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

The present study investigated the role of arachidonic acid and acetylcholine in mediating endothelium-dependent relaxations of rabbit aorta. Isolated thoracic aortic rings were precontracted with a submaximal concentration of norepinephrine, and the effect of various agents on arachidonic acid- and acetylcholine-induced relaxations was examined. Arachidonic acid elicited a concentration-related relaxation that was potentiated by the cyclooxygenase inhibitor indomethacin. Treatment with the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked but the cytochrome P450 inhibitor metyrapone had no effect on arachidonic acid-induced relaxation. NG-Monomethyl-L-arginine and nitro-L-arginine, compounds that inhibit the nitric oxide-like endothelium-derived relaxing factor, had little or no effect on arachidonic acid-induced relaxations. In contrast, nordihydroguaiaretic acid, metyrapone, NG-monomethyl-L-arginine, and nitro-L-arginine all attenuated the relaxation to acetylcholine; however, indomethacin had no effect on acetylcholine-induced relaxations. Arachidonic acid and acetylcholine had no effect on denuded rabbit aorta. Incubation of rabbit aorta with [14C]arachidonic acid resulted in the synthesis of major radioactive metabolites that comigrated with the prostaglandins and hydroxyeicosatetraenoic acids. Indomethacin selectively inhibited prostaglandin formation, nordihydroguaiaretic acid attenuated both prostaglandins and hydroxyeicosatetraenoic acids, and metyrapone blocked the epoxyeicosatrienoic acids. Additionally, acetylcholine elicited a twofold increase in tissue cyclic guanosine monophosphate content in contrast to a 59% reduction in cyclic guanosine monophosphate content observed with arachidonic acid. Therefore, these data suggest that in rabbit aorta, arachidonic acid-induced relaxations are mediated by an endothelium-dependent factor (or factors) that differs from the factor (or factors) released by acetylcholine. These results support the existence of multiple endothelium-derived relaxing factors.
Hypertension 1992 Nov
PMID:Arachidonic acid- and acetylcholine-induced relaxations of rabbit aorta. 133 Sep 23

The central role of eicosanoids in reproduction was studied in areas of important clinical interest. First, their involvement in pregnancy-induced hypertension was investigated. Urine of normotensive and hypertensive pregnant women was analysed for 6-keto-PGF1 alpha, TXB2 and PGE2 by HPLC/RIA. PGE2 and 6-keto-PGF1 alpha excretion was markedly reduced in the preeclamptic subgroup of hypertensive patients during the last two trimesters. A reduced urinary excretion of 6-keto-PGF1 alpha, TXB2 and PGE2 was also found in a hypertension animal model (rat). Further, tissue cultures of human placentas, deciduas and fetal membranes from hypertensive pregnancies displayed a reduced prostaglandin production. Secondly, in the same in-vitro model the central role of PGE2 of fetal membrane origin for the beginning or parturition was shown. Thirdly, concerning endometrial function, the enhancement of PGF2 alpha and PGE2 formation in secretory endometrial cells by estradiol-17 beta and progesterone was documented. Fourthly, lipoxygenase product content in peritoneal fluid of endometriotic patients did not differ from controls.
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PMID:The role of eicosanoids in reproduction. 144 35

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and omega/omega 1 hydroxylases to epoxyeicosatrienoic acids and omega/omega-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na(+)-K(+)-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.
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PMID:The renal cytochrome P-450 arachidonic acid system. 145 35

An inflammatory response was elicited in the rabbit eye by intracameral injection of platelet activating factor (PAF). PAF induced severe aqueous flare, corneal edema, pupillary constriction and marked biphasic changes in intraocular pressure (IOP) in a dose-dependent manner. All of the responses to PAF were inhibited by the PAF receptor antagonist, BN 52021 (20 mg/kg, i.p.). The cyclooxygenase inhibitor, indomethacin (30 mg/kg, i.p.) caused significant inhibition of the early phase PAF-induced aqueous flare, pupillary constriction and intraocular hypertension, but did not effect PAF-induced corneal edema or intraocular hypotension. NDGA (10 mg/kg, i.p.), a lipoxygenase inhibitor, did not inhibit the inflammatory effects of PAF. PAF-induced chemotactic response was evaluated by tissue chemiluminescence. Intracamerally injected PAF did not significantly increase chemiluminescence in cornea or iris-ciliary body, but intracorneal injection of PAF did cause a chemotactic response in both the conjunctiva and cornea. These data suggest that PAF may be an important mediator of intraocular inflammation and that some PAF-induced effects are prostaglandin dependent, while others may be independent of eicosanoid synthesis and release.
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PMID:Intracamerally injected platelet activating factor (PAF) induces marked intraocular inflammatory reactions. 148 37

The present study examined whether the dual cyclooxygenase/lipoxygenase inhibitor phenidone would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and hypertensive renal disease. Vehicle-treated SHRSP (N = 6), fed stroke-prone rodent diet and 1% saline, exhibited severe systolic blood pressure elevation (261 +/- 10 mm Hg, mean +/- SEM), marked proteinuria (90 +/- 12 mg/day), and stroke, with an average age at death of 14 +/- 1 weeks. In a second group of six saline-loaded SHRSP, treatment with phenidone (60 mg/kg/day) was started at 8.4 weeks of age. Despite establishment of severe hypertension in this group (274 +/- 10 mm Hg), proteinuria remained at basal levels (28 +/- 13 mg/day), and signs of stroke were absent (P less than .01 v vehicle) through at least 16 weeks of age. Phenidone treatment also prevented the declines in body weight and food intake observed in vehicle-treated SHRSP, and maintained urine volume and saline intake. Serum 12-hydroxy-eicosatetraenoic acid (12-HETE) generation was significantly inhibited greater than 50% in incubates of whole blood from phenidone-treated SHRSP. We have previously shown that agents which interfere with the renin-angiotensin system afford protection from renal and cerebrovascular injury in saline-loaded SHRSP; cyclooxygenase inhibition alone will hasten the onset of these pathologic changes. Whether phenidone, which has been reported to attenuate angiotensin II-mediated effects, affords vascular protection by interference with a lipoxygenase-mediated action of angiotensin II remains to be elucidated.
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PMID:The lipoxygenase inhibitor phenidone protects against proteinuria and stroke in stroke-prone spontaneously hypertensive rats. 155 Jun 66

Previous studies have shown that inhibition of the lipoxygenase pathway of arachidonic acid metabolism can prevent the development of elevated blood pressure in renin-dependent models of hypertension. Agents that inhibit the lipoxygenase pathway such as phenidone and the flavonoid baicalein can selectively attenuate contractile responses to angiotensin II in vivo as well as in isolated vascular tissue. In the present study, the effects of lipoxygenase inhibitors on pressor-induced changes in cytosolic calcium were examined in cultured rat vascular smooth muscle cells using the fluorescent dye fura-2. Two structurally unrelated lipoxygenase inhibitors, baicalein and 5,8,11-eicosatriynoic acid, attenuated angiotensin II-stimulated increases in cytosolic calcium in both normal and calcium-poor buffer. The addition of 5-, 12-, or 15(S)-hydroxyeicosatetraenoic acid alone to the cells had no acute effect on intracellular calcium concentration. However, the addition of 12(S)-hydroxyeicosatetraenoic acid but not 5- or 15(S)-hydroxyeicosatetraenoic acid restored the initial calcium response to angiotensin II in vascular smooth muscle cells pretreated with both inhibitors; 5,8,11-eicosatriynoic acid also reduced [Arg8]-vasopressin and endothelin-stimulated increases in intracellular calcium. The attenuation of vasopressor-induced calcium transients by agents that inhibit lipoxygenase may explain their observed hypotensive effects in vivo. Moreover, lipoxygenase products, in particular 12(S)-hydroxyeicosatetraenoic acid, may act as mediators for the intracellular actions of angiotensin II and possibly other pressor hormones in vascular tissue by regulation of intracellular calcium metabolism.
Hypertension 1992 Aug
PMID:12-Lipoxygenase products modulate calcium signals in vascular smooth muscle cells. 163 55

The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs, phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However, the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg, delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP, r = 0.67, P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin, an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg, P less than 0.001; delta LW 0.0 +/- 0.1 g, P less than 0.001), and by imidazole, an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg, P less than 0.001; LW 0.0 +/- 0.3 g, P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg, P less than 0.05; delta LW 3.1 +/- 0.3 g, P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets. 190 12

Production of some lipoxygenase and cyclooxygenase derivatives of arachidonic acid was measured in placental tissue obtained from women with gestational hypertension and with normal pregnancies. The levels of leukotriene B4 were about five times higher in placentas from hypertensive women and also raised thromboxane A2 and reduced prostaglandin E2 levels were observed. Prostacyclin production was lowered only in women with more severe hypertension, in association with the highest measured levels of leukotriene B4 and thromboxane A2. It is suggested that increased placental levels of leukotriene B4 and thromboxane A2 appear already in mild gestational hypertension, while depression of prostacyclin may occur only at more severe stages of gestational hypertensive disease.
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PMID:Increased placental production of leukotriene B4 in gestational hypertension. 196 52

Eicosanoids, especially prostaglandins and other arachidonic acid metabolites, play an important role in gestosis. Experimental and clinical evidence suggest prostacyclin deficiency, enhanced platelet reactivity and increased production of thromboxane A2 as possible reasons for gestosis. In addition, pathological interactions between cyclooxygenase-derived products and the renin-angiotensin- and kallikrein-kinin systems may exist and contribute to hypertension and reduced fetoplacental blood flow. Moreover, pregnancy-induced hypertension appears to be also related to lipoxygenase products and enhanced lipid peroxidation. In general, little is known about the regulation of arachidonic acid metabolism in gestosis. It is also unknown whether altered activities of mediators and hormones are cause or effect of pregnancy-induced hypertension. This is particularly relevant to the site of eicosanoid formation, i.e. platelets, the trophoblast or endothelial cells. At this time, it is not possible to give therapeutical recommendations, which are specifically designed to correct changes in eicosanoid production in gestosis. Antihypertensive therapy alone is insufficient, particularly with regard to the fetal situation. Preventive treatment with low-dose acetylsalicylic acid may have a protective effect against pregnancy-induced hypertension. Presently, more selective antagonists of thromboxane generation and/or action are being developed and might provide fresh insights both into the pathology of the disease and improved drug treatment.
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PMID:[The significance of eicosanoids in gestosis]. 212 6

To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats. 212 26


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