Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have evidenced an association between the time of heparin discontinuance and coronary artery reocclusion. Some investigators have concluded that inadequate heparinization was responsible, and further heparin infusion or an increase in dose would have been indicated. However, several investigators (Rao: Thrombosis Research 24:181-186, 1981; Marciniak and Gockerman: Lancet September 17:581-584, 1977; Fisken et al.: Lancet December 10: 1231, 1977; Conard et al.: Thrombosis Research 22:507-511, 1981; Kakkar et al.: Lancet January 12:103-104; Green: Lancet February 16:374, 375; Harborne and Nicolaides: Thrombosis Research 43:657-662, 1986; Bonen et al.: Thrombosis Research 27:123-124, 1982; Blomback et al.: Acta Physiologica Scandinavica 58:306-318, 1963; Holm et al.: Scandinavian Journal of Haematology 35:564-569, 1985; Andersson et al.: Thrombosis Research 34:333-340, 1984) have demonstrated that antithrombin III levels are reduced in patients on intravenous heparin. Both reduced antithrombin III levels and reduced rate of antithrombin inhibition of thrombin at the time of heparin discontinuance may increase the risk of coronary rethrombosis. If this theory is correct, increasing heparin infusion may exacerbate this risk. We propose an investigation that will provide evidence for or against the decreased antithrombin III theory, and in doing so, test an experimental therapy designed to prevent coronary reocclusion upon heparin discontinuance. In a randomized, placebo-controlled double-blinded study, we will determine whether simultaneous administration of warfarin with heparin initiation provides more time to increase antithrombin III levels and prevent coronary reocclusion upon heparin discontinuance, compared to heparin without warfarin therapy.
Cathet Cardiovasc Diagn 1990 Jun
PMID:Hypothesis: warfarin administered simultaneously with heparin infusion will prevent heparin-discontinuance associated coronary thrombosis. 219 83

Relaxation of rat aorta segments with sodium nitroprusside and endothelium-dependent vasodilators, such as acetylcholine, histamine, A23187, ATP, thrombin, and trypsin, is associated with cyclic-GMP (cGMP) accumulation in a concentration- and time-dependent fashion. With rat aorta segments, these agents also increase cyclic GMP-dependent protein-kinase activity and alter the incorporation of 32P into numerous smooth-muscle proteins. Identical patterns of protein phosphorylation were observed with both classes of relaxants on two-dimensional gel electrophoresis and autoradiography. The effects of nitroprusside were observed with or without the endothelium present. In contrast, the effects of the endothelium-dependent agents on all of these parameters (cGMP, cGMP-dependent protein kinase and protein phosphorylation) required the integrity of the endothelium. Various inhibitors of phospholipase and lypoxygenase prevented the effects of the endothelium-dependent agents, suggesting that a metabolite of arachidonic acid is the endothelium-relaxant factor and responsible for guanylate-cyclase activation. A smooth-muscle protein with decreased 32P incorporation after treatment with either class of relaxants has been identified as myosin light chain. A model is presented suggesting that the effects of endothelium-dependent vasodilators and directly acting nitrovasodilators converge at the level of guanylate-cyclase activation and cGMP accumulation, which explains the common biochemical and physiological effects on smooth muscle of these two classes of vasodilators.
J Cardiovasc Pharmacol 1985
PMID:Role of cyclic-GMP in relaxations of vascular smooth muscle. 240 83

A number of naturally occurring substances can evoke endothelium-dependent responses in isolated blood vessels. In most arteries studied, acetylcholine, adenosine diphosphate (ADP), adenosine triphosphate (ATP), arachidonic acid, bradykinin, and thrombin cause endothelium-dependent relaxations. In veins, however, the endothelium-dependent inhibitory effect of acetylcholine, ATP, and thrombin often is transient and/or modest, as it is masked by the direct stimulating action of these substances on the venous smooth muscle; arachidonic acid evokes endothelium-dependent augmentation of the contractile response to norepinephrine. Aggregating platelets cause an endothelium-dependent relaxation of certain but not all arteries and veins that is probably mediated by released serotonin and ADP. The endothelium of the coronary artery may enhance the relaxations caused by catecholamines. Vasopressin causes endothelium-dependent relaxations in cerebral and coronary arteries but not in systemic blood vessels. Hypoxia causes endothelium-dependent increases in tension in systemic arteries and in pulmonary arteries and veins but not in limb veins. The heterogeneity in endothelium-dependent responsiveness may reflect variations in sensitivity of either endothelial or vascular smooth-muscle cells of different anatomical origin.
J Cardiovasc Pharmacol 1985
PMID:Heterogeneity of endothelium-dependent responses in mammalian blood vessels. 240 85

A number of drugs such as unfractionated heparin, oral anticoagulants, and agents inhibiting platelet function, are being used in the prevention of arterial thrombosis; novel antithrombotic substances are in the making. Among the latter are low-mol-wt heparin and semisynthetic heparin analogs, unfractionated and low-mol-wt heparin covalently complexed or not with anti-thrombin III, pyridoxal phosphate, scavengers of free radicals, synthetic inhibitors of serine proteases, and stimulators of endogenous fibrinolysis.
J Cardiovasc Pharmacol 1985
PMID:Prevention of thrombosis in arteries: novel approaches. 240 94

The release reaction and the metabolism of inositol lipids were studied in parallel in washed human platelets following the activation by low doses of thrombin. The breakdown of phosphatidylinositol 4,5-bisphosphate (PI-P2) was accompanied by the release of serotonin. These events preceded the breakdown of the other phosphoinositides and the release of alpha-granules and lysosome constituents, respectively. The secretion of serotonin probably is triggered by products of thrombin-induced activation of the phospholipase C directed against PI-P2.
J Cardiovasc Pharmacol 1985
PMID:Serotonin release and phosphoinositide breakdown in thrombin-induced activation of human platelets. 241 47

The sympathetic nervous activity contributes to the pathophysiology of essential hypertension in an early phase and in younger patients mainly through increased beta-adrenoceptor-mediated functions and in a later phase and in older patients in whom beta-adrenoceptor-mediated functions are blunted, through increased alpha-adrenoceptor-mediated and calcium-influx-dependent vasoconstriction. Intracellular free calcium concentration is elevated in platelets of hypertensive patients and relates directly to the degree of their blood pressure, likely reflecting increased intracellular calcium concentration in vascular smooth muscle cells. A sympathetic factor is suggested further by the enhanced alpha 1-and alpha 2-adrenoceptor-mediated and calcium influx-dependent, vasoconstriction both of which are normalized by antihypertensive treatment in parallel with a normalization of intracellular free calcium and of the increased adrenaline sensitivity of platelets. The higher sensitivity to adrenaline for thrombin-induced calcium increases in platelets of hypertensive patients indicates potentiation of calcium influx (and mobilization from intracellular stores) by adrenaline, a mechanism that is mediated by alpha 2-adrenoceptors. As this effect is more pronounced in younger patients, increased adenylate cyclase sensitivity may prevail in the early and alterations in calcium influx-dependent mechanisms in the later phase of essential hypertension. The transition into a hypertensive state with reduced-reflex cardiovascular counterregulation codetermines the antihypertensive effectiveness of calcium antagonists in these patients.
J Cardiovasc Pharmacol 1985
PMID:Adrenoceptors, calcium, and vasoconstriction in normal and hypertensive humans. 241 75

Occlusion of the transected bronchus after pneumonectomy was achieved by transthoracic fibrin sealing in 14 domestic pigs. In 9 additional animals standardized bronchus stump fistulae could also be closed with fibrin sealant which was applied through a flexible bronchoscope. An average of 1 ml of fibrin sealant containing 500 units of thrombin and 3500 units of Aprotinin was necessary to achieve bronchial closure and to prevent early dissolution of the sealant. Endoscopic closure of a bronchus fistula by fibrin plug was successfully employed in one clinical case.
Thorac Cardiovasc Surg 1985 Dec
PMID:Endoscopic treatment of bronchus stump fistulae following pneumonectomy with fibrin sealant in domestic pigs. 241 69

We have recently reported that exogenous thrombin produced a dose- and endothelium-dependent coronary vasodilation in both intact open-chested dogs and in isolated dog coronary artery preparations. To determine whether the observed vasodilatory effect may be related to thrombin proteolytic enzymatic activity, effects of other proteases, such as trypsin, chymotrypsin, and pepsin, on the mechanical responses of isolated dog coronary arteries were studied. Among the four proteases evaluated, only thrombin (0.01-0.1 U/ml) and trypsin (0.03-0.67 U/ml) consistently produced a potent dose- and endothelium-dependent relaxation, that was reproducible with repeated testings. Addition of chymotrypsin (0.01-1.0 U/ml) produced only a minimal effect and was not reproducible, while addition of pepsin, as much as 10 U/ml, did not produce any effect. The specific soybean trypsin inhibitor and aprotinin, but not heparin and hirudin, competitively shifted the trypsin dose-response to the right, whereas heparin, hirudin, and antithrombin III proved to be more effective than trypsin inhibitors in inhibiting the thrombin-induced vasodilation. In all cases, the thrombin- and trypsin-induced vasodilation were equally sensitive to inhibition by the specific synthetic thrombin inhibitor, PPACK (D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone, 1-30 nM). PPACK, however, had no effect on the other endothelium-dependent coronary vasodilators, such as acetylcholine and adenosine triphosphate, in our isolated dog coronary artery preparations. Biochemical determinations of the amidolytic activity of thrombin, using Tosylglycyl-L-prolyl-L-arginine-p-nitroanilide as a chromogen, also indicated a similar PPACK and heparin-antithrombin III dose-dependent inhibition of the thrombin enzymatic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Mechanism of thrombin-induced endothelium-dependent coronary vasodilation in dogs: role of its proteolytic enzymatic activity. 241 89

At least two signal-generating systems are involved in the actions of various hormonal factors in human platelets--the adenylate cyclase system and the phosphoinositide-metabolizing pathway. The formation of cyclic AMP (cAMP) by the adenylate cyclase system--consisting of the catalyst itself, the Ns and Ni proteins, and various hormone receptors--is stimulated by prostaglandins and adenosine, and is inhibited by alpha 2-adrenergic agonists, ADP, vasopressin, platelet-activating factor, and thrombin. On the other hand, the formation of inositol trisphosphate and diacylglycerol by the phosphoinositide-metabolizing pathway is stimulated by some of the latter agents, particularly by thrombin. There are apparently several mutual interactions between these two signal-generating systems. On the one hand, increases in the level of cAMP inhibit the formation of inositol phosphates and diacylglycerol. It is presently unclear whether this inhibitory effect of cAMP is due to a direct action at the phospholipase C itself or to an indirect mechanism, for example, a depletion of the substrate of the enzyme. On the other hand, protein kinase C, which is activated by diacylglycerol, largely interferes with the adenylate cyclase system. This kinase, when activated by diacylglycerol or phorbol esters, apparently phosphorylates the guanine nucleotide-binding alpha-subunit of Ni, which results in an impairment or loss of the inhibitory hormonal signal transduction to the adenylate cyclase. Thus, available evidence indicates that the two signal-generating systems present in platelet membranes are not completely separated, and furthermore suggests that they may even be causally related to each other.
J Cardiovasc Pharmacol 1986
PMID:Interactions between the hormone-sensitive adenylate cyclase system and the phosphoinositide-metabolizing pathway in human platelets. 243 28

Experiments were designed to determine the role of the endothelial cells and the metabolism of arachidonic acid in anoxic contractions of isolated canine basilar arteries. Rings, with and without endothelium, of these arteries were suspended for isometric tension recording; anoxia was induced by switching the mixture gassing the organ chamber from 95% O2-5% CO2 to 95% N2-5% CO2. In rings with endothelium, anoxia evoked increases in tension under basal conditions and during contractions to 5-hydroxytryptamine, uridine triphosphate, prostaglandin F2 alpha, and high K+. Under control conditions, these anoxic contractions were not prevented by alpha-adrenergic and serotonergic antagonists, by apyrase, or by inhibitors of cyclooxygenase. Anoxia prevented endothelium-dependent relaxations evoked by vasopressin and thrombin. In rings without endothelium, anoxia caused increases in tension during contractions evoked by various agonists, and in unstimulated preparations after inhibition of cyclooxygenase. Anoxic contractions were abolished by calcium entry blockers. These observations suggest that anoxic contractions of isolated canine basilar artery can be explained by the release of endothelium-derived contracting factor(s) and the accelerated entry of calcium in the smooth muscle cells, which possibly results from a diversion of arachidonic acid from the cyclooxygenase to the lipoxygenase pathway.
J Cardiovasc Pharmacol 1986
PMID:Anoxic contractions in isolated canine cerebral arteries: contribution of endothelium-derived factors, metabolites of arachidonic acid, and calcium entry. 243 36


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