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

Recent evidence suggests the possible involvement of inducible nitric oxide synthase (iNOS) in the development and maintenance of hypertension in certain animal models. Inflammatory cytokines activate nuclear factor (NF)-kappaB, which plays a major role in transactivation of the inducible nitric oxide synthase (iNOS) gene. However, it remains unknown whether cytokine-mediated iNOS expression in vascular smooth muscle cells (VSMCs) requires signaling pathway(s) other than NF-kappaB activation. The purpose of this study was to determine whether the p42/p44 MAP kinase pathway is involved in cytokine-induced NF-kappaB activation and/or iNOS expression in cultured rat VSMCs. Nitrite/nitrate (NOx) production stimulated by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha in VSMCs was markedly suppressed by inhibiting MAP kinase by pretreatment with a p42/p44 MAP kinase kinase (MAPKK)-1 inhibitor (PD98059) or by transfecting the dominant-interfering form of the nonphosphorylated MAPKK-1 expressing construct (MAPKK S222A). Inhibition of p42/p44 MAP kinase also antagonized the upregulation of iNOS mRNA and protein, as demonstrated by the quantitative RT-PCR method and Western blot analysis, respectively. Furthermore, rat iNOS promoter activity using an iNOS-luciferase construct stimulated by cytokines was inhibited by MAPKK-1 inhibition. However, kappaB-dependent transcription analysis revealed that cytokine-stimulated NF-kappaB activity was unaffected by MAP kinase inhibition. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies showed that PD98059 had no effect on transient phosphorylation or degradation of IkappaB-alpha by cytokines. An electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that MAP kinase inhibition did not block cytokine-stimulated activation of NF-kappaB. These data suggest that the MAP kinase pathway is in part involved in cytokine-induced iNOS expression independent from NF-kappaB activation in rat VSMCs.
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PMID:Cytokine-activated p42/p44 MAP kinase is involved in inducible nitric oxide synthase gene expression independent from NF-kappaB activation in vascular smooth muscle cells. 1113 Dec 79

Intraglomerular hypertension is a primary causal factor in the progressive glomerulosclerosis that characterizes diabetic nephropathy or severe renal ablation. However, inflammation of the glomerular mesangium also participates in at least the early phase of these diseases. In glomerulonephritis, where inflammation is thought to be the predominant causal factor, intraglomerular hypertension is also often present. Mesangial cells (MCs) are critical in orchestrating key functions of the glomerulus including extracellular matrix metabolism, cytokine production, and interaction with leukocytes. Because MCs are subject to increased stretching when intraglomerular hypertension is present, and in glomerulonephritis MC/leukocyte interactions seem to be mediated primarily via the up-regulation of intercellular adhesion molecule-1 (ICAM-1), we examine the possibility that cyclic stretching is a stimulus for increased MC ICAM-1 activity. We demonstrate that the normal low levels of MC ICAM-1 mRNA and protein are dramatically up-regulated by even short intervals of cyclic stretch. This effect is dose- and time-dependent, and requires little amplitude and a brief period of elongation for significant induction. Stretch-induced MC ICAM-1 also leads to a marked elevation in phagocytic leukocyte adherence. This stimulated adherence is equal or greater than that induced by the inflammatory cytokine tumor necrosis factor-alpha, whereas an additive effect occurs when both are applied in combination. Our results indicate that stretch-induced ICAM-1 may provide a direct link between hypertension and inflammation in the progression of injury and glomerulosclerosis in diabetes, renal ablation, and other forms of glomerulonephritis.
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PMID:Cyclic stretching of mesangial cells up-regulates intercellular adhesion molecule-1 and leukocyte adherence: a possible new mechanism for glomerulosclerosis. 1114 73

In addition to established factors such as hyperlipidemia, smoking and hypertension, inflammation and infection have recently been implicated as major risk factors for atherosclerotic disease. Proatherogenic effects induced by infection may be related to both systemic inflammation and to direct effects on the vascular wall. We report here that a high fat diet combined with a protozoal infection with known tropism to the heart induced early atherosclerosis and intimal inflammatory infiltrates (CD4+, CD8+ cells and macrophages) in aortas of all (n = 7) CBA/J mice investigated. These mice are normally quite resistant to atherosclerotic development and in the control group (n = 7) receiving only a fatty diet, only one mouse presented a lesion. This lesion was completely devoid of infiltrating CD8+ cells. Parasite-infected mice receiving a normal diet exhibited vasculitis, but no signs of atherosclerosis and control mice receiving normal diet, as expected, exhibited neither signs of vasculitis nor atherosclerosis. Secretion of IL-6, TNF-alpha, and IFN-gamma were demonstrated in all atherosclerotic lesions and IL-6 appeared to be the dominant cytokine, both in the lesions themselves as well as in the intimal-medial junction. There were no traces of parasites present in the artery wall, indicating that atherosclerosis was induced via an indirect route. We conclude that a high fat diet in conjunction with infection and systemic (or localized) inflammation may have a strong proatherogenic effect. Finally, we suggest that CBA/J mice infected with T. cruzi parasites and given a fatty diet could serve as a useful experimental model in the continued analysis of factors contributing to the induction of atherosclerosis.
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PMID:Induction of early atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and a high cholesterol diet. 1116 16

Vascular repair in response to injury or stress (often referred to as remodeling) is a common complication of many cardiovascular abnormalities including pulmonary hypertension, systemic hypertension, atherosclerosis, vein graft remodeling and restenosis following balloon dilatation of the coronary artery. It is not surprising that repair and remodeling occurs frequently in the vasculature in that exposure of blood, vessels to either excessive hemodynamic stress (e.g. hypertension), noxious blood borne agents (e.g. atherogenic lipids), locally released cytokines, or unusual environmental conditions (e.g. hypoxia), requires readily available mechanisms to counteract these adverse stimuli and to preserve structure and function of the vessel wall. The responses, which were presumably evolutionarily developed to repair an injured tissue, often escape self-limiting control and can result, in the case of blood vessels, in lumen narrowing and obstruction to blood flow. Each cell type (i. e. endothelial cells, smooth muscle cells, and fibroblasts) in the vascular wall plays a specific role in the response to injury. However, while the roles of the endothelial cells and smooth muscle cells (SMC) in vascular remodeling have been extensively studied, relatively little attention has been given to the adventitial fibroblasts. Perhaps this is because the fibroblast is a relatively ill-defined cell which, at least compared to the SMC, exhibits few specific cellular markers. Importantly though, it has been well demonstrated that fibroblasts possess the capacity to express several functions such as migration, rapid proliferation, synthesis of connective tissue components, contraction and cytokine production in response to activation or stimulation. The myriad of responses exhibited by the fibroblasts, especially in response to stimulation, suggest that these cells could play a pivotal role in the repair of injury. This fact has been well documented in the setting of wound healing where a hypoxic environment has been demonstrated to be critical in the cellular responses. As such it is not surprising that fibroblasts may play an important role in the vascular response to hypoxia and/or injury. This paper is intended to provide a brief review of the changes that occur in the adventitial fibroblasts in response to vascular stress (especially hypoxia) and the role the activated fibroblasts might play in hypoxia-mediated pulmonary vascular disease.
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PMID:Hypoxia-induced pulmonary vascular remodeling: contribution of the adventitial fibroblasts. 1119 56

We previously showed that primary cultures of mTAL cells express cyclooxygenase 2 (COX-2) when challenged with tumor necrosis factor alpha (TNFalpha) or phorbol myristate acetate (PMA). Moreover, expression of COX-2 was linked to decreases in TNFalpha-mediated 86Rb uptake, an in vitro correlate of natriuresis. mTAL cells in primary culture express calcium sensing receptor (CaR), a G-protein coupled receptor that senses changes in extracellular calcium concentration and ultimately increases intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activity. PGE2 synthesis by mTAL cells increases in a dose- and time-dependent manner after exposure of these cells to extracellular Ca2+. Similar effects were observed when cells were challenged with the CaR-selective agonist, poly-L-arginine. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to mTAL PGE2 synthesis. As TNF production is calcium-sensitive in some cells types, we postulate that these effects involve the regulation of COX-2 expression via a TNF-dependent mechanism. The functional implications of these studies relate to a cytokine-mediated mechanism that contributes to salt and water balance, and suggests that small changes in Ca(2+)o may contribute to the regulation of these events. The possibility that the effects of Ca(2+)o involve activation of CaR suggests that novel calcimimetic molecules might be useful in conditions, such as hypertension or other conditions, in which manipulation of extracellular fluid volume provides beneficial effects.
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PMID:Regulation of cyclooxygenase isoforms in the renal thick ascending limb: effects of extracellular calcium. 1119 33

-Atherosclerosis is characterized by infiltration in the lesions of cytokine-producing T cells and macrophages, where oxidized LDL may play an important role. However, little is known about the role of the immune system in the development of hypertension. Lysophosphatidylcholine (LPC) is formed by phospholipase A(2)-induced hydrolysis and/or by oxidation of LDL and other phospholipid-containing membranes. The objective of the present study was to investigate the role of antibodies to LPC in borderline hypertension (BHT). Seventy-five men with BHT were compared with 75 age-matched normotensive (NT) men (diastolic blood pressure 85 to 94 and <80 mm Hg, respectively). Antibody levels to LPC of IgM and IgG isotypes and IgG subclasses were determined with ELISAs. BHT men had significantly lower anti-LPC antibody levels of both IgG class (P:=0.0002) and IgM class (P:=0.0003) than did NT controls. Subclass analysis indicated that IgG(1) (P:=0.0005), but not IgG(2), was decreased. Anti-LPC antibodies or immunoglobulin subclasses thereof were negatively associated with atherosclerosis on the basis of intima-media thickness (P:=0.02), metabolic factors (P:=0.02), smoking (P:=0.02), and endothelin (P:=0.03). LPC has proinflammatory properties and is toxic at higher concentrations and thus may play a role in atherogenesis. Furthermore, LPC functions as a vasoconstrictor in experimental systems by inhibiting NO-mediated vasorelaxation. An intriguing possibility is that anti-LPC antibodies counteract these effects. Taken together, our data indicate that anti-LPC antibodies may constitute a novel factor in the development of hypertension and atherosclerosis.
Hypertension 2001 Jan
PMID:Antibodies to Lysophosphatidylcholine Are Decreased in Borderline Hypertension. 1120 71

There is increasing evidence that systemic inflammation and insulin resistance constitute interrelated events that contribute to atherosclerosis. We studied the effect of the association between circulating interleukin 6 (IL-6) levels, one of the major mediators of inflammation, and C-reactive protein on insulin resistance and blood pressure in 228 healthy volunteers. The plasma IL-6 concentration was significantly and similarly associated with systolic (SBP) and diastolic (DBP) blood pressure, fasting insulin, and the fasting insulin resistance index (FIRI) in all subjects. When smokers were excluded from the analysis, plasma IL-6 levels correlated with percent fat mass (r = 0.19; P = 0.02), absolute fat mass (r = 0.17; P = 0.03), SBP, DBP, fasting insulin levels, and FIRI. The latter associations persisted after controlling for body mass index (r = 0.15 and r = 0.19; P = 0.02 and P: = 0.0004 for SBP and DBP, respectively; r = 0.24 and r = 0.19, P = 0.004 and P = 0.03, for fasting insulin and FIRI, respectively). Gender and smoking status significantly influenced the results. Although IL-6 levels were significantly associated with fasting insulin and FIRI in men, these significant correlations were not observed in women. Conversely, although IL-6 levels were significantly associated with SBP and DBP in women, these coefficients were not statistically significant in men. All of these associations were lost among smokers and remained significant in nonsmokers. As IL-6 is the major mediator of the acute phase response by hepatocytes and induces the synthesis of C-reactive protein (CRP), we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all the subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS), in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers. For insulin and FIRI they were stronger in women and in nonsmokers. CPR significantly correlated with the WHR only in men (r = 0.22; P = 0.01). Using multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of its variance in men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, only SBP (P = 0.04) contributed to 5% of its variance. When CRP was introduced into the model, again only SBP (P = 0.01) contributed to 10% of the variance in IL-6 levels. In 25 of these subjects, insulin sensitivity was determined using the frequently sampled iv glucose tolerance test with minimal model analysis, and circulating IL-6 levels were strongly associated with the insulin sensitivity index (r = -0.65; P < 0.0001). Again, this relationship was even stronger in men (r = -0.75; P < 0.001) and was not significant in women (r = -0.26; P = NS). In all of these subjects, only insulin sensitivity (P = 0.0037), not fat mass, contributed to 21% of the variance of IL-6 levels in a multiple linear regression analysis. In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitute a significant proatherogenic cytokine. The mechanisms of these associations should be further investigated.
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PMID:Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. 1123 1

Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-beta(1) (TGF-beta(1)) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-beta(1) production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-beta(1) production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-beta(1) and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 x 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-beta(1), and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-beta(1). Amlodipine did not affect TGF-beta(1) concentrations. In contrast, losartan reduced the plasma levels of TGF-beta(1) by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P: = 0.01); the majority of the patients reached normal levels of TGF-beta(1). ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-beta1 concentrations. These differences could be important for the management of chronic allograft nephropathy.
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PMID:Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. 1127 44

Leptin, a recently described type-1 cytokine, is involved in cellular maturation and growth and appears to have a relationship to some obstetrical and gynecologic diseases. The MEDLINE database was accessed, and leptin-related articles published during the past 6 years were reviewed for their relevance to gynecologic and obstetrical diseases. The relationships between this cytokine and obesity, puberty, polycystic ovary syndrome, endometriosis, assisted fertility, and menopause are discussed. The role of leptin in fetal physiology and in normal and abnormal fetal growth as well as its role in diabetes, pregnancy, and pregnancy-induced hypertension are reviewed.
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PMID:Leptin in obstetrics and gynecology: a review. 1128 35

Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The time proximity to therapy with drugs that are known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses and possible response to corticosteroids may further support such a diagnosis. Cancer therapeutic agents clearly associated with NCPE are cytarabine, gemcitabine, and interleukin-2, as well as all-trans retinoic acid in acute promyelocytic leukemia patients, while a few other compounds have rarely or occasionally been implicated. The pathophysiology of lung injury in drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its pathogenesis. By distinction to drug-induced pulmonary pneumonitis that may lead to permanent pulmonary fibrosis, NCPE if not fatal, can be reversed upon prompt recognition, following immediate discontinuation of the offensive drug and start of intensive supportive treatment and intravenous corticosteroids.
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PMID:Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy. 1130 27


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