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 intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

1. Platelet volume was measured in citrated blood in two groups of patients at risk of having atherosclerotic renal artery stenosis, namely (i) 30 patients with severe hypertension, and (ii) 44 patients with peripheral vascular disease. 2. Platelet volume was increased in patients with hypertension who had atherosclerotic renal artery stenosis diagnosed by angiography: no renal artery stenosis, median 7.2 (interquartile range 0.5) x 10(-15)/l; renal artery stenosis 7.8 (0.8) x 10(-15)/l; platelet mass also increased with increasing severity of renal artery stenosis. Platelet volume correlated with severity of renal artery stenosis (rs = 0.391, 2p = 0.033, n = 30). Similarly, platelet volume correlated with severity of renal artery stenosis in patients with peripheral vascular disease (rs = 0.319, 2p = 0.035, n = 44). Serum immunoreactive platelet-derived growth factor (predominantly released from platelets) and plasma immunoreactive interleukin-6 (a cytokine which has been postulated to regulate platelet volume) concentrations were not different between hypertensive patients with and without renal artery stenosis. 3. Since large platelets are hyperactive, increased platelet volume may contribute to the development of atherosclerotic renal artery stenosis. However, the present data do not lend support to the hypothesis that platelet-derived growth factor is central to renal artery atherogenesis. Interleukin-6 does not appear to regulate platelet volume.
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PMID:Increased platelet volume and platelet mass in patients with atherosclerotic renal artery stenosis. 792 72

Immunosuppressants such as cyclosporine are considered to constrain cell growth by preventing the production of growth stimulatory cytokines (e.g., interleukin-2). The possibility exists, however, that CsA and other immunosuppressants might restrain cell growth by promoting the production of growth-inhibitory cytokines. We have explored herein the hypothesis that CsA stimulates the production of transforming growth factor-beta (TGF-beta), and restrains new DNA synthesis in mammalian cells via a TGF-beta-dependent mechanism. To investigate this new postulate independently of an IL-2-dependent mechanism, we utilized, as probes, two mammalian cell lines, distinguished by their sensitivity to growth inhibition by TGF-beta and resistance to IL-2: CCL-64 mink lung epithelial cells (CCL-64 cells) and A-549 human adenocarcinoma cells (A-549 cells). Our experimental approach revealed the following: (A) CsA and not cyclosporine H, an inactive analogue of CsA, mediates growth inhibition of TGF-beta-sensitive cells, CCL-64 cells, and A-549 cells; (B) CsA stimulates these mammalian cells to secrete TGF-beta; and (C) TGF-beta induced by CsA is biologically active in inducing cell growth inhibition (demonstrated by the reversal of CsA-associated inhibition with anti-TGF-beta monoclonal antibodies). Our observations suggest that CsA can regulate cell growth via a TGF-beta-dependent mechanism. Since the multifunctional cytokine TGF-beta can enhance extracellular matrix accumulation as well as augment endothelin production, our findings also advance a mechanism that links, via TGF-beta, the beneficial (immunosuppression) and the harmful (fibrosis, hypertension) consequences of CsA usage.
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PMID:Regulation of new DNA synthesis in mammalian cells by cyclosporine. Demonstration of a transforming growth factor beta-dependent mechanism of inhibition of cell growth. 811 45

In 10 patients undergoing laparoscopic cholecystectomy, creation of pneumoperitoneum caused immediate venous hypertension and stasis in the lower extremities as measured by percutaneous catheter and duplex scanning. These changes disappeared after deflation. As measured by spirometry, significant reductions in forced vital capacity of 23% and forced expiratory volume in 1 second of 22% were present 24 hours after surgery, and plasma interleukin-6 levels rose to 18 pg/mL. The visual analogue scale of resting pain increased to a median value of 2.5 postoperatively. When compared with other studies of open cholecystectomy, our results showed fewer restrictions of ventilation, lower cytokine levels, and lower pain scores. The minimal soft tissue trauma and early ambulation after laparoscopic cholecystectomy may decrease the risk of thrombosis despite an acute episode of venous stasis.
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PMID:Hemodynamic, respiratory, and metabolic effects of laparoscopic cholecystectomy. 823 48

Pentoxifylline (PTX) has recently been shown to modulate TNF-alpha production and to reduce the incidence and severity of all major complications after BMT, including mucositis, veno-occlusive disease, renal insufficiency, hypertension, and graft-versus-host disease. To analyze in detail the effect of PTX on immune complications after BMT, we investigated the immunomodulatory effect of PTX on immune responses in vitro. The continuous presence of PTX significantly reduced the proliferative response of PBMC to PHA stimulation and to alloantigens in a dose-dependent manner. Starting at concentrations of 100 micrograms/ml, PTX was able to inhibit and, at 1000 micrograms/ml, completely block mitogen-induced proliferation. Maximal inhibition of more than 90% (91 +/- 4%) was also observed at PTX concentrations of 1000 micrograms/ml in the mixed lymphocyte culture (MLR) and by addition on day 0. However, lower but still significant suppression (13 +/- 7%) was achieved at concentrations of 10 micrograms/ml PTX. The inhibitory capacity of PTX was increased by mAbs against TNF-alpha (34 +/- 5% additional suppression at 100 micrograms/ml PTX) and not reversed by the addition of rTNF-alpha. The effect of PTX on the generation of CTLs in vitro was studied in the cell-mediated lymphotoxicity assay. PTX (100 micrograms/ml) significantly inhibited (P = 0.0178) the in vitro generation of CTLs when PTX was added to the culture on day 0. PTX also showed profound modulatory properties in the NK assay, with a reduction of 23 +/- 3% in specific lysis at 10 micrograms/ml PTX and maximal reductions of 88 +/- 3% at 1000 micrograms/ml PTX. Immunomodulatory properties of PTX were not only associated with blockage of TNF-alpha, as shown by decreased mRNA expression and TNF-alpha values in the culture supernatants, but also with an impaired production of other cytokines and secondary messages such as IFN-gamma and neopterin. PTX treatment, however, did not affect IFN-alpha or IL-1 beta production, and IL-6 release was even increased. PTX, therefore, has profound immunomodulatory properties in vitro, which are associated with selective inhibition of cytokine release and can be enhanced by the addition of mAbs against TNF-alpha, but not reversed by the addition of rTNF-alpha.
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PMID:Immune response modulation by pentoxifylline in vitro. 833 42

We examined the possibility that platelet-activating factor (PAF) might be a mediator of cardiopulmonary alterations induced by a 6-h coinfusion of human recombinant tumor necrosis factor (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) in anesthetized pigs. Our hypothesis was tested by pretreating TNF-alpha + IL-1 alpha-infused pigs with WEB 2086 (3 mg/kg from -0.5 to 0 h + 0.75 mg.kg-1.h-1 from 0-6 h), a specific PAF receptor antagonist. Each cytokine was infused intravenously at 0.5 microgram/kg from 0-0.5 h + 5 ng.kg-1.min-1 from 0.5-6 h. WEB 2086 attenuated the early (0.25 h) cytokine-induced increases in mean pulmonary arterial pressure and pulmonary vascular resistance and blocked or markedly attenuated the later occurring (4-6 h) systemic hypertension and increased systemic vascular resistance. WEB 2086 lessened the severity of TNF-alpha + IL-1 alpha-induced hemoconcentration and airway constriction, but did not modify leukopenia, granulocytopenia, or the cytokine-induced increases in plasma concentrations of thromboxane B2, prostaglandin F2 alpha, and 6-ketoprostaglandin F1 alpha. Microscopically, WEB 2086 did not modify the increased number of granulocytes present in lung tissue derived from pigs infused with TNF-alpha + IL-1 alpha. We conclude that PAF occupies a physiological role in modulating TNF-alpha + IL-1 alpha-induced hemoconcentration, the early changes in pulmonary hemodynamics, and the later alterations in systemic hemodynamics.
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PMID:Effect of PAF receptor antagonism on cardiopulmonary alterations during coinfusion of TNF-alpha and IL-1 alpha in pigs. 838 47

Advances in immunosuppressive therapy have resulted in significantly improved patient and graft survival after solid organ transplantation. However, increased use has brought attention to specific toxicities associated with the use of these agents. Corticosteroid therapy can result in a wide array of short and long term toxicities. Management of these effects has focused on alternate day and dosage reduction protocols. Myelosuppression, hepatotoxicity, alopecia and gastrointestinal adverse effects are associated with azathioprine and generally respond to a reduction in dosage or withdrawal. Cyclophosphamide myelosuppression is managed in a similar manner. Use of cyclosporin, while the mainstay of immunosuppressive therapy, is often complicated by several well documented adverse effects. Short and long term nephrotoxicity is often managed through pharmacokinetic dosing strategies as well as pharmacological intervention with calcium channel blockers, prostaglandin analogues, pentoxifylline and thromboxane antagonists. Cyclosporin-induced hypertension, hyperlipidaemia, hyperkalaemia and hyperuricaemia are generally responsive to appropriate dietary restrictions and pharmacological therapies. The adverse effects associated with polyclonal antilymphocyte agents (fever, chills, rash, arthralgias) occur in response to the administration of foreign protein substances but can be prevented by pretreatment with corticosteroids, diphenhydramine and paracetamol (acetaminophen). The administration of muromonab CD3 (OKT3) stimulates the release of cytokines resulting in potentially severe complications seen during the first 1 or 2 doses. Pretreatment with diphenhydramine, low dose corticosteroids and paracetamol as well as proper fluid management has reduced the incidence of this syndrome. However, agents such as high dose corticosteroids, indomethacin, pentoxifylline and anti-tumour necrosis factor monoclonal antibodies may further decrease the severity of cytokine-induced toxicity. Antimurine antibodies may also develop during muromonab CD3 therapy, potentially limiting the efficacy of this agent. However, continued concomitant immunosuppressive therapy has significantly reduced antibody formation. In summary, as newer agents are developed with narrow therapeutic windows, it will be critical to identify specific drug toxicity and to develop preventative and management therapeutic strategies.
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PMID:Prevention and management of the adverse effects associated with immunosuppressive therapy. 839 89

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

Recent experimental findings indicate that endotoxin (i.e. lipopolysaccharide) interacts with specific membrane receptors localized to mononuclear phagocytic cells and neutrophils. Binding of endotoxin to these cells, together with endotoxin-induced activation of host vascular endothelium, initiates a series of signal transduction events that culminate in release of numerous biochemical mediators. The latter include cytokines, platelet-activating factor, thromboxane A2, prostaglandins, leukotrienes, nitric oxide, proteases, toxic O2 radicals, and vasoactive amines. These mediators orchestrate complex biological interactions and amplification signals that lead to cardiopulmonary dysfunction and multi-organ failure within 4-6 h of experimental infusion of endotoxin into animals. The pathophysiological changes include decreased cardiac output, systemic hypotension, decreased blood flow and O2 delivery to tissues, intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased permeability, pulmonary oedema, ventilation-to-perfusion inequalities, hypoxaemia, and haemoconcentration. Metabolic alterations include increased blood lactate and pyruvate, metabolic acidosis, hyperkalaemia and hypoglycaemia. Potential therapeutic modalities for treatment of endotoxaemia/septic shock include specific antagonists directed against lipopolysaccharide, cytokine, and platelet-activating factor receptors, monoclonal antibodies directed against cytokines and lipid A/core polysaccharides of endotoxin, antiproteases, and agents that block release of toxic O2 and arachidonic acid metabolites.
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PMID:Mediators and vascular effects in response to endotoxin. 855 9

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2


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