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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A2. Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [14C]arachidonate liberation nor prostacyclin synthase of the smooth muscle cells. Indapamide eliminated a stable free radical in a cell-free system, lowered the formation of malondialdehyde from lipid peroxides in rat brain homogenate, and reduced lipid peroxidation by the free radical generating system of xanthine-xanthine oxidase. Indeed, the scavenging action of indapamide significantly attenuated the inhibitory activity of 15-hydroperoxy-arachidonate to prostacyclin synthase activity. These results indicate that indapamide diuretic increases prostacyclin generation in the vascular smooth muscle cells possibly through antioxidant effects and that the enhanced prostacyclin generation is partly responsible for its direct vasodilator action.
Hypertension 1990 Feb
PMID:Radical scavengers of indapamide in prostacyclin synthesis in rat smooth muscle cell. 210 10

To define the roles of vascular prostacyclin (PGI2) synthase for PGI2 generation in deoxycorticosterone acetate (DOCA)-salt hypertension, we investigated PGI2 synthase, phospholipase A2 and phospholipase C activities in the aortic wall of DOCA-salt prehypertensive and established hypertensive rats. Vascular PGI2 generation in the DOCA-salt hypertensive rats was increased by 91%, and was associated with an 88% increase in PGI2 synthase activity and lowered phospholipase C and A2 activity. In the prehypertensive stage, DOCA-salt rats showed reduced vascular PGI2 generation. Prostacyclin synthase activity was equal to that of controls. These data clearly suggest that DOCA-salt hypertensive rats increase their vascular PGI2 generation when they develop hypertension, and that this may be due to the activation of vascular PGI2 synthase.
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PMID:Alterations to the vascular vasodepressor prostaglandin system in DOCA-salt hypertensive rats and their enzymatic analysis. 324 Dec 24

Uterine prostacyclin synthase (PGI synthase) and prostaglandin endoperoxide synthase (PGH synthase) concentrations, measured by specific immunoradiometric assays, did not differ between patients with severe pregnancy-induced hypertension (syn. pre-eclampsia; n = 5) and normotensive gravidae (n = 6) with comparable gestational ages (34 - 38 weeks). Myometrial microsomes from pre-eclamptic women contained ten times more PGI synthase than PGH synthase and the ratio of PGI synthase to PGH synthase (mean +/- SD; 10.1 +/- 3.9) was not different from that in normotensive pregnancies. None of the pre-eclamptic patients had myometrial enzyme levels that were more than one standard deviation below the mean established previously for pregnancies ranging from 32 to 42 weeks of gestation. These findings indicate that the commonly observed association between deficient PGI2 production and pregnancy-induced hypertension cannot be explained in terms of a generalized lack of immunoassayable prostacyclin or prostaglandin endoperoxide synthases.
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PMID:Control of prostacyclin synthesis in pregnancy-induced hypertension. 392 69

In addition to the hemodynamic components, the roles of various humoral factors have been emphasized in the progression of vascular and renal injury in hypertension. Radical scavenging properties have attracted much attention in this field. This article discusses the implication of antioxidant properties of the antihypertensive diuretic indapamide on renal injury in Dahl salt-sensitive (Dahl S) rats. Hydroxyl radicals, oxygen radicals toxic to cellular membranes, are eradicated by indapamide in different assay systems, e.g., reduction of alpha-alpha-diphenyl-beta-picrylhydrazyl, rat brain homogenate, or xanthine-xanthine oxidase systems. Such antioxidant effects of indapamide are primarily due to inhibition of lipid peroxidation induced by hydroxyl radicals, and this mechanism may stimulate prostacyclin generation through activation of prostacyclin synthase. In fact, the antioxidant properties of indapamide are well expressed in vivo as well; indapamide treatment reduced oxygen radicals in the kidney of Dahl S rats with hypertension. This was accompanied by a functional improvement of the kidney; decreases in urinary protein and n-acetylglucosaminidase excretion and an increase in glomerular filtration rate were observed. In addition, indapamide morphologically ameliorated the renal injury, and decreased glomerular sclerosis score, arterial injury, and renal tubular injury. Trichloromethiazide reduces blood pressure similar to that produced by indapamide. However, trichloromethiazide did not lead to reduction of oxygen radicals in the kidney, and did not improve the functional disturbance or morphological injury seen in Dahl S rats. These results indicate that indapamide has antioxidant properties, and in addition to blood pressure reduction, such radical scavenging effects may contribute to its beneficial effects on renal function in vivo.
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PMID:Oxygen radical scavengers and renal protection by indapamide diuretic in salt-induced hypertension of Dahl strain rats. 750 60

Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. Eicosanoids subserve both prohypertensive and antihypertensive mechanisms. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A2 (TXA2) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA2 and/or prostaglandin (PG) H2 is increased. The cancellation of TXA2- and/or of PGH2-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA2/PGH2 receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part by decreasing the synthesis of lipoxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of these agents is accompanied by increased vascular formation of PGI2 and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE2 and PGI2, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.
Hypertension 1998 Jan
PMID:Arthur C. Corcoran Memorial Lecture. The role of eicosanoids in angiotensin-dependent hypertension. 945 2

We analyzed the mechanisms involved in the effect of tert-butyl hydroperoxide (t-BOOH) in isolated aortic rings with and without endothelium from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 6, 18, and 24 months of age. t-BOOH (1 microM-10 mM) induced concentration-dependent contractions that were scarcely modified by aging and potentiated in SHR and by endothelium removal. The nitric oxide synthase and prostacyclin synthase inhibitors N(G)-nitro-L-arginine methyl ester (100 microM) and tranylcypromine (100 microM), respectively, increased both basal tone and the t-BOOH-induced contractions in intact segments from WKY, with these effects not observed in SHR. Indomethacin (10 microM), a nonspecific cyclooxygenase inhibitor, and SQ 29,548 (10 microM), a prostaglandin H(2)/thromboxane A(2) receptor blocker, abolished the t-BOOH-induced vasoconstriction, independent of age and hypertension. In both strains, these contractile responses were unaltered by the thromboxane synthase inhibitor imidazole (10 microM). The cyclooxygenase-2 inhibitor NS-398 (10 microM) abolished or markedly reduced the t-BOOH-induced contractions in segments with or without endothelium, respectively. In addition, expression of cyclooxygenase-2 protein was detected in aorta from WKY and SHR in either basal condition or after stimulation with t-BOOH. These results suggest that (1) t-BOOH-induced vasoconstriction in the aorta from WKY and SHR is essentially mediated by cyclooxygenase-2 metabolites, different from thromboxane-A(2), probably prostaglandin-H(2), and/or isoprostanes; (2) aging scarcely modifies, whereas endothelium negatively modulates, these contractions in both strains; and (3) nitric oxide and prostacyclin exert a negative modulator role on the t-BOOH-induced vasoconstriction in WKY, with this modulator role lost in SHR.
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PMID:Oxidative stress induced by tert-butyl hydroperoxide causes vasoconstriction in the aorta from hypertensive and aged rats: role of cyclooxygenase-2 isoform. 1073 55

The year 1999 saw considerable activity in the area of hypertension-related molecular genetics. Several new monogenic hypertensive disorders, as well as a monogenic form of hypotension, were elucidated. Molecular genetics has made significant inroads in explaining basic mechanisms of magnesium homeostasis. Linkage strategies have been applied in family studies, sib-pair analyses, and twin studies. More stringent criteria for association studies have been formulated. The 11 beta-hydroxysteroid dehydrogenase gene, the prostacyclin synthase gene, genes coding for variants in G proteins, and adrenergic receptor genes have received particular attention. On the horizon are better phenotyped patient and subject collectives, expanded genotyping with the availability of a 300,000 genome-wide single-nucleotide polymorphism map, multigenic studies in the form of metabolic control analyses, and new bioinformatic strategies including neural networks.
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PMID:Molecular genetics of human hypertension. 1084 27

Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patient's family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.
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PMID:Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension. 1237 4

Preeclampsia is characterized by an imbalance between two cyclooxygenase metabolites of arachidonic acid, thromboxane and prostacyclin, that favors thromboxane. Because of the biologic actions of these two eicosanoids, this imbalance might explain major clinical symptoms of preeclampsia, such as hypertension, platelet aggregation and reduced uteroplacental blood flow. In the maternal circulation, this imbalance is primarily manifested by decreased production of prostacyclin by endothelial cells. Platelet thromboxane synthesis is only increased in severe preeclampsia. In the placenta and in leukocytes, the imbalance is exacerbated by increased production of thromboxane coupled with decreased production of prostacyclin in both mild and severe preeclampsia. Longitudinal measurements of urinary metabolites of thromboxane and prostacyclin reveal that the thromboxane/prostacyclin imbalance predates the onset of clinical symptoms of preeclampsia. The imbalance between thromboxane and prostacyclin is most likely caused by oxidative stress, which is manifest in preeclampsia by increased lipid peroxidation and decreased antioxidant protection. Oxidative stress may drive this imbalance because lipid peroxides activate the cyclooxygenase enzyme to increase thromboxane synthesis, but at the same time they inhibit prostacyclin synthase to decrease prostacyclin synthesis. Low-dose aspirin therapy (50-150 mg/day) has been considered for the prevention of preeclampsia because it selectively inhibits thromboxane synthesis. Several studies reported dramatic decreases in the incidence of preeclampsia with low-dose aspirin therapy. However, two large multicenter studies reported only modest decreases, which dampened enthusiasm. The two large studies were "intent to treat" studies which included patients who were noncompliant and who discontinued the use of aspirin. In one of the studies for which compliance statistics were available only 53% of the aspirin group had a compliance rate greater than 75%, which raises a question as to whether the effectiveness of aspirin was being tested. Low-dose aspirin therapy should not yet be dismissed for the prevention of preeclampsia, but be reconsidered with emphasis on compliance using doses of aspirin in the range of 100-150 mg/day combined with antioxidants.
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PMID:Eicosanoids in preeclampsia. 1468 95

When working on the regulation of prostacyclin synthase (PGIS), we found that PGIS was selectively inhibited by peroxynitrite (ONOO-), a potent oxidant formed by the combination of superoxide anion and nitric oxide (NO) at a rate of diffusion-controlled. None of the cellular antioxidants studied (i.e. GSH, Vitamins C and E, and others) prevented the inhibition of ONOO- on PGIS. This unexpected behavior was explained by a catalytic reaction of the iron-thiolate center of PGIS with ONOO- anion. In contrast, ONOO- activated both thromboxane A2-synthase and cyclooxygenases. In addition, we demonstrated that sub-micromolar levels of ONOO- inhibited PGI2-dependent vasorelaxation and triggered a PGH2-dependent vasospasm, indicating that ONOO- increased PGH2 formation as a consequence of PGIS nitration. We have subsequently demonstrated that endogenous ONOO- caused PGIS nitration and TxA2 activation in several diseased conditions such as atherosclerotic vessels, hypoxia-reperfusion injury, cytokines-treated cells, diabetes, as well as hypertension. Since NO is produced physiologically it seems that excessive formation of superoxide not only eliminates the vasodilatory, growth-inhibiting, anti-thrombotic and anti-adhesive effects of NO and PGI2 but also allows and promotes an action of the potent vasoconstrictor, prothrombotic agent, growth promoter, and leukocyte adherer, PGH2. We conclude that the nitration of PGIS nitration might be a new pathogenic mechanism for superoxide-induced endothelium dysfunction often observed in vascular diseases such as atherosclerosis, hypertension, ischemia, endotoxic shock, and diabetes.
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PMID:Peroxynitrite and protein tyrosine nitration of prostacyclin synthase. 1716 39


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