UMLS:C0020538 - FACTA Search

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

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

We investigated the age-related changes of renal cytochrome P450-dependent arachidonic acid metabolism in 3-, 5-, 7-, 9-, 11-, 13- and 20-week-old male Dahl salt-sensitive (DS) and -resistant (DR) rats on a low sodium diet (0.3% NaCl). NADPH-dependent arachidonic acid metabolism was separated and measured by a radio-HPLC system. The formation of 19-hydroxyeicosatetraenoic acid (HETE), 20 HETE, 1,20-dioic acid, epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acid (DHET) was age dependent in both DS and DR rats. omega-Hydroxylase (20-HETE and 1,20-dioic acid formation) and (omega-1)-hydroxylase (19-HETE formation) were increased from 3 to 5 weeks age, then decreased with aging in DR rats. Whilst omega/(omega-1)-hydroxylase activities were increased from 3- to 9-week-old rats, they decreased with aging in DS rats. omega/(omega-1)-Hydroxylase activities were higher in 3-5-week-old DR than DS rats. Epoxygenase activities (EETs and DHET formations) were highest in 3-week-old DS and DR rats, and showed no significant differences between two strains of rats at any ages tested. Renal cytochrome P450-dependent arachidonic acid metabolites have a wide and contrasting spectrum of biological and renal effects, and their relative rates of production may influence not only renal hemodynamics but also pro- and antihypertensive mechanisms of hypertension in Dahl rats.
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PMID:Effect of aging on renal cytochrome P450-dependent arachidonic acid metabolism in Dahl rats. 835 95

The present study compared the effect of spontaneous hypertension and salt-loading on in vitro metabolism of 18:2n-6 (linoleic acid) and 20:3n-6 (dihomo-gamma-linolenic acid). Ten weanling spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto rats (WKY) maintained on a rodent lab chow were given tap water with (n = 5) or without (n = 5) addition of 1% NaCl for 4 weeks. Thereafter, animals were killed and liver microsomes were prepared. Aliquots of microsomes suspended in the phosphate-sucrose buffer containing MgCl2, ATP, CoA, and NADPH were incubated with 0.3 microCi of [1-14C]-18:2n-6 or [2-14C]-20:3n-6 at 37 degrees C for 15 min. The activity of delta 6- and delta 5-desaturases, and the distribution of radioactivity in different lipid fractions and in phospholipid fatty acids were determined. Results showed that both spontaneous hypertension and salt-loading suppressed the desaturation of radiolabeled 18:2n-6 and of 20:3n-6. Incubation of microsomes with [1-14C]-18:2n-6 resulted in 29% of radioactivity being associated with phospholipid fraction, of which 3% was associated with 18:3n-6. Incubation with radiolabeled 20:3n-6 resulted in 30% of the radioactivity being incorporated into phospholipids, of which 50% was associated with 20:4n-6 (arachidonic acid). Salt-loading suppressed the incorporation of radiolabeled fatty acids into phospholipids, more so in SHR than in WKY. Thus, salt-loading not only suppressed the desaturation of 18:2n-6 and 20:3n-6, but also interfered with the acylation of n-6 fatty acids into the phospholipid fraction.
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PMID:Effect of salt-loading and spontaneous hypertension on in vitro metabolism of [1-14C]linoleic and [2-14C]dihomo-gamma-linolenic acids. 838 2

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates glucocorticoid interactions with mineralocorticoid and glucocorticoid receptors in vivo, by converting 11 beta-hydroxyglucocorticoids to their inactive 11-ketone derivatives. Defective 11 beta-oxidation of glucocorticoids has been associated with hypertension. The objective of this study was to investigate whether 11 beta-HSD contributes to the occurrence of hypertension in spontaneously hypertensive rats (SHRs). The liver and kidney microsomal oxidations of corticosterone (the physiological glucocorticoid in rats) in organs from juvenile (3 weeks old) and adult (3 months old) SHR and Wistar-Kyoto (WKY) rats, with NAD and NADP, show no differences between rat strains. For cortisol, with NADP, adult SHRs show (1.3-3 times; P < 0.05) lower kidney microsomal oxidation rates. The liver microsomal reduction of cortisone shows remarkable interstrain differences; with NADH, reduction is conducted only by adult WKY rats, whereas with NADPH, juvenile animals show similar reduction rates, but at adulthood, only WKYs reduce cortisone. Using Western blot analysis with antibodies against 11 beta-HSD1, positive signals are obtained only for liver microsomes, appearing somewhat lower in SHRs for juvenile but not adult animals. Urinary corticosterone/11-dehydrocorticosterone ratios (measured in adult animals) are not different between rat strains, but are elevated after administration of corticosterone in both strains (although significant only in SHRs). The data provide no indications for exaggerated stimulation of renal corticosteroid receptors, due to modified 11 beta-HSD, in SHRs. However, the experiments suggest the existence of multiple 11 beta-HSDs, in addition to 11 beta-HSD1 and 11 beta-HSD2, some of which may be modified in SHR, but the nature and physiological role of these 11 beta-HSDs is unclear.
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PMID:Comparison of 11 beta-hydroxysteroid dehydrogenase in spontaneously hypertensive and Wistar-Kyoto rats. 858 2

With retrograde tracing using fluorogold injection into the superior cervical ganglion and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry, the present comparative study revealed that the retrogradely labelled neurons in n. intermediolateralis pars funicularis (ILf) and n. intermediolateralis pars principalis (ILp) of the autonomic region in the upper thoracic cord exhibited a much stronger reactivity for NADPH-diaphorase in Wistar-Kyoto (WKY) rats than those in spontaneously hypertensive rats (SHR). It was found that in ILf in WKY rats, 77.62% of the fluorogold-labelled neurons were NADPH-d positive, while in SHR, only 56.43% of the labelled neurons were NADPH-d positive. The frequency distribution of NADPH-d positive retrogradely labelled neurons was significantly reduced in ILf of the spinal cord of SHR (U-test: P < 0.01). In ILp in WKY rats, 65.25% of fluorogold-labelled neurons were NADPH-d positive in WKY rats, while in SHR, only 56.28% of the labelled neurons were NADPH-d positive. Although the difference (P > 0.05) in the frequency of NADPH-d positive neurons in ILp between the two strains of rats was not significant, the reductions in SHR seemed considerable. Examination of the preganglionic sympathetic trunk and the superior cervical ganglion between SHR and WKY rats revealed that virtually all the NADPH-d positive fibers were derived from the sympathetic preganglionic neurons. In SHR, the NADPH-d positive fibers were not as intensely stained as those of WKY rats. This preliminary results suggest that nitric oxide, as an inhibitory neurotransmitter, may be implicated in the onset of hypertension.
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PMID:A comparative study of NADPH-diaphorase in the sympathetic preganglionic neurons of the upper thoracic cord between spontaneously hypertensive rats and Wistar-Kyoto rats. 859 47

We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.
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PMID:Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. 862 76

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.
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PMID:11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. 873 12

2-Hydroxylation is one of the major metabolic pathways of estrogens and is believed to be catalyzed by a form of cytochrome P450. Recently it has been reported that estrogen 2-hydroxylase activity in human placenta is catalyzed by aromatase. Some investigators suggested the effect of catechol estrogen on human placental steroidogenesis which may be related to pregnancy-induced hypertension (PIH) through the inhibition of catechol-O-methyltransferase (COMT) activity. In order to better understand the interrelationship between placental aromatase and estrogen 2-hydroxylase activities in PIH patients, both activities were evaluated in the PIH placentas. Human placental microsomes obtained from PIH patients were incubated with [1 beta-3H]androstenedione or [2-3H]estradiol in the presence of NADPH. Aromatase and estrogen 2-hydroxylase activities were assessed by the tritium water method. The immunosuppression patterns of both activities due to monoclonal antiaromatase cytochrome P450 antibody (MAb3-2C2) were studied. Estrogen 2-hydroxylase activity was significantly higher in PIH placentas (4.7 +/- 0.9 pmol/min/mg protein, n = 7) than in normal placentas (3.0 +/- 0.7 pmol/min/mg protein, n = 7). When the PIH placental microsomes were subjected to immunosuppression by 1 to 100 micrograms IgG of MAb3-2C2, estrogen 2-hydroxylase activity was suppressed by 94 to 65% whereas aromatase activity was strongly suppressed by 72 to 17%, respectively. From our results of high estrogen 2-hydroxylase activity in PIH placentas, it is assumed that there is a different estrogen catalyzing mechanism in PIH placentas.
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PMID:Aromatase and estrogen 2-hydroxylase activities of human placental microsomes in pregnancy-induced hypertension. 893 May 23

Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.
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PMID:p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. 897 21

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