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

In the Western hemisphere, the incidence of insulin resistance and its complications has been growing rapidly and is reaching epidemic proportions. Over the past decade, evidence has accumulated, indicating that nitric oxide (NO) plays a key role in the regulation of metabolic and cardiovascular homeostasis. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes insulin resistance, arterial hypertension and dyslipidemia in mice, and characterizes insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction in mice, may also cause metabolic insulin resistance, suggesting a Yin-Yang effect of NO in the regulation of glucose homeostasis. Here, we will review the evidence for this novel concept, and thereby provide the conceptual framework for the use of NO-delivery drugs and pharmacological agents that modulate the bioavailability of endogenously produced NO for the treatment of insulin resistance.
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PMID:Insulin resistance, a new target for nitric oxide-delivery drugs. 1268 2

We reported recently that an upregulation of the inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, is a crucial determinant for the elicitation of cardiovascular depression during experimental endotoxemia. The current study evaluated the hypothesis that a downregulation of the molecular synthesis and functional expression of angiotensin subtype 1 receptor (AT1R) in the RVLM is consequential to this upregulated iNOS. In adult Sprague-Dawley rats maintained under propofol anesthesia, intravenous administration of Escherichia coli lipopolysaccharide (15 mg/kg) elicited a reduction, followed by an augmentation and a secondary decrease in sympathetic vasomotor outflow, together with progressive hypotension and bradycardia. There was also a progressive increase in iNOS mRNA and protein level in the ventrolateral medulla. This was followed by a significant downregulation of both mRNA and protein levels of AT1R in the ventrolateral medulla, alongside reduced efficacy of angiotensin II (50 pmol) to induce an increase in systemic arterial pressure, heart rate, or sympathetic vasomotor outflow on unilateral microinjection into the RVLM. Pretreatment with microinjection of a selective iNOS inhibitor, S-methylisothiourea (250 pmol) bilaterally into the RVLM significantly reversed the reduction in both synthesis and activity of AT1R. We conclude that a downregulation of molecular synthesis and functional expression of AT1R in the ventrolateral medulla is consequential to the overproduction of NO through upregulation of iNOS in the RVLM and may underlie the cardiovascular depression that takes place during experimental endotoxemia.
Hypertension 2003 Jul
PMID:Downregulation of angiotensin subtype 1 receptor in rostral ventrolateral medulla during endotoxemia. 1281 Jul 55

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.
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PMID:Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. 1285 18

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPARgamma is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPARgamma in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) increased promoter activity, whereas cotransfection of a dominant negative PPARgamma inhibited it. To determine the role of 15dPGJ2 in expression of proinflammatory genes, we tested its effect on interleukin-1beta induction of cyclooxygenase-2 (COX-2). 15dPGJ2 decreased interleukin-1beta stimulation of COX-2 by 40% and PGE2 production by 73%. We next questioned whether 15dPGJ2 was modulating the expression of inducible prostaglandin E2 synthase (PGES) and found that it completely blocked interleukin-1beta induction of PGES. Use of a second PPARgamma agonist, troglitazone, and the selective PPARgamma antagonist GW9662 demonstrated that the effects seen were PPARgamma-dependent. In addition, we found that 15dPGJ2 blocked interleukin-1beta stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ2 may play an anti-inflammatory role in a PPARgamma-dependent manner, decreasing COX-2, PGES, and PGE2 production, as well as iNOS expression.
Hypertension 2003 Oct
PMID:PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. 1288 95

Renal artery stenosis (RAS) may lead to renal injury, partly mediated through increased oxidative stress. However, the potential effects of chronic oral antioxidant intervention on the stenotic kidney remain unknown. This study was designed to test the hypothesis that chronic antioxidant vitamin supplementation in RAS would preserve renal function and structure. Single-kidney hemodynamics and function were quantified in vivo in pigs using electron-beam CT after 12 weeks of unilateral RAS (n=7), a similar degree of RAS orally supplemented with vitamins C (1 g) and E (100 IU/kg) (RAS+Vitamins, n=7), or controls (normal, n=7). Renal tissue was studied ex vivo using Western blotting and immunohistochemistry. Mean arterial pressure was similarly elevated in both RAS groups, while ischemic renal volume and glomerular filtration rate were similarly reduced. Renal blood flow was decreased in RAS compared with normal (326.5+/-99.9 versus 553.4+/-48.7 mL/min, respectively, P=0.01), but preserved in RAS+Vitamins (485.2+/-104.1 mL/min, P=0.3 versus normal). The marked increase in the expression of the NADPH-oxidase subunits p47phox and p67phox, nitrotyrosine, endothelial and inducible nitric oxide synthase, and nuclear factor-kappaB observed in RAS (P<0.05 versus normal) was normalized in RAS+Vitamins (P>0.1). Furthermore, trichrome staining and the expression of transforming growth factor-beta and tissue inhibitor of matrix-metalloproteinase-1 were also decreased in RAS+Vitamins. In conclusion, chronic blockade of the oxidative stress pathway in RAS using antioxidant vitamins improved renal hemodynamics and decreased oxidative stress, inflammation, and fibrosis in the ischemic kidney. These observations underscore the involvement of oxidative stress in renal injury in RAS and support a role for antioxidant vitamins in preserving the ischemic kidney.
Hypertension 2003 Oct
PMID:Beneficial effects of antioxidant vitamins on the stenotic kidney. 1292 65

Chromosome mapping based on congenic strains can restrict quantitative trait loci (QTLs) for blood pressure (BP) into small intervals that are otherwise indistinguishable in linkage analysis. Also, congenic strains can be created to test a candidate gene to be a BP QTL. Taking full advantage of these features, we produced 10 congenic strains by replacing various segments of chromosome (Chr) 10 of the Dahl salt-sensitive (DSS) rat with those of the Lewis (LEW) rat. These strains were made to systematically cover an entire section of Chr 10. Three of the strains were designed to narrow the intervals that harbor previously mapped QTL1 and QTL2. Two of the strains were designed for the express purpose of testing the QTL candidacy of loci for inducible nitric oxide synthase (Nos2) and angiotensin-converting enzyme (Ace) genes. BPs of these strains were measured by telemetry and compared with those of the DSS rat. Consequently, QTL1 and QTL2 were narrowed to segments of 53.5 and 100.4 centiRays, respectively. A new QTL, QTL3, was found between QTL1 and QTL2. Both Nos2 and Ace have been disqualified as QTLs in the DSS and LEW comparison. Therefore, there are no obvious candidate genes in the segments that harbor these 3 QTLs, which represent genes previously not thought to be involved in BP regulation. These QTLs will likely have an influence on studies of human hypertension because of their homology with the human CHR 17 region in which QTLs for BP have been found.
Hypertension 2003 Oct
PMID:Comprehensive congenic coverage revealing multiple blood pressure quantitative trait loci on Dahl rat chromosome 10. 1293 33

It is widely accepted that n-3 polyunsaturated fatty acids (PUFAs) rich in fish oils protect against several types of cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis, or hypertension. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be the active biological components of these effects. Although the precise cellular and molecular mechanisms underlying the beneficial effects are still uncertain, the protective effects of n-3 PUFAs are attributable to their direct effects on vascular smooth muscle cell (VSMC) functions. These n-3 PUFAs activate K(+)(ATP) channels and inhibit certain types of Ca(2+) channels, probably via at least 2 distinct mechanisms. N-3 PUFAs favorably alter the eicosanoid profile and regulate cytokine-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 via mechanisms involving modulation of signaling transduction events. N-3 PUFAs also modulate VSMC proliferation, migration, and apoptosis. These recent data suggest that modulation of these VSMC functions contribute to the beneficial effects of n-3 PUFAs on various cardiovascular disorders. Furthermore, recent studies strongly suggest that DHA has more potent and beneficial effects than EPA. However, many questions about the cellular and molecular mechanisms still remain to be answered.
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PMID:Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid. 1293 15

Biochemical and pharmacological studies have suggested that NOS2 (inducible nitric oxide synthase) has a functional role in the blood pressure response to increases in dietary salt intake. On a high-salt diet, the Dahl/Rapp salt-sensitive (S) strain of rat, a genetic model of salt-sensitive hypertension, did not show increased nitric oxide production. NOS2 from S rats possesses a point mutation that results in substitution of proline for serine at position 714. In the present study, rat NOS2 was shown to be ubiquitinated in vitro and in vivo and to be degraded by the proteasome; this process was accelerated for the S714P mutant. Accelerated degradation of the S714P mutant enzyme accounted for the diminished enzyme activity of this mutant. Hsp90 (heat-shock protein 90) associated with NOS2 and modulated degradation, but was not responsible for the accentuated degradation of the S714P mutant enzyme. The combined findings demonstrate the integral role of ubiquitination and degradation by the proteasome in the regulation of NO production by rat NOS2. Demonstrating that this process is responsible for the abnormal function of the S714P mutant NOS2 in S rats confirms the physiological importance of the proteasome in NOS2 function.
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PMID:Accelerated ubiquitination and proteasome degradation of a genetic variant of inducible nitric oxide synthase. 1295 38

Oxidative stress implies an increased production of reactive oxygen species (ROS) or a decreased capacity to metabolize them. Superoxide anion (O) can bioinactivate nitric oxide (NO). Therefore, many effects of ROS are manifest as NO deficiency. The afferent arteriole and macula densa cell both contain a full complement of components of nicotine adenine dinucleotide phosphate (NADPH) oxidase that generates O. Nitric oxide synthase (NOS) type 1 or neuronal NOS (nNOS) is expressed in the macula densa and NOS type II or endothelial NOS (eNOS) in the afferent arteriole. Whole animal studies in models of hypertension and oxidative stress demonstrate that metabolism of O by a superoxide dismutase (SOD) mimetic can reduce renal vascular resistance. In vivo studies of single nephron function and in vitro studies with the double-perfused juxtaglomerular apparatus preparation have shown extensive interaction between O and NO in macula densa to regulate afferent arteriolar tone mediated by the tubuloglomerular feedback response. In vitro studies of rabbits isolated, perfused afferent arterioles have shown a similar interaction in this vessel. These data indicate important roles for O in the macula densa and afferent arterioles to enhance preglomerular resistance in animal models of oxidative stress. As an increase in afferent arteriolar resistance can precede hypertension, oxidative stress could be important in determining the long-term blood pressure and thereby contribute to hypertension.
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PMID:Redox regulation of the afferent arteriole and tubuloglomerular feedback. 1461 37

Accumulating evidence indicates that vascular dysfunction in atherosclerosis, hypertension, and diabetes is either caused by or accompanied by oxidative stress in the vessel wall. In particular, the role of redox processes as mediators of vascular repair and contributors to post-angioplasty restenosis is increasingly evident. Yet the pathophysiology of such complex phenomena is still unclear. After vascular injury, activation of enzymes such as NADPH oxidase leads to a marked increase in superoxide generation, proportional to the degree of injury, which rapidly subsides. Such early superoxide production is significantly greater after stent deployment, as compared to balloon injury. Recent data suggest the persistence of low levels of oxidant stress during the vascular repair reaction in neointimal and medial layers. Despite the compensatory increase in expression of iNOS and nNOS, nitric oxide bioavailability is reduced because of increased reaction rates with superoxide, yielding as by-products reactive nitrogen/oxygen species that induce protein nitration. Concurrently, the activity of vascular superoxide dismutases exhibits a sustained decrease following injury. This decreased activity appears to be a key contributor to vasoconstrictive remodeling and a major determinant of the occurrence of nitrative/oxidative stress. Replenishment of superoxide dismutase (SOD), as well as treatment with vitamins C and E or the lipid-lowering drug probucol and its analogs, led to decrease in constrictive remodeling and improved vessel caliber. Better understanding of the redox pathophysiology of vascular repair should help clarify the pathogenesis of many other vascular conditions and may provide novel therapeutic strategies to prevent vascular lumen loss.
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PMID:Redox processes underlying the vascular repair reaction. 1496 Nov 89


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