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)

Arachidonic acid (AA)-induced pressor response and production of thromboxane YXB2, the stable metabolite of TXA2, prostaglandin (PG)-like substance (PLS) and 6-keto-PGF1 alpha the stable metabolite of prostacyclin (PGIs), were studied using isolated, perfused kidneys of 6- and 18-week old spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), two-kidney, one clip hypertensive rats (RHR) and DOCA/salt hypertensive rats (DOCA/salt HR). The AA-induced pressor response and release of TXB2 were highest in the 6-week old SHR, whereas, the release of PLS and 6-keto-PGF 1 alpha was marked in the 18-wek old SHR and the established hypertensive stages of both RHR and DOCA/salt HR. In the kidneys of SHR and WKy, exogenous TXA2 induced a severe vasoconstriction and there was a positive correlation between the AA-induced pressor response and the release of TXB2 or PLS. Thus, the initiation of hypertension in SHR may follow an accelerated synthesis of TXA2 against PGI2 in response to stimuli which induce a release of AA.
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PMID:Enhanced thromboxane A2 biosynthesis in the kidney of spontaneously hypertensive rats during development of hypertension. 722 52

Among endothelial secretogogues prostacyclin (PGI2), nitric oxide (NO) and tissue plasminogen activator (t-PA) play a crucial role in maintaining thromboresistance, tone and structure of the vascular wall. Most receptor agonists, such as B2 kinin receptor agonists, or shear force produce a coupled release of all three secretogogues, and therefore interactions between them are to be expected. Essentially, PGI2 is a platelet suppressant, NO a vasodilator and t-PA a fibrinolytic agent. These and other properties of endothelial secretogogues supplement each other in protecting the cardiovascular system from injuries. It is not surprising that disturbances of the secretory function of endothelial cells are associated with atherosclerosis, diabetes, thrombosis or hypertension. Traditionally, PGI2, NO, t-PA or their substitutes are used individually for the treatment of peripheral arterial disease, angina pectoris or acute myocardial infarction. In light of recent findings, their joint administration can be advocated. For instance, NO donors will potentiate platelet-suppressant action of PGI2 analogues, whereas exogenous PGI2 or TXA2 synthase inhibitors (i.e. following increase in endogenous PGI2) will abolish a paradox of prothrombotic action of t-PA or streptokinase. The replacement therapy with PGI2, NO or t-PA should match as closely as possible the physiologically coupled release of these secretogogues.
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PMID:Interactions between endothelial secretogogues. 754 32

The clinical efficiency and mechanism of traditional Chinese medicinal herb Salvia Miltiorrhizae Bge (SMB) and Ligustrazine (L) on pregnancy induced hypertension (PIH) were studied in 30 patients. Before and after the administration of SMB and L, the following parameters: mean arterial pressure (MAP), proteinuria, levels of Thromboxane A2 (TXA2) and Prostacyclin (PGI2) were observed. TXA2 and PGI2 were measured by their stable hydration products Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by an established radioimmunoassay. The results of treatment were compared with the base line values and showed as follows: MAP and proteinuria decreased significantly (P < 0.05); no marked difference existed in TXB2; the level of 6-keto-PGF1 alpha increased significantly (P < 0.05); the rate of TXB2/6-keto-PGF1 alpha decreased significantly (P < 0.05). The results suggested that SMB and L can invigorate blood circulation by decreasing vasoconstriction.
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PMID:[The effects of Salvia miltiorrhizae Bge and Ligustrazine on thromboxane A2 and prostacyclin in pregnancy induced hypertension]. 771 82

The aim of the present study was to assess whether changes in prostacyclin (PGI2) and thromboxane (TXA2) generation precede the manifestation of pregnancy-induced hypertension (PH). The metabolites 6-oxo-PGF1 alpha and TXB2 were measured in the urine of 69 randomly selected pregnant women from 16-20 weeks of gestation (wg) until delivery and more than 6 weeks postpartum. Between 16-20 and 21-24 wg 6-oxo-PGF1 alpha excretion did not change in patients who later developed PIH (n = 6) but increased significantly in the control group (n = 63). In contrast, a marked rise in TXB2 excretion was found in the PIH group but not in controls. Thereafter significant differences between both groups persisted from 25 wg until delivery. The 6-oxo-PGF1 alpha/TXB2 ratio was below the 10th percentile from 21-24 wg until delivery in patients with developing PIH. The excretion of both metabolites was substantially lower in the non-pregnant state without any difference between patient groups. These results show an altered urinary excretion of both 6-oxo-PGF1 alpha and TXB2 preceding the onset of the disease. A pathophysiological role of PGI2 deficiency and increased TXA2 formation in PIH appears substantiated.
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PMID:Excretion of prostacyclin and thromboxane metabolites before, during, and after pregnancy-induced hypertension. 782 3

LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2-dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619-induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist.
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PMID:Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate. 784 31

We tested the hypothesis that a prostanoid-mediated mechanism of vascular contraction is expressed in rats with aortic coarctation-induced hypertension. Rings of descending thoracic aorta taken from normotensive and hypertensive rats were contrasted in terms of constrictor responsiveness to arachidonic acid (AA), AA-induced release of eicosanoids, and ability to convert exogenous prostaglandin (PG) H2 to PGI2. AA (10(-8) to 10(-5) mol/L) increased isometric tension in aortic rings (bathed in Krebs' bicarbonate buffer) of hypertensive but not normotensive rats. AA (10(-5) mol/L) also elicited the release of PGI2, PGE2, thromboxane (TX) A2, and monohydroxyeicosatetraenoic acids (HETEs); this release from the aortic rings of hypertensive rats exceeded the corresponding release from the aortic rings of normotensive rats. However, the rate of conversion of exogenous PGH2 to PGI2 by aortic rings of hypertensive rats was < 50% the rate of conversion by aortic rings of normotensive rats. The constrictor effect of AA in aortic rings of hypertensive rats was abolished by an inhibitor of cyclooxygenase (indomethacin, 10 mumol/L) and a blocker of TXA2-PGH2 receptors (SQ29548, 1 mumol/L) but was not affected by an inhibitor of TXA2 synthesis (CGS13080, 10 mumol/L), suggesting mediation by PGH2. The lipoxygenase inhibitor baicalein (75 mumol/L) also attenuated the constrictor effect of AA in aortic rings of hypertensive rats while decreasing the associated release of HETEs and correcting the impairment in the conversion of PGH2 to PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of prostaglandin H2-mediated mechanism of vascular contraction in hypertensive rats. Relation to lipoxygenase and prostacyclin synthase activities. 829 59

The effect of U 46619 (5 micrograms/kg i.v.) alone or in combination with acetylsalicylic acid (ASA) (100 mg/kg po.) on mean arterial blood pressure (MABP) was investigated in male and female spontaneously hypertensive rats (SHR). In male SHR, a significant increase of MABP was observed 1 min after administration of U 46619. Pretreatment of male SHR with ASA delayed the increase of MABP after intravenous injection of U 46619 compared to U 46619 alone. Whereas in control animals the elevated MABP returned to baseline values 5 min after intravenous application of U 46619, the MABP of ASA-pretreated male SHR remained significantly increased by about 30 mmHg. In contrast, the MABP of female SHR did not respond to U 46619 alone or to the combination of U 46619 and ASA. Sex differences were further shown by the vascular formation of thromboxane B2 (TXB2). Whereas in male SHR the vascular formation of TXB2 was increased by U 46619, the TXB2 formation of female SHR was decreased. The vascular formation of 6-keto-PGF1 alpha of male and female SHR was not influenced by U 46619 alone or a combination of U 46619 and ASA. In conclusion, our results demonstrate that the blood pressure of SHR respond differently to the TXA2 mimetic U 46619 in the two sexes. Furthermore, by modulating blood pressure response to TXA2, vasoactive prostanoids may be significantly involved in the maintenance of hypertension with male SHR.
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PMID:U 46619 induces different blood pressure effects in male and female spontaneously hypertensive rats (SHR). 834 25

Thromboxane A2 (TXA2) and ET-1 have been known to play important roles in modulating vascular contraction and growth. The present study was undertaken to examine the effect of TXA2 on the induction of endothelin-1 (ET-1) mRNA and protein levels in smooth muscle cells derived from rat heart. U-46619, a stable TXA2 mimetic, superinduced preproET-1 mRNA in the presence of cycloheximide in these cells. This effect could be blocked by SQ-29548, a TXA2/prostaglandin H2 receptor antagonist and by actinomycin D, and RNA synthesis inhibitor. In addition, H7, a protein kinase C inhibitor, could abolish the induction. Transient transfection experiment revealed that the elevated ET-1 mRNA level after U-46619 treatment was a result of the activation of ET-1 gene activity. The elevated ET-1 message level was accompanied by increased ET-1 release into the cultured medium. These results show that the short-lived TXA2 can induce potent and long-lived ET-1. These findings support a potential role for ET-1 in the pathogenesis of coronary atherosclerosis and hypertension evoked by TXA2.
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PMID:Regulation of endothelin-1 production by a thromboxane A2 mimetic in rat heart smooth muscle cells. 878 42

The disparate results reported in the literature on the effects of low dose aspirin in preventing pre-eclampsia might be caused by non-compliance in the more recent large trials in low-risk patients. All the earlier small trials were done on identified high-risk patients who consider themselves as patients, as do their doctors. Compliance in these patients will be very high. In fact, the only study in healthy subjects in which aspirin intake was controlled for (Hauth et al 1993) showed a marked reduction in the incidence of pre-eclampsia. However, the recent large trials have demonstrated, without any doubt, that low dose aspirin is not a miracle drug. The combined literature points at a 25% reduction in the incidence of pre-eclampsia in association with the use of aspirin (Collins, 1994). The correct indication for the use of low-dose aspirin appears to be the patient that is at very high risk of developing early-onset (less than 32 weeks gestation) pre-eclampsia. Since early-onset pre-eclampsia can begin at any time after 20 weeks gestation, it is necessary to initiate low-dose aspirin therapy early in pregnancy, preferably at 10-14 weeks gestation. The results of the recent large trials emphasize the need for a reliable, sensitive method of predicting or detecting pre-eclampsia at a very early gestational age (Dekker and Sibai, 1991). Valensise et al (1993) recently confirmed earlier studies (McParland et al, 1990) on the useful combination of uteroplacental Doppler flow velocimetry and aspirin in low-risk primigravidae. Results from current large-scale trials, such as the ECPPA, the BLASP, the WHO Jamaica and the second NICHHD studies, will be available in the near future. The results of especially the second NICHHD study on low-dose aspirin, in more than 2000 high-risk women (previous pre-eclampsia/eclampsia, chronic hypertension, class B to F diabetes or multiple gestation), will hopefully give us a more definitive picture on the potential benificial effects of low-dose aspirin in high-risk patients. The effect of aspirin on placental TXA2 deserves further studies. It might be that the optimal level to inhibit placental TXA2 and lipid peroxide production is actually higher than the minimal effective doses of aspirin that are needed to inhibit platelet TXA2 production (Walsh, 1994). Low-dose aspirin appears to be safe for the fetus and neonate. If there is an increased risk of abruptio placentae, this risk appears to be minimal. The final word on the use of low-dose aspirin has not yet been reached; however, we may be getting closer to profiling patients for whom the therapy may be efficacious and beneficial to both mother and fetus. Further studies are also necessary on combinations of aspirin and other antithrombotic drugs, such as heparin or ketanserin (Tanaka et al, 1993; Bolte et al, 1994; North et al, 1994). North et al (1994) demonstrated that treatment of women with severe renal disease with heparin plus aspirin reduced the prevalence of superimposed pre-eclampsia, compared with no treatment or aspirin alone. Next to low-dose aspirin, there appear to be several new and promising pharmaceutical approaches for reducing the consequences of EC dysfunction. Among these are selective TXA2-synthetase or TXA2-receptor antagonists, Serotonin2-receptor blockers, stable PGI2 analogues and NO donors.
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PMID:The pharmacological prevention of pre-eclampsia. 884 53

Experiments were performed to determine the effect of chronic therapy with the potent and long-acting thromboxane (TX) A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban, on hypertension development and the incidence of stroke in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP instrumented with radiotelemetry probes, for continuous monitoring of arterial blood pressure, were given 1% NaCl to drink and Stroke-Prone Rodent Diet and were chronically treated with ifetroban (20 mg/kg/day, n = 10) or vehicle (n = 12) starting at 16.5 weeks of age. Ifetroban did not affect blood pressure or the development of proteinuria and cerebrovascular lesions. Chronic administration of a higher dose ifetroban (40 mg/kg/day) starting at 7 weeks of age was also without effect on blood pressure and stroke in noninstrumented saline-drinking SHRSP. These results do not support a major role for TXA2 and its endoperoxide precursors in the elevation of blood pressure and the development of cerebrovascular lesions in saline-drinking SHRSP.
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PMID:Effect of ifetroban, a thromboxane A2 receptor antagonist, in stroke-prone spontaneously hypertensive rats. 886 99


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