Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the inhibitory effect of porcine C-type natriuretic peptide (CNP) on endothelin-1 secretion stimulated by thrombin and angiotensin II (Ang II) in cultured porcine endothelial cells. The results were compared with the effects of atrial (ANP) and brain (BNP) natriuretic peptides. Thrombin and Ang II produced a concentration-dependent stimulation of immunoreactive endothelin-1 secretion, and porcine CNP-22 potently inhibited this stimulated secretion in a concentration-dependent manner. CNP-22 had a stronger inhibitory effect than either porcine ANP(1-28) or porcine BNP-26. In addition, CNP potently increased the cellular level of cyclic guanosine 3',5'-monophosphate (GMP), with the inhibition of immunoreactive endothelin-1 secretion in response to thrombin and Ang II being paralleled by the increase in the cyclic GMP level. The increase of cyclic GMP produced by CNP was also greater than that due to porcine ANP(1-28) or porcine BNP-26. The immunoreactive endothelin-1 in the culture medium had two components on high-performance liquid chromatography; the major one corresponded to endothelin-1 (1-21) and the minor one to big endothelin-1 (porcine 1-39). Treatment with CNP did not affect this profile. Our results suggest that CNP probably inhibits the endothelin-1 secretion stimulated by thrombin and Ang II through a cyclic GMP-dependent process. The increase of cyclic GMP levels and the inhibition of immunoreactive endothelin-1 secretion produced by CNP appear to be greater than those produced by ANP or BNP.
Hypertension 1992 Apr
PMID:C-type natriuretic peptide inhibits thrombin- and angiotensin II-stimulated endothelin release via cyclic guanosine 3',5'-monophosphate. 131 93

Of 165 consecutive patients undergoing computerized tomography- or magnetic resonance imaging-guided stereotactic brain biopsies at the Cleveland Clinic between June, 1987, and November, 1989, four patients (2.4%) developed arterial hemorrhage refractory to conventional efforts to secure hemostasis. Craniotomy was performed in one of these patients to control the hemorrhage; in the other three, 0.5 to 2 cc of thrombin (5000 U/cc) was slowly injected via the biopsy cannula, resulting in immediate control of bleeding in all three cases. Postoperatively, the first two patients treated with 1 to 2 cc of thrombin were slow to awaken; one had evidence of vasospasm by transcranial Doppler ultrasound studies and multiple infarcts on cranial computerized tomography, while the other had a moderate-sized frontal hematoma with intracranial hypertension. After prolonged recovery periods, only mild neurological deficits persisted in both patients. The third patient, treated with 0.5 cc of thrombin, had an uneventful postoperative course. Thrombin is highly effective for stopping intractable arterial hemorrhage during stereotactic brain biopsy; however, it is a vasospastic agent and may have been responsible for the cerebral infarctions in one patient. Therefore, thrombin should be used only as a last resort, short of craniotomy, to control intractable arterial hemorrhage during stereotactic brain biopsy.
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PMID:Treatment of intractable arterial hemorrhage during stereotactic brain biopsy with thrombin. Report of three patients. 198 4

It was reported that in essential hypertension, basal platelet free cytosolic (Ca)i measured with the fluorescent dye Quin 2, is elevated, but increases normally after thrombin stimulation. These data, were interpreted to suggest that plasma membrane fluxes are altered but the release of internal Ca2+ stores is intact. Previous studies have shown that Quin 2 inhibits Ca2+ release from internal stores following thrombin (T)-stimulation. Thus, we reassessed resting and T-stimulated platelet (Ca)i using the fluorescent dyes Fura 2 or Quin 2 in 11 subjects, 5 controls and 6 hypertensives. Mean basal (Ca)i with Quin 2 in controls was 138 +/- 15 nM vs 114 +/- 11 nM in hypertensives, (NS). By contrast, in the same platelet preparation (Ca)i with Fura 2 was higher in hypertensives than controls, 217 +/- 27 nM vs 120 +/- 4 nM, P less than .05. Blood pressure was correlated to (Ca)i obtained with Fura 2, R = 0.55. Thrombin 0.5 U/ml added to platelets in Ca-free media caused a multiphasic rise in (Ca)i with Fura 2. Although the absolute rise in (Ca)i in controls (592 +/- 104 nm) vs hypertensives (512 +/- 60 nm) did not differ, the % rise was less in hypertensives. Thus, 1) in the same population a higher resting (Ca)i was detected in platelets from essential hypertensives with Fura 2, but not with Quin 2; and 2) Ca2+ release from internal stores is altered in hypertension. Thus, Fura 2 is superior to Quin 2 in evaluating platelet (Ca)i.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Basal and stimulated cytosolic platelet calcium in essential hypertension. 233 78

There is controversy as to whether platelet intracellular free calcium ([Ca2+]i) is increased in spontaneously hypertensive rats (SHR) as compared with Wistar-Kyoto (WKY) rats. Discrepant results may be due to methodological problems including platelet activation during the collection process and leakage of intracellular dye used for [Ca2+]i measurement. To provide further insight into this problem, [Ca2+]i was estimated in fura-2-loaded platelets isolated from eight SHR and seven WKY rats at 12-14 weeks of age by using a two-syringe blood collection method and a correction method for fura-2 leakage. Basal [Ca2+]i was higher in SHR than in WKY rats (61.6 +/- 5.6 vs. 54.0 +/- 3.9 nM, p less than 0.02). However, the difference disappeared when a correction for fura-2 leakage was not used (109.7 +/- 18.4 vs. 94.9 +/- 9.2 nM, p less than 0.1). Thus, differences in [Ca2+]i between SHR and WKY rats may be obscured if dye leakage from platelets is not taken into account. Thrombin (0.1 units/ml) induced a rise in [Ca2+]i that was greater in SHR than WKY rats, both in the presence (491.4 +/- 31.6 vs. 377.5 +/- 21.7 nM, p less than 0.002) and absence (264.9 +/- 33.6 vs. 228.2 +/- 30.1 nM, p less than 0.05) of calcium in the media. These results indicate that thrombin-stimulated calcium influx as well as discharge of calcium from intracellular stores is increased in SHR platelets. Thus, under both basal and stimulated conditions, platelet calcium handling is abnormal in the SHR.
Hypertension 1990 Jun
PMID:Abnormal calcium handling by platelets of spontaneously hypertensive rats. 234 23

The mechanism of platelet dysfunctions in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated. Platelet aggregation was inversely correlated with blood pressure or heart weight/body weight ratios in various strains of spontaneously hypertensive rats (SHR), indicating genetic defects. Thrombin-induced 47 kDa protein phosphorylation was markedly reduced in platelets of SHRSP compared with that in Wistar-Kyoto (WKY) rat platelets, accompanying reduced aggregation and secretion, but in 20 kDa protein phosphorylation was unchanged. Ca2+ ionophore A23187-induced responses were also significantly decreased in SHRSP, and the degrees of the changes were greater than those by thrombin. However, 12-O-tetradecanoylphorbol 13-acetate-induced responses in SHRSP were similar to those in WKY rats, suggesting that protein kinase C activity and its substrate were normally present in SHRSP platelets. Phosphatidylinositol content in platelets of SHRSP was 20% less than that in WKY rat platelets, but the contents of other phospholipids, including phosphatidylinositol-4-monophosphate and phosphatidylinositol-4,5-bisphosphates, were unaltered. Thrombin-induced formation of diacylglycerols and phosphatidic acid did not differ from each other at the low concentrations. In the absence of Ca2+, thrombin-induced responses occurred to a similar degree in both platelets, whereas the enhancements by Ca2+ were much greater in WKY rats than in SHRSP. These results suggested that defective Ca2+ functions in receptor-mediated activation of protein kinase C and postkinase-mediated events appear to be an underlying mechanism for the hypofunctions in SHRSP platelets.
Hypertension 1989 Sep
PMID:Defective protein phosphorylation associated with hypofunctions in stroke-prone spontaneously hypertensive rat platelets. 250 71

Thrombin-induced aggregation and serotonin release were markedly enhanced in platelets from spontaneously hypertensive rats (SHR) when compared with those from normotensive Wistar-Kyoto rats (WKY). Since phosphoinositides are involved in calcium-mediated platelet responses, the metabolism of these lipids was investigated in SHR and WKY 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 were identical in SHR and WKY. This finding 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]phosphatidic acid, was significantly higher in SHR than in WKY. For example, a 20-second exposure to thrombin, 0.3 U/ml, induced the formation of 1.6 times more [32P]phosphatidic acid in SHR than in WKY. These results provide evidence for a leftward shift of the dose-response and time-course curves of thrombin-induced [32P]phosphatidic acid formation in SHR. Moreover, the extent of the difference between SHR and WKY was independent of the extracellular calcium concentration. Following thrombin stimulation, [32P]phosphatidic acid formation likely reflects the initial agonist-receptor interaction; therefore, these results suggest that phospholipase C activity is enhanced in platelets of SHR and that the hypersensitivity of phospholipase C in SHR may play a role in the overall alteration of cell calcium handling and, hence, in the platelet responses of SHR.
Hypertension 1987 Nov
PMID:Hypersensitivity of phospholipase C in platelets of spontaneously hypertensive rats. 282 75

We have shown earlier that abnormal platelet aggregation in spontaneously hypertensive rats (SHR) is not caused by prostaglandins. In this study platelets from SHR and normotensive (Wistar Kyoto, WKY) rats were used to examine the role of phosphoinositides and phosphorylation of 47,000 and 20,000 Dalton proteins in abnormal platelet activation in hypertension. Thrombin (0.05 U/ml) induced a rapid decrease in (32P)-P04 labelled phosphatidylinositol-4, 5-bisphosphate (PIP2), phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol (PI) in washed rat platelets. However, significantly greater loss of PIP2 and PI was seen in SHR platelets than in WKY platelets. For example the level of PIP2 declined by 32% in SHR platelets and only by 13% in WKY platelets at five seconds of incubation with thrombin. The loss of PI was similar in SHR and WKY platelets for the first five seconds of incubation with thrombin. However, by 15 seconds SHR platelets showed a significantly greater loss (24%) in PI than in WKY platelets (8%). Thrombin induced a 14% and 18% decrease in PIP at three seconds in WKY and SHR platelets respectively. In SHR platelets PIP level returned to the baseline in five seconds and then rose to 20% above the baseline by 30 seconds. In contrast PIP level in WKY platelets slowly reached the basal value by 30 seconds. Thrombin also produced a two- to three-fold greater accumulation of (32P)-phosphatidic acid (PA) in SHR platelets than in WKY platelets. Thrombin (0.05 U/ml) induced rapid phosphorylation of 47,000 Dalton (P47) and 20,000 Dalton (P20) proteins in both WKY and SHR platelets. Thrombin induced a four-fold greater increase in phosphorylation of P47 in SHR platelets than in WKY platelets in the first five seconds. Thrombin produced significantly greater increase in phosphorylation of P20 in SHR platelets (34% and 41%) than in WKY platelets (18% and 28%) at 5 and 15 seconds. Phosphorylation of P20 was followed by dephosphorylation in both WKY and SHR platelets. Aspirin (500 microM) did not affect phosphorylation of either P47 or P20 in SHR or WKY platelets. In other experiments prostaglandin E1 (0.5 microM), which stimulates adenylate cyclase via a guanine nucleotide regulatory protein termed Gs, caused an eighteen-fold increase in cyclic AMP level in SHR platelets as compared to a six-fold increase in WKY platelets. These data lead us to suggest that increased turnover of phosphoinositides and increased phosphorylation of P47 and P20 are involved in abnormal platelet activation in SHR platelets.
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PMID:Thrombin-induced abnormal platelet activation in spontaneously hypertensive rats is linked with phosphoinositides turnover and phosphorylation of 47,000 and 20,000 dalton proteins. 283 38

Thrombin-induced serotonin secretion from platelets from age-matched spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) was compared in the presence of different Ca2+ and Mg2+ concentrations. Platelets from SHR were more reactive than those of WKY, and the difference was more marked in 11-week-old than in younger rats. The responses to three concentrations of extracellular Ca2+ and one extracellular Mg2+ concentration of 10(-3) M were compared. A high external Ca2+ concentration (2 X 10(-3) M) increased secretion in platelets of both strains without suppressing the difference between them. Platelets from SHR were more sensitive than those from WKY to a low external Ca2+ concentration (2 X 10(-6) M). Platelet secretion which is independent of external Ca2+ concentration was higher in platelets from SHR than in those from WKY. External Mg2+ exerted an inhibitory effect on serotonin secretion in both types of platelets, but platelets from SHR were less sensitive to Mg2+ than were those from WKY. This inhibitory effect appeared to be complex. It could be observed in the absence of external Ca2+, and in this case, the difference in reactivity between platelets SHR and WKY depended on the external Mg2+ concentration (up to 2 X 10(-3) M). Furthermore, a Mg2+ -induced antagonism of the stimulatory effect of external Ca2+ concentration appeared at higher concentrations of extracellular Mg2+ and was more potent in platelets from WKY than in those from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1986 Aug
PMID:Hyperreactivity of platelets from spontaneously hypertensive rats. Role of external magnesium. 373 14

We examined the role of thromboxane in mediating the alterations in pulmonary hemodynamics and in lung fluid and protein exchange after thrombin. Studies were made in control sheep and in sheep pretreated with the thromboxane synthetase inhibitor, Dazoxiben (injection of 10 mg/kg followed by infusion of 4 mg/kg per hr). Thrombin infusion caused an increase in mixed venous and aortic concentrations of thromboxane B2, a stable degradation product of thromboxane A2, whereas the concentrations of 6-keto-PGF1 alpha, a degradation product of prostacyclin, did not change significantly. In sheep pretreated with Dazoxiben, thromboxane B2 concentrations did not increase, indicating effectiveness of the thromboxane synthetase inhibitor. The blood concentrations of 6-keto-PGF1 alpha after thrombin increased in the thromboxane synthetase-inhibited group, indicating shunting towards prostacyclin synthesis. Thrombin in untreated sheep increased pulmonary lymph flow (Qlym) and the lymph protein clearance (Qlym X lymph-to-plasma protein concentration ratio). The increases in lymph parameters were due to an increase in pulmonary vascular permeability to proteins because raising left atrial pressure further increased Qlym but did not change lymph-to-plasma ratio. Dazoxiben prevented the thrombin-induced increase in pulmonary vascular permeability because the increase in left atrial pressure resulted in an increase in Qlym and a decrease in lymph-to-plasma ratio, as was the case after left atrial hypertension in normal animals. Therefore, thrombin results in selective release of thromboxane A2 which precedes the increase in pulmonary vascular permeability. Thromboxane A2 may contribute to the increased permeability after thrombin, since inhibition of thromboxane synthesis prevents the permeability change.
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PMID:Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance. 668 1

We examined the relationship between the activation of fibrinolysis and the increase in lung vascular permeability after pulmonary microembolization (PM). Sheep were prepared with lung lymph fistulas to assess pulmonary transvascular fluid and protein dynamics. Studies were made in three groups: group I (n = 8) in which PM was induced by an iv infusion of thrombin (60 +/- 13 NIH U/kg); group II (n = 7) in which PM was induced by an iv infusion of 50-micrometers-diameter fibrin microaggregates (0.32 +/- 0.009 g/kg); and group III in which the left atrial pressure was increased by 10-15 Torr by inflation of a balloon catheter. Thrombin caused an increase in pulmonary lymph flow (Qlym) without a change in the lymph-to-plasma protein concentration ratio (L/P ratio) indicating an increase in the lung vascular permeability to proteins. Fibrin microaggregates also increased Qlym, but the increase was associated with a decrease in the L/P ratio. The results in the latter group were similar to those obtained after left atrial hypertension in normal sheep. The increase in permeability after PM induced with thrombin was associated with large increases in the plasma concentration of fibrin degradation products, as compared with PM induced by fibrin microaggregates. The process of intravascular coagulation with the resultant generation of fibrinolysis and fibrin degradation products may be required for the increase in lung vascular permeability to proteins after pulmonary microembolization.
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PMID:Lung fluid balance after pulmonary embolization: effects of thrombin vs. fibrin aggregates. 710 66


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