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 amounts of tissue factor (TF) expressed by brain microvascular endothelial cells (BMECs) from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were compared after stimulating the cells with different doses of lipopolysaccharide (LPS), thrombin, phorbol myristic acid (PMA), Ca(2+)-ionophore (A23187), or tumor necrosis factor (TNF) and interleukin-1 (IL-1). Treatment of cultured BMECs from WKY and SHR with all of these factors dose-dependently increased their total amount of TF; no substantive differences in the levels of enhanced TF expression were observed between WKY and SHR BMECs. We conclude that stimulated endothelium from rats with hypertension, a major stroke risk factor, is not hyperresponsive with respect to TF expression when compared to normotensive controls.
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PMID:Comparison of stimulated tissue factor expression by brain microvascular endothelial cells from normotensive (WKY) and hypertensive (SHR) rats. 147 6

A 70-year-old woman was treated for renal cell carcinoma with recombinant human tumor necrosis factor, 450,000 U/m2 of body surface area, daily for 5 days, once a month. She had had psoriasis for 25 years. After two courses of recombinant human tumor necrosis factor her psoriasis resolved. A 40-year-old man with severe psoriasis was subsequently treated with a total of seven complete and incomplete 5-day courses of recombinant human tumor necrosis factor at doses of 50,000 to 300,000 U/m2/day. Significant toxicity (fever, chills, hypertension, and hypotension) was encountered. Partial resolution of the lesions was seen. Tumor necrosis factor is an active agent in psoriasis.
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PMID:Response to tumor necrosis factor in two cases of psoriasis. 186 45

The cells that make up blood vessel walls appear to participate actively in local immune and inflammatory responses, as well as in certain vascular diseases. We tested here whether smooth muscle cells (SMC) can produce the important inflammatory mediator IL6. Unstimulated SMC in vitro elaborated 5 X 10(3) pg recIL6/24h (i.e., biological activity equivalent to 5 X 10(3) pg recombinant IL6 (recIL6), as determined in B9-assay with a recIL6 standard). Several pathophysiologically relevant factors augmented IL6 release from SMC including 10 micrograms LPS/ml (10(4) pg recIL6), 10 ng tumor necrosis factor/ml (4 X 10(4) pg recIL6), and most notably 10 ng IL1/ml (greater than or equal to 3.2 X 10(5) pg recIL6). Production of IL6 activity corresponded to IL6 mRNA accumulation and de novo synthesis. SMC released newly synthesized IL6 rapidly, as little metabolically labeled material remained cell-associated. In supernatants of IL1-stimulated SMC, IL6 accounted for as much as 4% of the secreted proteins. In normal vessels SMC seldom divide, but SMC proliferation can occur in hypertension or during atherogenesis. We therefore tested the relationship between IL6 production and SMC proliferation in response to platelet-derived growth factor (PDGF) in vitro. Quiescent SMC released scant IL6 activity, whereas PDGF (1-100 ng/ml) produced concentration-dependent and coordinate enhancement of SMC proliferation and IL6 release (linear regression of growth vs. IL6 release yielded r greater than 0.9). IL6 itself neither stimulated nor inhibited SMC growth or IL6 production. Intact medial strips studied in short-term organoid culture produced large quantities of IL6, similar to the results obtained with cultured SMC. These findings illustrate a new function of vascular SMC by which these cells might participate in local immunoregulation and in the pathogenesis of various important vascular diseases as well as in inflammatory responses generally.
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PMID:Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. 231 24

Sixteen previously treated (with only one prior regimen) patients with histologically proven metastatic or locally recurrent colorectal carcinoma were treated with recombinant tumor necrosis factor (rTNF) administered by 30-minute i.v. infusions twice daily for 5 consecutive days every other week for 8 weeks. Patients received 100 micrograms/m2 twice daily on day 1 of cycle 1 with escalation to 150 micrograms/m2 twice daily thereafter. Patients were concomitantly treated with indomethacin 25 mg every 6 hours and acetaminophen 650 mg every 4 hours to obviate fever and chills. Toxicities included: nausea/vomiting (69%), headache (25%), chills (69%), pain at tumor sites (63%), hypotension (31%), and hypertension (38%). Hematologic toxicity included leukopenia less than 2000 cells/mm3 (38%) and thrombocytopenia less than 100,000 cells/mm3 (13%). Liver function abnormalities occurred independently of the site or extent of metastatic disease and inconsistently in each treatment cycle. Four patients developed bilirubinemia greater than 2.5 x baseline values (range, 2.5 to 10.3 U/L); five patients had greater than 2.5 x elevations in alkaline phosphatase (range, 624 to 1663 U/L). Two patients developed retinal vein thrombosis in the absence of hemostatic abnormalities. In both instances, this complication occurred several weeks after completion of therapy. No objective responses were noted in 14 evaluable patients (95% confidence interval: 0 to 0.23). Three patients had stable disease for a median duration of 4.5 months. In conclusion, i.v. rTNF at this dose and schedule has no demonstrable antitumor efficacy. Twice-daily i.v. administration of this agent is associated with more hepatotoxicity than previously reported in trials using subcutaneous or once daily i.v. administration. Retinal vein thrombosis may be a late complication of i.v. rTNF at this dose and schedule.
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PMID:A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma. 238 95

A phase I trial of human recombinant tumor necrosis factor (rH-TNF) has been carried out in patients with advanced solid tumors. Sixty-six courses of the drug were given by 1 h IV infusion, daily for 5 days to 33 patients at doses of 5, 10, 20, 30, 45, 60, and 80 x 10(4) U/m2/day. All patients received isotonic saline (up to 21/day) and either indomethacin or ketoprofen. Acute toxicity resembled that seen with the phase I study of a single dose (5). Dose limiting toxicity was acute, rapidly reversible, hepatic dysfunction and hypotension. Hypertension during drug infusion and dyspnea were marked in some patients. There was one complete and one minor response, both in patients with renal cell carcinoma. The dose of 80 x 10(4) U/m2/day x 5 was poorly tolerated and the recommended starting dose for phase II studies is 60 x 10(4) U/m2/day x 5. Caution is recommended in treating patients with pre-existing hepatic function abnormalities, hypertension, hypotension or significant obstructive airway disease.
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PMID:A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days. 292 76

15 patients aged between 24 and 66 years with 10 different malignant tumor diseases were treated with a recombinant human tumor necrosis factor preparation PAC-4D in a phase-I trial. The starting dose was 10(5) U PAC-4D as an intravenous short infusion. The maximally tolerable dose is around 18 X 10(5) U/m2. As the main clinical side effects were observed: fever, chills, hypertension with subsequent hypotension, lethargy, transient somnolence, headache, neurological deficiency symptoms, nausea and vomiting. Important laboratory-chemical parameters were the increase in transaminases and, in higher dose levels, leukocytosis with the left shift and lymphopenia in the differential blood picture. As dose-limiting toxicity are estimated hypotension, and neurological side effects and hepatotoxicity. In one female patient who received 27 X 10(5) U PAC-4D there appeared pronounced, histologically verified necroses in the metastases of a malignant fibrous histiocytoma.
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PMID:Human pharmacological investigation of a human recombinant tumor necrosis factor preparation (PAC-4D) a phase-I trial. 337 52

A phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48 X 10(4) units/m2. Drug was given as 1-h i.v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearance and a short plasma half-life, generally less than 0.5 h.
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PMID:Phase I clinical trial of recombinant human tumor necrosis factor. 366 33

In cultured vascular smooth muscle cells, the baseline mRNA and protein levels of an inducible type of nitric oxide synthase were barely detectable. Interferon gamma, tumor necrosis factor-alpha, and interleukin-1 beta each markedly increased mRNA and protein levels of this enzyme in parallel with the production of nitrite, a stable oxidative metabolite of nitric oxide. Actinomycin D abolished the cytokine-induced increases in mRNA levels and nitrite production. Cycloheximide, which abolished the cytokine-induced increase in nitrite production, had no effect on the interferon-gamma-induced increase in mRNA levels but partially inhibited that induced by interleukin-1 beta and markedly inhibited that induced by tumor necrosis factor-alpha. Transforming growth factor-beta 1, which inhibited the interferon gamma-, interleukin-1 beta-, and tumor necrosis factor-alpha-induced nitrite production, did not affect the increases in mRNA levels caused by these cytokines. Transforming growth factor-beta 1, however, significantly inhibited the increase in protein levels caused by these cytokines. These findings suggest that interferon gamma directly induces the expression of the inducible nitric oxide synthase gene, whereas tumor necrosis factor-alpha and interleukin-1 beta induce it, at least in part, via the induction of intermediary protein(s), and that transforming growth factor-beta 1 inhibits cytokine-induced nitric oxide production by blocking the posttranscriptional synthesis of inducible nitric oxide synthase.
Hypertension 1994 Jan
PMID:Expression of nitric oxide synthase by cytokines in vascular smooth muscle cells. 750

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.
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PMID:Monocyte adhesion to cerebromicrovascular endothelial cells derived from hypertensive and normotensive rats. 752 99

8-Bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), an analogue of cyclic guanosine monophosphate (cGMP), induced a time- and dose-dependent enhancement of interleukin-1-induced nitric oxide production in vascular smooth muscle cells. Human atrial natriuretic polypeptide, which stimulates cGMP accumulation in vascular smooth muscle cells, also enhanced interleukin-1-induced nitric oxide release at a concentration of 100 nmol/L. In contrast, coincubation with 10 mumol/L methylene blue, an inhibitor of soluble guanylate cyclase, inhibited interleukin-1-induced nitric oxide release from vascular smooth muscle cells. Furthermore, coincubation with 8-Br-cGMP also enhanced the interleukin-1-induced increase in inducible nitric oxide synthase messenger RNA in vascular smooth muscle cells. However, the enhancement of nitric oxide production induced by 8-Br-cGMP was significantly prevented by coincubation with neutralizing antibody against tumor necrosis factor-alpha. Furthermore, 8-Br-cGMP enhanced the interleukin-1-induced increase in tumor necrosis factor-alpha messenger RNA level in vascular smooth muscle cells. These findings indicate that cGMP may upregulate inducible nitric oxide synthase gene expression through the stimulation of tumor necrosis factor-alpha production in vascular smooth muscle cells. Thus, there may be a positive feedback mechanism between nitric oxide and the cGMP system in vascular smooth muscle cells.
Hypertension 1995 Apr
PMID:cGMP upregulates nitric oxide synthase expression in vascular smooth muscle cells. 753 12


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