Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Phospholipase C activity, which influences the control of platelet physiological responses, was investigated in platelets of human essential hypertensives and of spontaneously hypertensive rats (SHR) compared with appropriate normotensive controls, in order to determine whether this enzyme activity could account for the enhanced platelet responses exhibited by hypertensive subjects. After 32P-labelling of cells, the enzyme activity was estimated by measuring the variations in 32P-phosphatidic acid. In resting platelets no difference was observed between hypertensives and normotensives. In contrast, the thrombin-induced increase in 32P-phosphatidic acid in platelets of human hypertensives and of SHR was 30% higher than in controls, suggesting hypersensitivity to phospholipase C in hypertensives. Since, as revealed by phorbol-stimulated phosphorylation of 47-kilodalton protein, intrinsic protein kinase C activity is similar in SHR and controls, our data strengthen the hypothesis than hypersensitivity to phospholipase C influences the hyperreactivity of platelets in primary hypertension.
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PMID:Impaired phospholipase C activity is involved in the hyperreactivity of platelets in primary hypertension. 324 Dec 20

Blood platelets of patients with essential hypertension display signs of both increased sensitivity in vitro to aggregating stimuli believed to contribute to thrombosis and of activation in vivo possibly expressing the release of vasoactive products. The mean features of the modified platelet profile in hypertension include an increased alpha 2-adrenergic receptor density, an enhanced rate of adhesion/aggregation in particular in response to ADP and arachidonic acid, a greater sensitivity for thrombin and adrenaline to stimulate increases in cytoplasmic-free Ca2+, increased resting levels of cytoplasmatic-free Ca2+, a reduced content of serotonin often combined with a defective uptake mechanism, a facilitated efflux rate of noradrenaline, an exaggerated release reaction in vivo as indicated by the increased plasma levels of Beta-thromboglobulin and a shortened platelet life span. These changes occur to various extents in some, but not all, hypertensive patients and are not always strictly related to the degree of blood pressure increase. On the contrary, platelet cyclooxygenase and thromboxane synthetase activity are in the normal range.
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PMID:Blood platelets in human essential hypertension. 353 21

The effects of a calcium antagonist nifedipine (Adalat) on platelet aggregation was examined in vitro and in vivo. In vitro examination: Platelet aggregation induced by adenosine disphosphate (ADP), epinephrine, collagen, arachidonate, and thrombin was all inhibited dose-dependently in the platelet-rich plasma prepared from the blood of healthy individuals by the addition of nifedipine to a final concentration of 5 or 10 micrograms/ml. In vivo examination: 20 patients with essential hypertension were treated with 30 mg/d of nifedipine for 8 weeks. Significant decreases in both systolic and diastolic pressures were observed 2 weeks after the beginning of the administration, and continued throughout the administration period. ADP-induced platelet aggregation decreased by 25% after 2 weeks, 36% after 4 weeks, and 44% after 8 weeks (p less than 0.05 for all decreases). Plasma thromboxane B2 level also decreased markedly from 217.3 +/- 91.7 pg/ml before the administration to 119.0 +/- 29.7 pg/ml (p less than 0.01) 2 weeks after, and 99.1 +/- 25.4 pg/ml (p less than 0.01) 8 weeks after the beginning of the administration, suggesting suppressed thromboxane A2 production.
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PMID:Effects of the calcium antagonist nifedipine on thromboxane B2 level and platelet aggregation in hypertensive patients. 381 28

Intracellular free calcium, [Ca2+]i, was studied in platelets of essential hypertensive subjects and normotensive controls under basal conditions and after stimulation with epinephrine, norepinephrine, angiotensin II, ouabain, and thrombin, using the fluorescent calcium indicator quin 2. Basal [Ca2+]i was significantly higher in hypertensive subjects (n = 32) than in normotensive controls (n = 30; 167.4 +/- 5.0 vs 143.2 +/- 3.1 nmol/L; p less than 0.001). Epinephrine, norepinephrine, angiotensin II, and ouabain had no effect on platelet calcium, whereas thrombin induced a dose-dependent increase in [Ca2+]i in both the presence and absence of extracellular calcium. This [Ca2+]i increase in the presence of extracellular calcium, which depends mainly on calcium influx, was significantly higher (p less than 0.05) in platelets of hypertensive subjects at all thrombin concentrations (ranging from 0.025-0.1 U/ml), while the [Ca2+]i increase in the absence of extracellular calcium, which depends only on release from intracellular stores, was similar in hypertensive subjects and controls. These results suggest that, in essential hypertension, there is not only increased platelet resting [Ca2+]i but also an increase in agonist-mediated calcium influx, which appears to indicate a cell membrane abnormality in the platelets of subjects with essential hypertension.
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PMID:Increased basal and thrombin-induced free calcium in platelets of essential hypertensive patients. 381 20

Sensitivity to adrenaline-antagonism of the inhibitory effect of PGI2 on thrombin-induced increase in [Ca2+]i was measured in platelets from normotensive and untreated hypertensive subjects. Platelets from hypertensive subjects exhibited an increased sensitivity to adrenaline. This effect was more pronounced in younger patients with hypertension, and suggests an increased adenylate cyclase sensitivity in the early hypertension. The data also indicate that a mechanism linked to calcium-influx plays an important role in older hypertensives. This may explain the greater efficacy of calcium entry blockers in older hypertensive patients with essential hypertension.
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PMID:Hormonal modulation of intracellular free calcium in platelets from normotensive and hypertensive subjects. 388 86

That adrenaline is involved in the pathophysiology of essential hypertension (EHT) is suggested by the observed elevation of plasma adrenaline concentration in some patients. Adrenaline, by stimulating the alpha-2 adrenoceptor, causes vasoconstriction in the smooth muscle cell and initiates shape change and aggregation in platelets. Therefore, the effect of adrenaline on intracellular free calcium concentration ([Ca2+]i) in the platelets of hypertensive subjects was investigated as a model for vascular smooth muscle. Platelets from untreated patients with EHT had an elevated [Ca2+]i and incubation with adrenaline for 30 min caused a greater increase in [Ca2+]i in treated patients with EHT than in normotensive controls. This long-term effect of adrenaline was possibly linked to a defective calcium extrusion mechanism in hypertension. No immediate effect was observed on [Ca2+]i by PGI2 and adrenaline, while both modulated [Ca2+]i if the platelets were stimulated with thrombin. PGI2 prevented the thrombin-induced increase in [Ca2+]i and adrenaline antagonized the effect of PGI2. Platelets from untreated patients with EHT exhibited an increased sensitivity to thrombin and adrenaline when compared to normotensive and treated hypertensive subjects. It is suggested that these supersensitivities are related to the elevated [Ca2+]i in untreated hypertensive patients.
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PMID:Free calcium response to adrenaline in platelets of normal and hypertensive (untreated and treated) subjects. 640 Mar 64

Using the fluorescent Ca-dependent dye quin-2 the authors measured the concentrations of free calcium in the platelet cytoplasm of rats with spontaneous hypertension (SHR) and in normotensive rats (NKWR) serving as control. There were no differences in the baseline levels of free Ca2+ between the platelets of the SHR and NKWR rats. When the cells were loaded with quin-2 in a calcium-free medium and transferred into a medium containing 1 mM of CaCl2, the concentration of Ca2+ in the platelets of the SHR rats became higher. An increase in the content of intracellular Ca2+ induced by thrombin administration was 70% higher in the platelets of the SHR rats as compared with the NKWR rats. The findings obtained suggest that the insufficiency of the Ca-transporting systems of the cellular membranes in primary hypertension described earlier is attended with disturbances in the regulation of the levels of cytoplasm free calcium.
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PMID:[Intracellular concentration of free calcium in thrombocytes: its characteristics in spontaneous hypertension]. 644 Oct 63

Enhanced Na+/H+ exchange has been reported to be increased in patients with essential hypertension. However, early variations of intracellular pH, although influenced by the antiport, are only partially dependent on the exchange. In this study, we measured the initial platelet pH response to agonists in a group of untreated subjects with essential hypertension (EH, n = 24) and in a group of age- and sex-matched normotensive control subjects (CS, n = 24). Intracellular pH was measured with the specific fluorescence indicator 2'7'bis(carboxyethyl)-5,6-carboxyfluorescein. Measurements were performed on platelets in the presence or absence of extracellular calcium, in a carbonate-free medium. Intracellular calcium was measured by the Fura 2 method. Mean pH values were slightly higher in the platelets of EH (7.469 +/- 0.017 U) compared with CS (7.423 +/- 0.012 U, P < .05), although there was a substantial overlap. When stimulated with physiologic agonists ADP and thrombin and with the calcium ionophore ionomycin, a biphasic response consisting of early acidification followed by alkalinization was observed, the second phase not being detectable with ADP. The initial acidification was greater in EH, particularly with ADP (EH, -0.046 +/- 0.002 U; CS, -0.036 +/- 0.002 U, P < .001) and with ionomycin (EH, -0.074 +/- 0.007 U; CS, -0.051 +/- 0.005 U, P < .05). This acidification proved in some way calcium dependent, as it was reduced in the absence of extracellular calcium (EGTA) in both EH and CS. After incubation with amiloride a further decrease in intracellular pH, more marked in EH, was observed. Alkalinization induced by thrombin was increased in EH (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early agonist-induced intracellular acidification is increased in platelets from patients with essential hypertension. 770 4

To investigate the possible relationships between blood pressure, parathyroid hormone (PTH) and platelet cytosolic Ca2+ concentration ([Ca2+]i) in patients with essential hypertension, we studied 17 patients with this disease aged 48 +/- 2 years and 17 normotensive controls aged 44 +/- 3 years. Platelet [Ca2+]i was measured by spectrofluorimetry using the dye Fura-2 acetoxymethylester. Patients with essential hypertension displayed lower levels of serum ionized Ca2+ (0.99 +/- 0.03 versus 1.1 +/- 0.01 mmol/l, P < 0.05) and higher serum intact PTH levels (37 +/- 3 versus 26 +/- pg/ml, (P < 0.01) than the normotensive controls. Although serum levels of intact PTH were significantly correlated with mean arterial pressure (MAP) in the combined group of subjects (r = 0.42, P < 0.05), there was no correlation when each group was considered separately. Resting platelet [Ca2+]i was also higher in patients than in controls (57 +/- 3 versus 48 +/- 2 nmol/l, P < 0.005). When platelets were stimulated in vitro with thrombin, the increment in [Ca2+]i was also greater in patients than in controls in the presence of extracellular Ca2+ (264 +/- 24 versus 194 +/- 19 nmol/l, P < 0.05) but not in its absence (123 +/- 12 versus 112 +/- 10 nmol/l). The thrombin-induced increment in [Ca2+]i was correlated with MAP in the hypertensive patients (r = 0.64, P < 0.01) and in the combined group of subjects (r = 0.42, P < 0.05). There was no relationship between resting or thrombin-induced [Ca2+]i and serum PTH in either group of patients or in the combined group of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone and platelet cytosolic calcium concentration in essential hypertension. 779 32

Differences in cation transport have been observed between African Americans and whites. These differences may underlie the increased predisposition of African Americans to essential hypertension. To further explore these racial differences, we used platelets as a cellular model for calcium regulation. We measured 45Ca fluxes in platelets from 21 African American and 25 white men. Additionally, using fura 2, we measured cytosolic free calcium levels in resting platelets and platelets treated with ouabain and thrombin. Platelet 45Ca uptake was described by two exchangeable pools: a small, rapidly exchangeable pool and a larger, slowly exchangeable pool. Both pools were larger in platelets from African Americans than from whites (263 versus 185 pmol per 1 x 10(8) platelets for the rapidly exchangeable pool, P < .05; 744 versus 532 pmol per 1 x 10(8) platelets for the slowly exchangeable pool, P < .01). 45Ca washout was described by a rapidly exchangeable pool and a static pool. The former was also higher in platelets from African Americans than from whites (246 versus 202 pmol per 1 x 10(8) platelets, P < .01). The cytosolic free calcium concentrations in resting platelets were lower in African Americans than in whites. After treatment with ouabain and thrombin, the sustained posttransient levels of cytosolic free calcium increased to a greater extent in platelets from African Americans (46.7 nmol/L) than from whites (34.5 nmol/L, P = .033). Platelets from African Americans demonstrate higher intracellular calcium stores than platelets from whites. This racial difference could explain the sensitivity of African Americans to vasoactive agents acting through calcium mobilization from intracellular stores and cytosolic calcium.
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PMID:Increased calcium stores in platelets from African Americans. 787 63


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