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

Adrenomedullin recently has been found to potently stimulate cAMP formation in cultured rat vascular smooth muscle cells (VSMCs). In the present study, we examined the effect of adrenomedullin on the production of a vasoconstrictive and growth-promoting peptide, endothelin-1, after stimulation with a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF), in cultured rat VSMCs. Thrombin and PDGF stimulated endothelin-1 production in a dose-dependent manner. Rat adrenomedullin significantly inhibited thrombin- and PDGF-stimulated endothelin-1 production in a dose-dependent manner between 10(-7) and 10(-9) mol/L. Inhibition by rat adrenomedullin of thrombin- and PDGF-stimulated endothelin-1 production was paralleled by an increase in the cellular level of cAMP. Human adrenomedullin also inhibited thrombin- and PDGF-stimulated endothelin-1 production and increased cAMP levels. The addition of 8-bromo-cAMP, a cAMP analogue, reduced thrombin- and PDGF-induced endothelin-1 production. Furthermore, forskolin, a potent activator of adenylate cyclase, reduced thrombin- and PDGF-induced endothelin-1 production. In contrast, basal production of endothelin-1 was not altered by rat or human adrenomedullin. These results indicate that adrenomedullin inhibits not basal but thrombin- and PDGF-induced ET-1 production in cultured VSMCs probably through a cAMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may modulate vascular tone as a paracrine regulator partially through the inhibition of VSMC endothelin-1 production in some pathophysiological states.
Hypertension 1995 Jun
PMID:Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. 776 61

This study was conducted to determine the mechanisms of increased platelet reactivity to thrombin in hypertension. Thrombin induced significantly greater platelet aggregation in spontaneously hypertensive (SHR) than in normotensive (Wistar Kyoto, WKY) rats. Fibrinogen and thrombin binding to platelets was determined using [125I]-fibrinogen and [125I]-thrombin respectively. Increased platelet aggregation in SHR correlated with thrombin-induced greater binding of fibrinogen to SHR than to WKY platelets. However, the number of thrombin receptors (binding sites/platelet) in WKY (19,500 +/- 3,000) and SHR (23,100 +/- 3,000) as well as thrombin dissociation constants were statistically similar in WKY (1.17 +/- 0.2 microM) and SHR (1.62 +/- 0.27 microM) platelets. Fura 2/AM, a fluorescent calcium indicator, loaded platelets were used to quantify the platelet ionized calcium ([Ca2+]i). The [Ca2+]i in unstimulated SHR and WKY platelets was essentially the same. In a calcium poor medium, thrombin-induced a 35% greater increase in [Ca2+]i in SHR than in WKY platelets. These data, taken together with our earlier observations that thrombin induces a significantly greater hydrolysis of phosphoinositide (Thromb. Res. 49, 5-21, 1988), lead us to suggest that thrombin-induced increased generation of inositol 1,4,5-trisphosphate and diacylglycerol induces greater fibrinogen binding and consequently increased aggregation in SHR than WKY platelets. The finding that the thrombin binding isotherms are similar in WKY and SHR platelets suggests that increased platelet sensitivity to thrombin in hypertension may be due to altered signal transduction and not due to changes in the number or affinity of thrombin receptors.
 ...
PMID:Normal thrombin binding leads to greater fibrinogen binding and increased platelet aggregation in spontaneously hypertensive rats. 825 59

Hypertension is a major complication of rHuEPO therapy in hemodialysis (HD) patients. We have previously reported that patients receiving rHuEPO intravenously (i.v.) had higher mean arterial pressure (MAP) and plasma endothelin-1 (ET-1) levels than those in which the hormone was administered subcutaneously (s.c.). To test whether the increased serum ET-1 levels associated with i.v. rHuEPO administration are the result of a direct effect of the hormone on ET-1 release by the endothelial cells (EC), we examined the effects of rHuEPO in vitro. Bovine pulmonary artery endothelial cells (BPAEC) were exposed to doses of rHuEPO of 0.8; 1.6; 3.3 and 6.6 U/ml. A 24 hour-time course showed maximal ET-1 production at 12 hours for all the doses tested. A significant increase in cell proliferation over controls was observed at 24 hours, for all rHuEPO doses, and no correlation was found between ET-1 values and cell proliferation. Inhibition of protein synthesis by cycloheximide (10 micrograms/ml) abolished the stimulation of ET-1 release by rHuEPO. Thrombin (4 U/ml) and angiotensin II (10(-7) M), two potent stimulators of ET-1 release, had additive effects to those of rHuEPO. Specific thrombin and angiotensin II antagonists blocked these additive effects, reducing ET-1 release to the level of rHuEPO stimulation alone. In summary, rHuEPO stimulates vascular EC in culture to increase ET-1 release through an increase in synthesis and in a time dependent fashion. The routes of stimulation seem to differ from other known ET-1 secretogoges. Our data also confirm a significant mitogenic effect of rHuEPO on the endothelial cell.
 ...
PMID:Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. 851 Mar 79

We have reported that cytosolic Ca2+ concentration ([Ca2+]i) is increased in platelets from spontaneously hypertensive rats (SHR) in both basal and thrombin-stimulated conditions. To determine whether the correlation between blood pressure and cellular Ca2+ metabolism exists in stroke-prone SHR (SHRSP), we investigated Ca2+ handling using fura 2 and aggregation response in platelets of 12- to 13-week-old male SHRSP, SHR, and Wistar-Kyoto rats (WKY). Systolic pressure was highest in SHRSP and lowest in WKY (213 +/- 8, 172 +/- 7, and 135 +/- 5 mm Hg, respectively). Basal [Ca2+]i was significantly higher in SHR than WKY (45.9 +/- 4.5 versus 41.2 +/- 4.8 nmol/L, P<.05), and that in SHRSP (40.2 +/- 2.8 nmol/L) was similar to that in WKY. Thrombin (0.1 IU/mL)-stimulated [Ca2+]i rise was greater in SHR and smaller in SHRSP than in WKY in the presence of extracellular Ca2+ (530 +/- 50 and 408 +/- 52 versus 475 +/- 50 nmol/L, respectively; P<.05). The recovery rate from the peak [Ca2+]i response to thrombin was greatest in SHRSP and least in WKY. Ionomycin (5 micromol/L)-stimulated [Ca2+]i rise was similar in WKY, SHR, and SHRSP (731 +/- 97, 743 +/- 88, and 683 +/- 70 nmol/L, respectively). Thrombin-induced maximum platelet aggregation response was higher in SHR and lower in SHRSP than WKY (82 +/- 4 percent and 61 +/- 15 percent versus 73 +/- 6 percent, respectively; P<.05). In contrast to SHR, basal [Ca2+]i in SHRSP was similar to that in WKY, and thrombin-stimulated [Ca2+]i was attenuated. These result suggest that platelet Ca2+ handling differs between SHR substrains and that an increased [Ca2+]i is not obligatory in genetically hypertensive rats.
Hypertension 1996 Jun
PMID:Platelet Ca2+ is not increased in stroke-prone spontaneously hypertensive rats: comparative study with spontaneously hypertensive rats. 864 41

Coagulation parameters and platelet count were studied in 30 neonates of mothers with pregnancy induced hypertension (PIH). 30 neonates born to normotensive mothers were taken as controls. The test group was further subdivided as neonates born to mothers with gestational hypertension, pre-eclamptic toxemia and eclampsia. The values of Prothrombin Time, Partial Thromboplastin Time with Kaolin, Thrombin Time, Fibrinogen Degradation Products were significantly raised and Fibrinogen and Platelet count were reduced significantly in both term and preterm test groups as compared to controls. The derangement in coagulation parameters was more marked with increasing severity of PIH.
 ...
PMID:Pregnancy induced hypertension: changes in coagulation profile of newborns. 881 60

Pregnancy is accompanied by a physiological activation of intravascular coagulation; however without disorder. Normal markers of coagulation are unchanged despite activation. Special coagulation parameter--such as Thrombin-Antithrombin-III-complex (TAT) or D-Dimer are increased also in normal pregnant women. Pregnancy induced hypertension (SIH) and preeklampsia may be associated with a disorder of coagulation that precedes the well known clinical manifestation of hypertension. Therefore it was the aim of the study to distinguish both the pregnancy induced hypertension (15 patients) and preeklampsia (10 patients) as far as it is possible by coagulation parameters such as thrombin generation (by TAT), fibrinolysis (by D-Dimer), AT-III, platelets and others comparing them with 25 normotensive pregnancies. In preeklampsia, the results showed that clinical signs were associated with simultaneous coagulation abnormalities. TAT and D-Dimere are significant increased whereas a decrease of AT-III and platelets was observed. There are no significant differences between SIH and normal pregnancies. Three days after delivery there was an increase of D-Dimer, AT-III and platelets and a decrease of TAT-complex in all groups. For risk pregnancy, the parameters TAT and D-Dimer may be useful as screening test. They although may support confirming the diagnosis of preeklampsia.
 ...
PMID:[Pre- and postpartum hemostatic characteristics in pregnancy-related hypertension and pre-eclampsia in comparison with normotensive pregnancies]. 896 81

Platelet cytosolic free calcium concentration ([Ca2+]i) and pH (pHi) have been reported to be altered in both human essential and rat spontaneous hypertension. The aim of our study was not only to search for the occurrence of such alterations in platelets of rats with salt-induced hypertension but also to investigate whether these changes might precede blood pressure rise in this form of experimental hypertension. Using fluorescent probes fura-2 and BCECF, basal values and thrombin-induced changes of [Ca2+]i and pHi were determined in platelets of young hypertension-prone (SBH) and hypertension-resistant (SBN) Sabra rats fed either low-salt (0.3% NaCl) or high-salt (4% NaCl) diets. Under the conditions of low salt intake, basal [Ca2+]i values were similar in SBH and SBN rats, whereas pHi was significantly lower in SBH than in SBN animals. Thrombin induced smaller [Ca2+]i elevation but greater pHi rise in SBH rats compared with SBN animals. The initial rate of thrombin-induced Mn2+ entry, which reflects the opening of a particular subclass of thrombin-operated Ca2+ channels, was similar in both strains. The moderate hypertension elicited in SBH rats by high salt intake was not associated with major alterations of basal [Ca2+]i or pHi values. High salt diet feeding did not influence [Ca2+]i and pHi responses to thrombin in either strain. In contrast, high salt intake reduced thrombin-induced Mn2+ entry in SBN but not in SBH rats. Basal platelet [Ca2+]i values correlated positively with systolic but not with diastolic blood pressure. This could be ascribed to a very close relationship of basal [Ca2+]i values with pulse pressure. The abnormalities of [Ca2+]i and pHi handling in platelets of Sabra rats with salt-dependent genetic hypertension differ from those described in essential hypertensive patients or rat strains with spontaneous forms of genetic hypertension. Our study also indicated that alterations of platelet [Ca2+]i do not precede blood pressure elevation in salt hypertension.
 ...
PMID:Abnormal regulation of cytosolic calcium and pH in platelets of Sabra rats in early phases of salt hypertension development. 902 81

Thrombin and the atrial natriuretic peptide (ANP) possess a number of functionally antagonistic properties in vascular endothelial cells. Thus, regulatory interactions that modulate the activity of one or the other could have important sequelae with regard to cardiovascular homeostasis. Thrombin treatment effected a dose- and time-dependent reduction in ANP receptor activity (maximal 70% to 80% inhibition) in cultured bovine aortic endothelial cells. This resulted from a decrease in total receptor number as well as a modest reduction in the affinity of the receptor for its ligand. The inhibition was largely confined to the type C receptor population, in that thrombin had no effect on maximal type A receptor-linked cGMP accumulation. The protein kinase C-activating phorbol ester 12-O-tetradecanoylphorbol 13-acetate effected a similar reduction in binding activity; however, suppression of protein kinase C activity did not reverse the thrombin effect. Pretreatment of endothelial cells with cycloheximide did not completely prevent the thrombin-dependent inhibition, and thrombin did not effect a reduction in type C receptor mRNA levels, findings that argue for a postsynthetic inhibitory locus. The inhibition of receptor activity was effectively irreversible in that suspension of protein synthesis blocked the recovery of receptor density on the cell surface. Reduction in type C receptor density was accompanied by modest increases in the stability of ANP in the culture medium and enhancement of the cellular cGMP response to the peptide, particularly at low ligand concentrations. These findings demonstrate a potentially important interaction between these two agonist systems in regulating endothelial cell function within the vascular wall.
Hypertension 1997 Jan
PMID:Thrombin inhibits atrial natriuretic peptide receptor activity in cultured bovine endothelial cells. 903 85

Exposure of rat aortic vascular smooth muscle cells to alpha-thrombin resulted in the appearance of sis-inducing factor-A (SIF-A)-like DNA binding activity. This response to alpha-thrombin was delayed (detectable at 1 hour) compared with the rapid activation (15 to 30 minutes) by platelet-derived growth factor and the cytokine interleukin-6. alpha-Thrombin-induced SIF-A was sensitive to treatment with the tyrosine kinase inhibitor genistein. The thrombin inhibitor hirudin prevented the alpha-thrombin-mediated SIF-A induction. Cycloheximide had no effect on the ability of alpha-thrombin to induce SIF-A, suggesting that induction does not require new protein synthesis. alpha-Thrombin-induced SIF-A could be resolved into two additional subcomplexes termed SIF-A, and SIF-As. Antibodies against Stat3 reacted with alpha-thrombin-induced SIF-Af, suggesting that Stat3 or a related protein is present in this subcomplex. Induction of SIF-A DNA binding activity may contribute to alpha-thrombin-mediated cellular responses, including wound healing, cell proliferation, and inflammation in the vasculature.
Hypertension 1997 Jan
PMID:Alpha-thrombin stimulates sis-inducing factor-A DNA binding activity in rat aortic smooth muscle cells. 903 27

1. Hypofunction of stroke-prone spontaneously hypertensive rat (SHRSP) platelets at developmental ages of hypertension is due to the defective protein (p47) phosphorylation which is mediated by protein kinase C. This study was undertaken to examine the genetic association of platelet functions and vascular reactivity with hypertension using male WKY, SHRSP, F1 and backcross generations at 16-18 weeks of age. 2. The distribution of blood pressure was continuous in each generation. 3. Contraction of mesenteric vascular bed with norepinephrine was positively correlated with blood pressure in the five generations (r = 0.77, n = 128). 4. Thrombin-induced platelet aggregation was inversely correlated with blood pressure (r = -0.87, n = 127). 5. The distribution of platelet aggregation and contraction was continuous in each generation, and backcross generations were not likely to have 1:1 segregation. 6. These results suggest the possibility that platelet hypoaggregability and peripheral vascular resistance are due to the pleiotropic effect of hypertensive genes, or that genes controlling these three characters are closely linked each other.
 ...
PMID:Correlation analysis of blood pressure and platelet aggregation/vascular reactivity in SHRSP, WKY, F1 and backcross generations. 907 15


<< Previous 1 2 3 4 5 Next >>