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

Cigarette smoking is a major risk for coronary atherosclerosis, but the mechanism of this is still unclear. The present study demonstrates that smoking produces a variable increase in plasma vasopressin concentration but that sensitivity of platelets to this elevated endogenous vasopressin release is blunted. This suggests that cigarette smoking contributes to atherosclerosis through the vascular effects of the hormones whose release it stimulates rather than by platelet activation. The mechanism for this blunted responsiveness to vasopressin was also investigated in vitro. The rise in intracellular free calcium concentration of platelets was markedly reduced following a second administration of vasopressin, whereas the in vitro shape change response was usually unaltered and could only be reduced with specific procedures for platelet preparation. This suggests that only a small increase of intracellular free calcium is necessary for a complete shape change response induced by vasopressin. The results indicate that the shape change is mediated by an increase in intracellular free calcium which is independent from the phosphoinositol pathway and the calcium is released from intracellular pools other than by those activated by serotonin or thrombin.
J Cardiovasc Pharmacol 1986
PMID:Smoking-induced increases in plasma vasopressin and reduced platelet hormone sensitivity. 243 66

The effects of divalent cations on human platelet vasopressin receptor binding characteristics and effects of receptor occupancy on endogenous protein phosphorylation were investigated. Binding of vasopressin to its receptor is modulated by both the nature and the concentration of ions. Whatever the cation present, guanosine 5'-triphosphate or 5' guanylylimidodiphosphate do not alter the receptor binding characteristics. In the presence of extracellular calcium, vasopressin stimulates the phosphorylation of a 45,000-dalton protein and to a lesser degree of a 20,000-dalton protein following a pattern observed with thrombin and 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester. Phosphorylation is also stimulated by a V1 vascular agonist, but not V2 renal agonists, and is more potently blocked by a V1 vascular antagonist than by a V2 renal antagonist. These results suggest that human platelets bear typical V1 vascular vasopressin receptors which stimulate the phosphorylation of specific substrates of protein kinase C and myosin light-chain kinase.
J Cardiovasc Pharmacol 1987 Jul
PMID:The human platelet vasopressin receptor and its intracellular messengers: key role of divalent cations. 244 Nov 50

We studied the effect of nicardipine on the release of preincorporated tritiated serotonin (5-HT) from washed rat platelets and on platelet 5-HT uptake. Nicardipine exerted a complex action. It partially antagonized thrombin-induced 5-HT secretion, but also induced the "selective" release of 5-HT without concomitant ATP release in the absence of platelet activation and inhibited active 5-HT uptake. The two latter effects were observed in the presence of EGTA and therefore could not be related to calcium channel blockade. Verapamil, TMB 8, and the calmodulin antagonists trifluoperazine and R 24571 also possessed this multiplicity of action; however, verapamil and TMB 8 were weaker inducers of selective 5-HT release and uptake inhibition. These results show that, in addition to its inhibitory effect on thrombin-induced platelet activation, nicardipine inhibits platelet 5-HT accumulation. Its administration may therefore result in 5-HT depletion.
J Cardiovasc Pharmacol 1987 Sep
PMID:Double action of nicardipine on serotonin release from rat platelets. 244 76

Thrombin-induced aggregation and serotonin release were markedly enhanced in platelets from spontaneously hypertensive rats (SHR) when compared to normotensive Wistar-Kyoto (WKY) controls. Since phosphoinositides are involved in calcium-mediated platelet responses, the metabolism of these lipids was investigated in SHR and WKY rats by using 32P-labeled quiescent platelets. In unstimulated cells, both the rate and extent of 32P incorporation into individual inositol-containing phospholipids and phosphatidic acid (PA) were identical in SHR and WKY rats. This suggests that the pool size and basal turnover of phosphoinositides did not differ between the two strains. In contrast, early thrombin-induced phosphoinositide metabolism, when monitored as changes in 32P-PA, was significantly higher in SHR than in WKY rats. Following thrombin stimulation, 32P-PA formation likely reflects the initial agonist-receptor interaction; therefore, our results suggest that phospholipase C activity is enhanced in SHR platelets. Thus, it can be postulated that the observed hypersensitivity of SHR phospholipase C may play a role in the overall alteration of cell calcium handling and hence in the SHR platelet response.
J Cardiovasc Pharmacol 1988
PMID:Relationship between enhanced phosphoinositide turnover and cellular responses in platelets from spontaneously hypertensive rats. 245 17

The thrombolytic dose-response effectiveness and pharmacokinetics of tissue-type plasminogen activator (rt-PA) was evaluated in anesthetized, open-chest dogs instrumented for the measurement of systemic hemodynamics. Intracoronary thrombi were formed by injecting thrombin (100 U) and CaCl2 (50 microM) into a cannulated, isolated segment of the left anterior descending coronary artery (LAD). Coronary blood flow was measured by placing an electromagnetic flow probe proximal to the LAD thrombus. Thirty minutes after formation of a stable LAD thrombus, intravenous infusion of rt-PA was given at rates of 0.5, 1, 2, 4, or 8 micrograms/kg/min (n = 8/dose) for 60-90 min, and the animals were followed for an additional 30 min. In vehicle-treated animals, residual thrombus wet weight, determined at the end of the experiment, was 30 +/- 4 mg (mean +/- SEM, n = 8) and spontaneous reperfusion did not occur. The rt-PA produced a dose-related increase in the number of animals reperfusing, a decrease in the time to reperfusion, and a decrease in residual thrombus weight, but had no effect on systemic hemodynamics. The increase in infusion rate from 0.5 to 4 micrograms/kg/min resulted in a linear increase in both the steady-state rt-PA plasma concentration and the area under the rt-PA plasma concentration versus time curve (n = 3-5 animals/dose); between the infusion rates of 4 and 8 microgram/kg/min there was a disproportionate increase in both these parameters that was due to a decrease in the total systemic clearance of rt-PA. The postdosing elimination half-life (t1/2 alpha) did not differ significantly at any dose of rt-PA, and the pooled half-life (t1/2 alpha) for all doses of rt-PA was 2.36 +/- 0.12 min (n = 19).(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1988 Sep
PMID:Evaluation of the acute hemodynamic effects and pharmacokinetics of coronary thrombolysis produced by intravenous tissue-type plasminogen activator in the anesthetized dog. 246 3

The present study was undertaken to clarify the underlying mechanisms responsible for contractions of isolated coronary arteries and aortae from rabbits in response to thrombin-stimulated autologous platelets. Thrombin-stimulated platelets evoked potent contractions of both arteries in a platelet concentration-related manner. Pretreatment of platelets with aspirin, which almost completely inhibited thromboxane A2 synthesis but not the release reaction of biologic monoamines from platelets, caused only slight suppression of platelet-induced contractions of both arteries. Ketanserin as well as methysergide markedly inhibited aortic contractions to platelets. In contrast, the contractile responses of coronary arteries to platelets were suppressed by methysergide but not by ketanserin. Pretreatment of the arteries with diphenhydramine did not inhibit the aortic responses to platelets, but significantly suppressed coronary arterial contractions induced by higher concentrations of platelets. Phentolamine had no inhibitory effects on the responses of either artery to platelets. Pretreatment of arteries with aspirin did not affect the contractile responses of either artery to platelets. The contractile responses of aortae to exogenously administered serotonin were competitively antagonized by ketanserin, but those of coronary arteries were not. Coronary contractions to serotonin were competitively inhibited by methiothepin and significantly suppressed by methysergide. The contractile responses of both arteries to histamine were antagonized by diphenhydramine but not by cimetidine. On the basis of our results obtained from studies in organ chamber, we conclude that a major role of thromboxane A2 was not demonstrated in platelet-induced contractions of the arteries, and that those of aortae were mainly mediated by platelet-derived serotonin at S2 receptor and those of coronary arteries at S1-like receptor. The contractions of coronary arteries in responses to higher concentrations of platelets were partly mediated by histamine at H1 receptor.
J Cardiovasc Pharmacol 1989 May
PMID:Role of serotonin, histamine, and thromboxane A2 in platelet-induced contractions of coronary arteries and aortae from rabbits. 247 28

Preproendothelin-1 (ppET-1) mRNA has previously been demonstrated to be markedly induced in cultured endothelial cells (EC) by the addition to the medium of thrombin, an agent known to stimulate phosphoinositide turnover in EC. In this study, the mechanism of regulation of ppET-1 mRNA expression was investigated in cultured human umbilical vein EC by RNA blot analysis with cloned ppET-1 gene as a probe. The mRNA for ppET-1 was rapidly upregulated by O-tetradecanoylphorbol-13-acetate (TPA) (0.5 microM) and by ionomycin (5 microM) within 10 min of addition to the medium, but not by forskolin (50 microM). The rapid induction of ppET-1 mRNA by TPA or ionomycin occurred even in the presence of cycloheximide, indicating that the mRNA induction does not require de novo protein synthesis. The ppET-1 mRNA was an extremely unstable species of mRNA with an apparent half-life of about 15 min. However, the half-life of ppET-1 mRNA was not appreciably affected by TPA or ionomycin, suggesting that the mRNA induction by these agents is mostly due to an activation of the transcription of the mRNA. These observations indicate that the production of ET-1 in human EC can be controlled by a transcriptional gene regulation directly coupled to the intracellular signals from the phosphoinositide-turnover pathway, i.e., activation of protein kinase C and increase in intracellular Ca2+. These mechanisms are discussed in relation to information on the primary structure of cloned ppET-1 gene.
J Cardiovasc Pharmacol 1989
PMID:The human preproendothelin-1 gene: possible regulation by endothelial phosphoinositide turnover signaling. 247 87

We investigated the in vivo vasoconstrictor effects of endothelin-1 (ET-1) on canine coronary arteries and the regulation of ET-1 gene expression with special reference to the pathogenesis of coronary vasospasm. ET-1, administered into the coronary arteries of anesthetized dogs, produced a profound and long-lasting reduction in coronary blood flow with myocardial ischemia. Coronary angiography revealed delayed filling of the distal branches and, in some cases, total occlusion in the epicardial portions of coronary arteries. The coronary vasoconstriction induced by ET-1 subsided after intracoronary administration of nitroglycerin. Pretreatment with the Ca2+-channel antagonist, nitrendipine, suppressed ET-1-induced vasoconstriction. In cultured porcine aortic endothelial cells, ET-1 gene expression was induced by agents related to thrombus formation, such as thrombin and transforming growth factor beta (TGF beta). These findings suggest that ET-1, produced by vascular endothelial cells, may contribute to the regulation of coronary circulation and the pathogenesis of coronary vasospasm with respect to intimal injury and subsequent thrombus formation.
J Cardiovasc Pharmacol 1989
PMID:The possible role of endothelin-1 in the pathogenesis of coronary vasospasm. 247 88

Endothelin-1 (ET-1) has been identified in the conditioned medium of porcine endothelial cells. Human endothelin (ET-1) cloned from a placenta cDNA library is similar to porcine, but it is not known whether endothelin itself is secreted by human endothelial cells. To answer this question, a conditioned medium taken every 48 h from confluent cultures of umbilical vein endothelial cells was analyzed by HPLC and all fractions were tested for their ability to inhibit [125I]ET-1 binding on human placenta membranes. Only one fraction did inhibit [125I]ET-1 binding. When the conditioned medium was spiked with ET-1, the same single fraction inhibited [125I]ET-1 binding showing that ET-1, itself, is present in the conditioned medium of human endothelial cells. ET-1 accumulates with time, reaching a plateau at 48 h. ET-1 secretion is not increased by a 24-h incubation of endothelial cells with phorbol myristate acetate, interleukin-1, tumor necrosis factor, thrombin or neuropeptide Y.
J Cardiovasc Pharmacol 1989
PMID:Human cultured endothelial cells do secrete endothelin-1. 247 22

Oral anticoagulants have been used for over three decades in long-term post-myocardial infarction treatment. The cumulated results of the early clinical trials showed a reduction of general mortality of 20%. The reduction reached 60% when trials with adequate anti-coagulant treatment were considered. The most recent study (Sixty Plus Study 1980), a very well designed and conducted study with optimal anticoagulant dosage, reported a 2-year reduction in total mortality of 43% (p less than 0.017 vs. controls) and a reduction of reinfarction of 64.1% (p less than 0.0002). However, the incidence of major hemorrhagic episodes (27 vs. 3) and of definite intracranial hemorrhages (8 vs. 1) was very high in the treatment group with 6 deaths vs. 1 due to hemorrhage. An alternative way for controlling blood clotting activation and thrombin generation appears to be low-dose heparin treatment. In a randomized controlled clinical trial heparin administered in low doses (12,500 i.u. daily by subcutaneous route) reduced the reinfarction rate by 63% (p less than 0.05 vs. controls) and general mortality by 47% (p less than 0.05) over 2 years. Even the frequency of the fatalities attributable to thromboembolic events was significantly decreased. No hemorrhagic complication occurred in any patients. Oral anticoagulants and low-dose heparin appears to be equally effective in secondary prevention of myocardial infarction. However, low-dose heparin treatment appears to be free from the elevated risk of major hemorrhages related to oral anticoagulants and does not require any blood clotting check.
J Cardiovasc Pharmacol 1989
PMID:Blood clotting active drugs in long-term post-myocardial infarction treatment. 248 37


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