Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stroke risk factor hypertension may function as a predisposing agent by increasing the vulnerability of blood vessels to thrombosis or hemorrhage. The research here demonstrates that cerebrovascular endothelial cells (EC) from spontaneously hypertensive (SHR) and Wistar-Kyoto normotensive (WKY) rats exhibit similar levels of adhesiveness for syngeneic peripheral blood monocytes (e.g., 22.53 +/- 1.32 and 24.35 +/- 1.16%, respectively). Monocyte adhesion to SHR EC was dramatically increased by treatment of EC with lipopolysaccharide, interferon-gamma, or interleukin-1 beta and tumor necrosis factor-alpha (e.g., 106, 68, and 171%, respectively). Identical treatment of WKY EC also increased adhesion albeit at significantly lower levels than observed on concomitantly tested SHR EC (e.g., 47.8, 12.7, and 60.7%, respectively). Allogeneic combinations of monocytes and EC again demonstrated significantly more upregulation of adhesion by treatment of SHR EC than WKY EC. Characterization of these adhesive interactions revealed the interplay of adhesion pathways, which include lymphocyte functional antigen-1/intercellular adhesion molecule-1 (ICAM-1), Mac-1/ICAM-1, and very late activation antigen-4/vascular adhesion molecule-1 as well as other undetermined mechanisms. In summary, these findings indicate hypertension may enhance responsiveness of endothelium to factors that promote monocyte adhesion.
 ...
PMID:Monocyte adhesion to cerebromicrovascular endothelial cells derived from hypertensive and normotensive rats. 752 99

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
Hypertension 1995 Apr
PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

Increased arterial blood pressure following a pyrogenic reaction has been reported in previous studies, however the mechanism of this hypertension has not been examined in detail. The present study investigated the effects of both intravenous (IV) and intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) from E. coli on body temperature (Tb), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), calculated total peripheral resistance (CTPR), stroke volume (SV) and plasma levels of adrenocorticotropin (ACTH) and arginine vasopressin (AVP) in conscious, chronically instrumented sheep. IV injection of LPS (1 microgram) increased Tb in a biphasic manner from 38.7 +/- 0.1 to 39.5 +/- 0.2 degrees C after 50 min and to 39.9 +/- 0.2 degrees C after 130 min, and MAP increased biphasically from 64 +/- 1 to 70 +/- 4 mmHg after 40 min and to 78 +/- 3 mmHg after 130 min. CO initially decreased from 4.4 +/- 0.1 to 3.5 +/- 0.1 after 40 min followed by a secondary rise to 4.8 +/- 0.1 l/min after 100 min. This occurred together with a large, biphasic increase in CTPR from 14.5 +/- 1.0 to 22.0 +/- 2.0 mmHg/l/min at 40 min, and to 18.1 +/- 0.1 mmHg/l/min at 120 min. HR increased from 68 +/- 4 to 97 +/- 4 b/min and SV decreased from 65 +/- 2 to 41 +/- 4 ml/beat during the first phase of activation. Plasma ACTH increased from 22 +/- 9 to 1043 +/- 175 pg/ml after 80 min, and plasma AVP increased from 0.7 +/- 0.2 to 12 +/- 4.0 pg/ml after 60 min. ICV injection of LPS produced a long-lasting increase in Tb and MAP, but had no effect on HR or plasma AVP. Plasma ACTH increased from 30 +/- 12 to 427 +/- 110 pg/ml. These changes suggest that intravenous pyrogenic infection produces a potent vasoconstrictor action in sheep to increase blood pressure, possibly mediated by the actions of AVP within the CNS, or other pyrogenically released vasoconstrictor factors. Furthermore, the duration of activation of the cardiovascular system following peripheral and central LPS administration is different, which together with the contrasting effects on ACTH and AVP, indicate the involvement of several hypertensive mechanisms.
 ...
PMID:Pyrogenic stimulation of vascular resistance in conscious sheep. 762 27

The involvement of bradykinin and nitric oxide (NO) in the early (within 1 h) hemodynamic effects of bacterial lipopolysaccharide (LPS) were investigated in anaesthetised rats. Infusion of rats with LPS (14 mg/kg/h) produced a transient hypotension (nadir at 20 min) and reduced pressor responses to noradrenaline (NA,.1-1 microgram/kg, intravenously (i.v.)). Pretreatment of rats with NG-nitro-L-arginine methylester (L-NAME, 1 mg/kg, i.v.) produced a hypertension which counteracted but did not abolish the hypotension induced by LPS, although it entirely prevented LPS-induced hyporeactivity to NA. In control rats, the bradykinin B2 receptors antagonist HOE 140 (10 nmol/kg, i.v.) produced a transient hypotension, but it did not modify the reactivity to NA. In rats pretreated with HOE 140, subsequently infused with LPS, the drop in blood pressure and its time course after the onset of LPS infusion were not different from those elicited by HOE 140 or LPS separately. In addition, HOE 140 partially prevented the onset of hyporesponsiveness to NA induced by LPS. These results support the view that both bradykinin and NO are involved in the early hyporesponsiveness to NA. They suggest that other mechanisms than NO release are involved in the early hypotensive effects of LPS.
 ...
PMID:Involvement of bradykinin and nitric oxide in the early hemodynamic effects of lipopolysaccharide in rats. 764 40

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.
 ...
PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

In addition to participating in protein synthesis in cells and tissues, L-arginine is essential for the synthesis of urea, creatine, creatinine, nitric oxide, and agmatine and influences hormonal release and the synthesis of pyrimidine bases. This places L-arginine, its precursors and its metabolites at the center of the interaction of different metabolic pathways and interorgan communication. Thus L-arginine participates in changing the internal environment in different but simultaneous ways, ranging from disposal of protein metabolic waste, muscle metabolism, vascular regulation, immune system function, and neurotransmission, to RNA synthesis and hormone-mediated regulation of the internal milieu. In normal rats, inhibition of the nitric oxide pathway results in systemic hypertension and decreased glomerular filtration rate and effective renal plasma flow. If the inhibition of this pathway is sustained, then glomerulosclerosis and death from uremia follow. Dietary intervention with L-arginine has resulted in amelioration of a number of experimental kidney diseases, such as those caused by subtotal nephrectomy, diabetic, nephropathy, cyclosporin A administration, salt-sensitive hypertension, ureteral obstruction, puromycin amino-nucleoside nephrosis, kidney hypertrophy due to high-protein feeding, and glomerular thrombosis due to administration of lipopolysaccharide. The present review addresses the current evidence for the beneficial effects of dietary intervention with L-arginine in a number of experimental renal diseases and describes the basis for the concept of L-arginine deficiency (absolute or relative) in certain settings in which supplementation of the diet with this amino acid may be beneficial.
 ...
PMID:Role of arginine in health and in renal disease. 809 48

Prior studies describe deficiencies of T-cell-mediated immunity in the spontaneously hypertensive rat (SHR) strain of Okamoto and Aoki. This report describes an alteration of humoral immunity: elevation of the plasma concentration of immunoglobulin (Ig) A and of circulating IgA autoantibodies to single-stranded DNA, double-stranded DNA, and thyroglobulin. The increased plasma IgA levels are evident in prehypertensive SHR, hence not secondary to the hypertension, and they result mainly from increments in polymeric IgA. Plasma IgA content also varied concordantly with the level of systolic blood pressure as influenced by age (older > younger) and gender (male > female) in both the SHR and control Wistar-Kyoto rat strains. Strain differences in plasma IgG or IgM were not observed. Studies of peripheral blood lymphocytes indicate that increased production of IgA is one mechanism for the increment in plasma content. The number of blood lymphocytes capable of producing IgA in vitro in response to the mitogen lipopolysaccharide is increased in SHR. When cultured in the absence or presence of lipopolysaccharide, peripheral blood lymphocytes of SHR secrete more IgA in vitro than do cells of the control strain. No significant strain differences in biliary or renal excretion of IgA were observed. The observed alterations of IgA in the SHR either are causative factors in the development of the hypertension or are the products of an epiphenomenon in which IgA and blood pressure are affected separately, but in parallel, by causative factors related to rat strain, age, and gender.
Hypertension 1993 May
PMID:Elevation of plasma immunoglobulin A in the spontaneously hypertensive rat. 849 8

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.
 ...
PMID:Mediators and vascular effects in response to endotoxin. 855 9

Nitric oxide, synthesized from the semiessential amino acid L-arginine by nitric oxide synthase, is a remarkable regulatory molecule and plays an important role in physiological functions. However, the physiological role of nitric oxide in cardiovascular regulation by the central nervous system is not well understood. In this study we investigated the cardiovascular effects of nitric oxide in the lateral ventricle, nucleus tractus solitarii, area postrema, and rostral ventrolateral medulla in urethane-anesthetized male Sprague-Dawley rats. Microinjection of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, into the cerebral ventricle of rats elicited a dose-dependent increase in blood pressure and heart rate. This suggests that nitric oxide may be involved in central cardiovascular regulation. Unilateral microinjection (60 nL) of L-arginine (1 to 100 nmol) into the nucleus tractus solitarii and rostral ventrolateral medulla produced prominent dose-related depressor and bradycardic effects and reduced renal sympathetic nerve activity. However, L-arginine had no significant cardiovascular effects in the area postrema. In addition, 4 to 6 hours after intravenous injection of bacterial endotoxin-lipopolysaccharide (10 mg/kg), there was a time-related potentiation of the L-arginine-induced depressor and bradycardic effects in the nucleus tractus solitarii. These results indicate that nitric oxide is involved in central cardiovascular regulation. The depressor effect of nitric oxide in the nucleus tractus solitarii and rostral ventrolateral medulla may be through inhibition of renal sympathetic nerve activity.
Hypertension 1996 Jan
PMID:Cardiovascular effects of nitric oxide in the brain stem nuclei of rats. 859 85

We previously showed that the lymphocyte proliferation response was significantly suppressed in spontaneously hypertensive rats (SHR) and that this depressed response was due to excessive production of nitric oxide (NO) in macrophages and vascular smooth muscle cells (VSMC). Whether lymphocyte depression and activation of NO synthesis are related to age and development of hypertension remains unclear. The present study addresses such a correlation by examining the time course of development of hypertension, NO synthesis alteration and lymphocyte depression in SHR. Our results show that 1) SHR spleen cell proliferation responses are depressed at 4, 8, and 12 weeks and 1 year of age, with the lowest response occurring at 4 weeks of age; 2) this depressed response is corrected by either NO synthase inhibitor or removal of macrophages from spleen cells; 3) NO production by SHR spleen macrophages is significantly higher in all age groups; 4) upon stimulation with lipopolysaccharide or cytokines, SHR VSMC produce a significantly greater amount of NO in all age groups; 5) the increase in NO synthesis in VSMC correlates significantly with the rise in blood pressure in SHR. However, statistical correlation analysis suggests that lymphocyte depression and the alteration of NO synthesis in macrophages were not associated with either age or increased blood pressure in SHR. On the contrary, the activation of NO synthesis in VSMC can be statistically correlated with elevated blood pressure throughout the development of hypertension in SHR. Nevertheless, the results also suggest that a general alteration in the NO synthesis system may exist in SHR.
 ...
PMID:Activation of nitric oxide synthesis in vascular smooth muscle cells and macrophages during development in spontaneously hypertensive rats. 872 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>