 42


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