Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.8. These results suggest that neither endogenous PAF nor NO modulate thrombin-induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin.
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PMID:The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit. 150 22

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.
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PMID:cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. 783 30

The cavernous carotid artery, that portion of the internal carotid artery that lies within the intracranial cavernous sinus, is covered by arterial (luminal surface) and venous (external surface) endothelium. The reactivity of the isolated canine, cavernous carotid artery, precontracted with 10(-5) M 5-hydroxytryptamine, was studied by using in vitro perfusion and superfusion to evaluate the effects of vasoactive stimuli applied to the internal or external surface. Acetylcholine (10(-8)-10(-4) M), thrombin (0.01-1 U/ml) or calcium ionophore A23187 (10(-8) - 10(-6) M) on the luminal side produced concentration-dependent relaxations which were reduced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or by removing either the internal or both endothelia. Thrombin or ionophore A23187 on the external side produced concentration-dependent contractions which were reduced by removing either the external or both endothelia, and by meclofenamate (10(-5) M). Acetylcholine on the external side, produced a concentration-dependent contraction that was unaffected by meclofenamate or by removing the external or both endothelia. Sodium nitroprusside (10(-7) - 10(-5) M) induced similar relaxation on both sides and regardless of whether the arteries were with or without endothelium. These results suggest firstly, that the cavernous carotid artery responds to acetylcholine, thrombin or calcium ionophore A23187 by relaxing or contracting when these agents act on the luminal or the external surface respectively. Secondly, the arterial endothelium mediates relaxation to these three substances by releasing NO, whereas the venous endothelium mediates contraction to thrombin and ionophore A23187 by releasing a cyclooxygenase product.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reactivity of the dog cavernous carotid artery. The role of the arterial and venous endothelium. 830 86

We hypothesized that endotoxin would impair agonist-induced calcium (Ca2+) mobilization in rat mesangial cells, owing to the induction of nitric oxide synthase (NOS) and augmented nitric oxide (NO) synthesis. We measured basal and bradykinin-induced peak free cytosolic Ca2+ concentrations through microspectrofluorimetry with fura-2 in confluent mesangial cells, and assayed conditioned medium for nitrite accumulation. Prior to measurement, cells were incubated overnight in serum-supplemented medium, with or without endotoxin, 1-arginine, indomethacin, meclofenamate, or N omega-nitro-L-arginine methyl ester (L-NAME). Endotoxin (1 mg/ml) decreased bradykinin-induced peak Ca2+ responses by 35 to 60% (p < 0.0001) and increased nitrite accumulation > 6-fold (p < 0.01). Arginine supplementation further (> 9-fold, p < 0.0001) increased nitrite accumulation without changing the effect on Ca2+. Inhibition of NOS abolished increments in nitrite concentration but had no effect on impaired Ca2+ responses. Cyclooxygenase (COX) inhibitors, present during incubation with endotoxin, but not afterward, normalized bradykinin-stimulated calcium responses. Thrombin-stimulated Ca2+ responses were similarly affected. We conclude that neither NO nor prostaglandins act directly to impair agonist-induced Ca2+ mobilization following endotoxin exposure; however, this effect may be an indirect effect of COX products, including reactive oxygen intermediates.
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PMID:Endotoxin impairs agonist-induced calcium mobilization in rat mesangial cells. 941 65

We have investigated the ability of protease-activated receptor-1 (PAR-1), PAR-2, PAR-3 and PAR-4 agonists to induce contractile responses in isolated guinea-pig gallbladder. Thrombin, trypsin, mouse PAR-1 activating (SFLLRN-NH(2)) peptide, and mouse PAR-2 activating (SLIGRL-NH(2)) and human PAR-2 activating (SLIGKV-NH(2)) peptides produced a concentration-dependent contractile response. Mouse PAR-4 activating (GYPGKF-NH(2)) peptide, the mouse PAR-1 reverse (NRLLFS-NH(2)) peptide, the mouse PAR-2 reverse (LRGILS-NH(2)) and human PAR-2 reverse (VKGILS-NH(2)) peptides caused negligible contractile responses at the highest concentrations tested. An additive effect was observed following the contractile response induced by either trypsin or thrombin, with the addition of a different PAR agonist (SFLLRN-NH(2) and SLIGRL-NH(2), respectively). Desensitization to PAR-2 activating peptide attenuated the response to trypsin but failed to attenuate the response to PAR-1 agonists, and conversely desensitization to PAR-1 attenuated the response to thrombin but failed to alter contractile responses to PAR-2 agonists. The contractile responses produced by thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were markedly reduced in the presence of the cyclo-oxygenase inhibitor, indomethacin, whilst the small contractile response produced by NRLLFS-NH(2) and LRGILS-NH(2) were insensitive to indomethacin. The contractile responses to thrombin, trypsin, SFLLRN-NH(2) and SLIGRL-NH(2) were unaffected by the presence of: the non-selective muscarinic antagonist, atropine; the nitric oxide synthase inhibitor, L-NAME; the sodium channel blocker, tetrodotoxin; the combination of selective tachykinin NK(1) and NK(2) receptor antagonists, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2] octane chloride (SR140333) and (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), respectively. The results indicate that PAR-1 and PAR-2 activation causes contractile responses in the guinea-pig gallbladder, an effect that is mediated principally by prostanoid release, and is independent of neural mechanisms.
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PMID:Evidence that PAR-1 and PAR-2 mediate prostanoid-dependent contraction in isolated guinea-pig gallbladder. 1103 Jul 17

Using a method employing front-surface fura-2 fluorometry to measure the cytosolic Ca(2+) concentration, [Ca(2+)](i), the mechanism of endothelium-dependent regulation of vascular tone by thrombin was studied in porcine renal interlobar arterial strips. At concentrations lower than 3 u ml(-1), thrombin evoked only early transient relaxation, while at 3 u ml(-1) and higher concentrations, thrombin caused an early relaxation and a subsequent transient contraction. Both thrombin-induced relaxation and contraction were abolished by removing the endothelium. Similar biphasic responses were observed with a protease-activated receptor-1-activating peptide. Early relaxation was associated with a decrease in [Ca(2+)](i), while the transient contraction was not associated with a change in [Ca(2+)](i) of smooth muscle cells. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited the thrombin-induced contraction, whereas a thromboxane A(2) synthase inhibitor (10(-5) M OKY-046) only partly inhibited it. When the thrombin-induced contraction was inhibited by ONO-3708, either pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME) or an increase in the amount of external K(+) to 40 mM did not abolish thrombin-induced relaxation during phenylephrine-induced sustained contraction. However, the combination of pretreatment with L-NAME and an elevation of external K(+) to 40 mM completely abolished the relaxation. There was no significant difference in the concentration-dependent effects of thrombin on the initial early relaxation between conditions in which the contractile components either were or were not inhibited. Thrombin is thus considered to mainly activate protease-activated receptor-1 and cause a biphasic response, early relaxation and a transient contraction, in the porcine renal interlobar artery in an endothelium-dependent manner. The thrombin-induced endothelium-dependent relaxation was mediated by nitric oxide and hyperpolarizing factors, while the contraction was mediated by TXA(2) and PGH(2).
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PMID:Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery. 1113 41

The proteolytic enzyme thrombin activates its receptor by cleavage of a peptide from the extracellular N-terminus. The newly generated N-terminus acts as a tethered ligand to activate the receptor. Receptor-mediated cellular effects of thrombin can be mimicked by synthetic peptides, which correspond to the amino acid sequence of the newly formed N-terminus. The aim of the present study was to investigate vascular effects of thrombin and the thrombin receptor activating peptide (TRAP: SFLLRN) in vitro and in vivo in rats. In precontracted rat aortic rings, both thrombin (0.3, 1, 3 U/ml) and TRAP (1, 3, 10, 20, 40 microM) induced endothelium-dependent relaxant responses. In anaesthetized rats, the mean arterial blood pressure (MAP) was measured continuously in the carotid artery by a pressure transducer. Thrombin and TRAP were administered as intravenous bolus injection via the femoral vein. Thrombin at doses of 3-100 U/kg, as well as TRAP at doses of 0.1-0.6 mg/kg i.v., caused a reversible decrease in MAP. Administration of TRAP at doses of 0.3 and 0.6 mg/kg led to a triphasic response in most of the animals treated (50% and 75%, respectively), i.e. a short drop of MAP was followed by an increase and finally a longer lasting decrease in MAP. Pretreatment with the nitric oxide (NO)-synthase inhibitor N(G)-nitro-L-arginine-methylester (L-NAME) suppressed the dose-dependent vasodilator effects of thrombin. Heparin and hirudin also inhibited the hypotensive response to thrombin. The TRAP-induced triphasic reaction on MAP was not affected by the serotonin antagonists ketanserin and tropisetron, as well as the aminopeptidase inhibitor amastatin. Pretreatment with L-NAME led to an inhibition of hypotension induced by TRAP at 0.1 mg/kg, as well as of the initial transient fall in blood pressure at doses of 0.3 and 0.6 mg/kg. The studies suggest that the thrombin- and TRAP-induced vasodilation in vitro and in vivo is in part due to the release of endothelial NO. In the blood pressure response to TRAP, additional effects seem to be involved.
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PMID:Systemic vascular effects of thrombin and thrombin receptor activating peptide in rats. 1132 4

The objective of this study was to develop an assay system that allows continuous monitoring of nitric oxide (NO) released from crystalloid perfused hearts. We utilized chemiluminescence reaction between NO and luminol-H(2)O(2) to quantify the NO level in coronary effluent. Isolated rat hearts were subjected to ordinary Langendorff's perfusion, and the right ventricle was cannulated to sample coronary effluent. After equilibration, the coronary flow rate was set constant and the hearts were paced at 300 bpm. Coronary effluent was continuously sampled and mixed with the chemiluminescent probe containing 0.018 mmol/l luminol plus 10 mmol/l H(2)O(2). Chemiluminescence from the mixture of coronary effluent and the probe was continuously measured. NO concentration was calibrated by various concentrations (0.5-400 pmol/l) of standard NO solution. The lower detection limit of NO was 1 pmol/l. Basal NO release from isolated perfused rat heart was 0.41 +/- 0.17 pmol/min/g of heart weight, and that was significantly suppressed by 0.1 mmol/l of L-NAME to 0.18 +/- 0.10 pmol/min/g of heart weight (n = 7). Application of 0.1 and 0.3 micromol/l acetylcholine increased NO level in the coronary effluent, in a concentration-dependent manner, from 6.6 +/- 1.7 in a baseline condition to 16.3 +/- 7.4 and 30.3 +/- 16.1 pmol/l at each peak, respectively. Thrombin at 1 and 10 U/ml also increased NO level from 17.6 +/- 4.3 in control to 35.5 +/- 10.4 and 48.7 +/- 8.7 pmol/l at each peak, respectively (n = 7). Thus, this assay system is applicable to the continuous real-time measurement of NO released from crystalloid perfused hearts, and it may be useful for the study of physiological or pathophysiological role of NO in coronary circulation.
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PMID:Real-time measurement of nitric oxide by luminol-hydrogen peroxide reaction in crystalloid perfused rat heart. 1249 78

The acute physiologic release of tissue-type plasminogen activator (t-PA) from the endothelium is critical for vascular homeostasis. This process is prostacyclin- and nitric oxide (NO)-independent in humans. It has been suggested that calcium signaling and endothelial-derived hyperpolarizing factors (EDHF) may play a role in t-PA release. G-protein-coupled receptor-dependent calcium signaling is typically Galphaq-dependent. EDHFs have been functionally defined and in various tissues are believed to be various regioisomers of the epoxyeicosatrienoic acids (EETs). We tested the hypothesis in vitro that thrombin-stimulated t-PA release from human microvascular endothelial cells (HMECs) is both Galphaq- and EDHF-dependent. Conditioned media was harvested following thrombin stimulation, and t-PA antigen was measured by ELISA. Thrombin-induced t-PA release was limited by a membrane-permeable Galphaq inhibitory peptide, the PLC-beta antagonist U73122, and the IP3 receptor antagonist 2-aminoethoxyphenylborane, while the Galphaq agonist Pasteurella toxin modestly induced t-PA release. The cytochrome P450 (CYP450) inhibitor, miconazole, and the arachidonic acid epoxygenase inhibitor MS-PPOH inhibited thrombin-stimulated t-PA release, while 5,6-EET-methyl ester stimulated t-PA release. The 5,6- and 14,15-EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid, inhibited t-PA release at the 100 microM concentration. However, thrombin-stimulated t-PA release was unaffected by the prostacyclin and NO inhibitors ASA and L-NAME, as well as the potassium channel inhibitors TEA, apamin and charybdotoxin. These studies suggest that thrombin-stimulated t-PA release is Galphaq-, PLC-beta-, IP3-, and 5,6-EET-dependent while being prostacyclin-, NO- and K+ channel-independent in HMECs.
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PMID:Acute tissue-type plasminogen activator release in human microvascular endothelial cells: the roles of Galphaq, PLC-beta, IP3 and 5,6-epoxyeicosatrienoic acid. 1726 56

This study investigated interactions between the effects of mechanical stretch and thrombin on RhoA activation in rat aortic smooth muscle cells (RASMC). Equibiaxial, pulsatile stretch, or thrombin produced a significant increase in RhoA activation. Surprisingly, in combination, 30 min of stretch inhibited the ability of thrombin to activate RhoA. NO donors and 8-bromo-cGMP significantly inhibited thrombin-induced RhoA activation. Interestingly, the nitric oxide synthase (NOS) inhibitor L-NAME increased basal RhoA activity, suggesting that NOS activity exerts a tonic inhibition on RhoA. Stretching RASMC increases nitrite production, consistent with the idea that NO contributes to the inhibitory effects of stretch. Thrombin stimulates MAP kinase and NF-kappaB pathways through Rho and these responses were blocked by 8-bromo-cGMP or stretch and restored by L-NAME. These data suggest that stretch, acting through NO and cGMP, can prevent the ability of thrombin to stimulate Rho signaling pathways that contribute to pathophysiological proliferative and inflammatory responses.
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PMID:Pulsatile equibiaxial stretch inhibits thrombin-induced RhoA and NF-kappaB activation. 1847 18


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