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)

The proinflammatory cytokine interleukin-1beta (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A2 (PLA2), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA2 and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in approximately 200-fold and 15-fold increases in PGE2 and 6-keto-PGF1alpha (the stable metabolite of PGI2), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA2 inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA2 products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.
Hypertension 1998 Jan
PMID:Phospholipase A2 metabolites regulate inducible nitric oxide synthase in myocytes. 945 6

Norepinephrine (NE) stimulates release of arachidonic acid (AA) from tissue lipids in blood vessels, which is metabolized via cyclooxygenase, lipoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to biologically active products. Moreover, NE and AA have been shown to stimulate proliferation of vascular smooth muscle cells (VSMCs) of rat aorta. The purpose of this study was to determine the possible contribution of AA and its metabolites to NE-induced mitogenesis in VSMCs of rat aorta and the underlying mechanism of their actions. NE (0.1 to 10 micromol/L) increased DNA synthesis as measured by [3H]thymidine incorporation in VSMCs, and this effect was attenuated by inhibitors of CYP-450 (17-octadecynoic acid, 5 micromol/L; 12-diabromododec-11-enoic acid, 10 micromol/L; and dibromo-dodecenyl-methylsulfimide, 10 micromol/L) and by the LO inhibitor (baicalein, 20 micromol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 micromol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to 0.5 micromol/L) and 12(S)-HETE, respectively, increased [3H]thymidine incorporation in VSMCs. Both NE and 20-HETE increased mitogen activated protein (MAP) kinase activity as measured by the in-gel kinase assay. The inhibitor of MAP kinase kinase, PD-98059 (50 micromol/L), attenuated NE as well as 20-HETE induced [3H]thymidine incorporation and MAP kinase activation in VSMCs. These data suggest that products of AA formed via CYP-450, most likely 20-HETE, and via LO mediate NE induced mitogenesis in VSMCs.
Hypertension 1998 Jan
PMID:Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. 945 10

Linoleic acid, a polyunsaturated C18 fatty acid, is one of the major fatty acids in the coronary arterial wall. Although diets rich in linoleic acid reduce blood pressure and prevent coronary artery disease in both humans and animals, very little is known about its mechanism of action. We believed that its beneficial effects might be mediated by changes in vascular tone. We investigated whether linoleic acid induces relaxation of porcine coronary artery rings and the mechanism involved in this process. Linoleic acid and two of its metabolites, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-hydroperoxyoctadecadienoic acid (13-HPODE), induced dose-dependent relaxation of prostaglandin (PG) F2alpha-precontracted rings that was not affected by indomethacin (10[-5] mol/L), a cyclooxygenase inhibitor, or cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC; 10[-5] mol/L), a lipoxygenase inhibitor. Removal of endothelial cells had no effect on vasorelaxation, suggesting a direct effect on the vascular smooth muscle cells (VSMC). When rings were contracted with KCl, linoleic acid failed to induce relaxation. Although tetrabutylammonium (5 x 10[-3] mol/L), a nonselective K+ channel blocker, slightly inhibited the relaxation caused by linoleic acid, glibenclamide (10[-6] mol/L), an ATP-sensitive K+ channel blocker, and charybdotoxin (7.5x10[-8] mol/L) or tetraethylammonium (5x10[-3] mol/L), two different Ca2+-activated K+ channel blockers, had no effect. However, relaxation was completely blocked by ouabain (5x10[-7] mol/L), a Na+/K+-ATPase inhibitor, or by a K+-free solution. In addition, linoleic acid (10[-6] mol/L) caused sustained hyperpolarization of porcine coronary VSMC (from -49.5+/-2.0 to -60.7+/-4.2 mV), which was also abolished by ouabain. We concluded that linoleic acid induces relaxation and hyperpolarization of porcine coronary VSMC via a mechanism that involves activation of the Na+/K+-ATPase pump.
Hypertension 1998 Feb
PMID:Linoleic acid induces relaxation and hyperpolarization of the pig coronary artery. 946 Dec 30

Lipoxygenase inhibitors reduce blood pressure in hypertensive rats. The vasodepressor effect of lipoxygenase inhibitors may be related to increased production of prostaglandin (PG) I2 since lipoxygenase-derived fatty acid hydroperoxides inhibit PGI2 synthase. This hypothesis was examined in rats made hypertensive by infusion of angiotensin II (200 ng/min i.p.) for 12 to 14 days. In hypertensive but not in normotensive rats, the lipoxygenase inhibitor baicalein (60 mg/kg s.c.) increased (P<.05) the conversion of exogenous PGH2 to PGI2 by aortic segments, the release of 6-keto-PGF1alpha by aortic rings, the concentration of 6-keto-PGF1alpha in blood, and the renal excretion of 6-keto-PGF1alpha. Treatment with baicalein did not affect the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 177+/-8 to 133+/-9 mm Hg after 120 minutes (P<.05). Also, the lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (8 mg/kg s.c.) was without effect on the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 182+/-4 to 139+/-8 mm Hg (P<.05). However, the blood pressure of hypertensive rats pretreated with indomethacin (5 mg/kg i.v.) was affected by neither baicalein nor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Moreover, in hypertensive rats in which baicalein had decreased blood pressure to 148+/-6 mm Hg, the administration of rabbit serum containing antibodies against 5,6-dihydro-PGI2 (0.3 mL i.v.) partially reversed the response to baicalein, increasing blood pressure to 179+/-7 mm Hg within 20 minutes (P<.05). The antibodies also were shown to block the vasodepressor effect of PGI2 but not of PGE2. Collectively, these data suggest contribution of PGI2 to the acute antihypertensive effect of baicalein in rats with angiotensin II-induced hypertension.
Hypertension 1998 Mar
PMID:Prostaglandin I2 contributes to the vasodepressor effect of baicalein in hypertensive rats. 949 74

The effects of the arachidonic acid metabolism inhibitors on the acetylcholine responses of aortae from control (CR) and deoxycorticosterone acetate (DOCA)-salt hypertensive (HR) rats were investigated. The acetylcholine decreased response observed in HR [relaxation (%): CR 95.5+/-2.7, n = 4; HR 52.0+/-6.3, n = 5, p < 0.05] was restored by the cyclooxygenase inhibitor piroxicam [relaxation (%): CR 99.8+/-0.2, n = 4; HR 86.0+/-4.0, n = 5] and by the thromboxane synthetase inhibitor and the thromboxane A2/prostaglandin H2 receptor antagonist ridogrel [relaxation (%): CR 92.1+/-4.4, n = 7; HR 93.1+/-2.0, n = 7] but not by the inhibitors of thromboxane synthetase, prostacyclin synthetase, cytochrome P-450 monooxygenase, and lipoxygenase. So, endoperoxide intermediates seem to be involved in the decreased endothelium-dependent relaxation to acetylcholine in DOCA-salt hypertension.
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PMID:Endothelial dysfunction in DOCA-salt hypertension: possible involvement of prostaglandin endoperoxides. 1021 85

Retrospective epidemiological studies have suggested that antioxidant therapy may decrease cardiovascular morbidity and mortality rates, although the mechanisms for this effect remain unclear. In the present study, we demonstrate that selective antioxidants can enhance expression of endothelial nitric oxide synthase (eNOS). We found that the antioxidants nordihydroguaiaretic acid (NDGA), catechol, glutaryl probucol, and N-acetylcysteine increased eNOS expression in cultured bovine aortic endothelial cells (BAECs). NDGA seemed to be the most potent of the phenolic antioxidants, producing a 3-fold increase in eNOS mRNA. This effect of NDGA was enhanced by nonphenolic antioxidants such as N-acetylcysteine and ascorbic acid. Nuclear run-on studies indicated that NDGA increased eNOS transcription. A similar increase in eNOS protein content was observed with Western blot analysis after treating BAECs or human aortic endothelial cells with NDGA. Exposure of BAECs to NDGA enhanced NO production, as measured by electron paramagnetic resonance spin trapping and eNOS activity, as measured by [14C]arginine-to-[14C]citrulline assay. Methylation of the phenolic hydroxyl groups completely inhibited the NDGA effect on eNOS mRNA levels. This effect of NDGA was not due to inhibition of lipoxygenase because cis-5,8,11,14-eicosatetraynoic acid did not alter eNOS expression. We conclude that antioxidants may not only increase the bioactivity of nitric oxide but also enhance expression of the eNOS enzyme. Such an effect may prove useful in conditions such as hypertension and atherosclerosis, in which nitric oxide production and/or biological activity is impaired.
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PMID:Modulation of expression of endothelial nitric oxide synthase by nordihydroguaiaretic acid, a phenolic antioxidant in cultured endothelial cells. 1038 91

Rats with fructose-induced hypertension were treated by oral gavage with either masoprocol (nordihydroguaiaretic acid) or vehicle. Masoprocol treatment resulted in significantly (P < .05 to .001) lower values for systolic blood pressure (120 +/- 3 v 164 +/- 5 mm Hg), as well as plasma insulin (30 +/- 5 v 44 +/- 4 microU/mL), free fatty acid (551 +/- 20 v 692 +/- 22 microEq/L), and triglyceride (79 +/- 5 v 219 +/- 32 mg/dL) concentrations. These results indicate that masoprocol, a lipoxygenase inhibitor, is able to lower blood pressure, as well as improve the metabolic abnormalities present in a rodent model of hypertension that simulates the characteristic of many patients with essential hypertension.
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PMID:Masoprocol lowers blood pressure in rats with fructose-induced hypertension. 1041 73

We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.
Hypertension 2000 Jan
PMID:Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension. 1064 41

Approximately 5% of all hypertensive patients have renovascular hypertension, although its true incidence is unknown. The pathophysiology of renovascular hypertension has been linked to other intrarenal systems, the lipoxygenase pathway, and renin angiotensin. Many advances have been made in this field, but emphasis is now being placed on using less invasive or non-invasive tests to identify functionally significant lesions with a high degree of accuracy. The treatment modalities have shifted from aggressive surgical revascularization to less invasive management. The use of arterial stents has simplified the management of patients with renovascular hypertension, but long-term results are not yet available.
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PMID:Renovascular hypertension. 1072 80

This study was designed to examine the contribution of lipoxygenase products to mechanisms of vascular contraction and elevated blood pressure in rats with aortic coarctation-induced hypertension. In cytosolic fractions of aortae taken from hypertensive rats, 12-lipoxygenase protein was increased as compared to normotensive controls. Aortic rings from hypertensive, but not from normotensive rats, exhibited a basal tone which was reduced 74+/-12 and 71+/-22%, respectively, by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10(-5) mol/L) and 5,8,11-eicosatriynoic acid (ETI, 10(-5) mol/L). CDC (8 mg/kg s.c.) did not affect the blood pressure of normotensive rats but decreased that of hypertensive rats from 182+/-6 to 151+/-10 mm Hg. The blood pressure lowering effect of CDC was blunted in hypertensive rats pretreated with indomethacin or antibodies against 5,6-dihydro-prostaglandin I2. These data suggest contribution of lipoxygenase-derived products to mechanisms underlying aortic smooth muscle basal tone and elevated blood pressure in rats with aortic coarctation-induced hypertension. The vasodepressor effect of CDC depends on a mechanism involving vasodilatory prostaglandins.
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PMID:Lipoxygenase-dependent mechanisms in hypertension. 1074 58


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