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)

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

The spontaneously hypertensive rat (SHR) is a stress-sensitive animal which exhibits moderate immune dysfunction that has been implicated in the onset of hypertension. In this study, we examined the morphology of SHR thymus and spleen and further characterized the immune deficiency using Wistar-Kyoto (WKY) and Fisher 344 (F-344) rats for comparison. The adult SHR thymus does not display the increase in medullary volume typically noted with aging and the volume density of the marginal zone is decreased in the spleen. In vivo tritiated-thymidine incorporation is also decreased in the spleen of unstimulated SHR. In mixed lymphocyte reactions (MLR), the proliferative response of SHR splenocytes is significantly decreased relative to controls, WKY and F-344. Addition of interleukin-1 (IL-1), interleukin-2 (IL-2), or indomethacin to the MLR cultures does not increase proliferation. The proliferative response to T cell receptor monoclonal antibody (mAb-TCR) or interleukin-2 (IL-2) are similarly impaired in the SHR. The depressed proliferative T cell response is reversed by prolactin. It is suggested that the SHR is a valuable model for the study of immune deficiency.
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PMID:Immune system of the spontaneously hypertensive rat: II. Morphology and function. 823 75

We investigated the effects of interleukin-2, which stimulates the proliferation and maturation of thymus-derived lymphocytes, on hypertension and organ injuries in genetically hypertensive rats. Interleukin-2 (5 x 10(4) U/kg body wt) was subcutaneously injected into Dahl salt-sensitive rats fed a 4% NaCl diet and spontaneously hypertensive rats once a week for 10 weeks. The effects on blood pressure, cardiovascular hypertrophy, and renal function were evaluated. Interleukin-2 treatment lowered blood pressure in Dahl salt-sensitive rats (162 versus 187 mm Hg, P < .005). This antihypertensive effect was associated with an increase in glomerular filtration rate (589 versus 428 mL/d per 100 g body weight, P < .005) and reduction in cardiac weight (268 versus 305 mg/100 g body weight, P < .05). Interleukin-2 also alleviated the marked glomerular sclerosis in Dahl salt-sensitive rats (glomerular injury score, 151 versus 220; P < .001). In contrast, interleukin-2 did not affect the development of hypertension or organ injuries in spontaneously hypertensive rats. Histologically, glomerular and arterial lesions of the kidney were much less marked in spontaneously hypertensive rats than in Dahl salt-sensitive rats. These data indicate that interleukin-2 ameliorates the development of hypertension and cardiac and renal injuries in Dahl salt-sensitive rats.
Hypertension 1994 Jan
PMID:Antihypertensive effect of interleukin-2 in salt-sensitive Dahl rats. 828 32

A 22-year-old woman harboring recurrent malignant astrocytoma presented with intracranial hypertension by tumor hemorrhage during repeated administration of lymphokine-activated killer (LAK) cells via Ommaya's reservoir. She first suffered from the tumor located at the right occipital lobe at the age of 13. The tumor regressed completely by subtotal removal of the tumor, followed by external irradiation. Nine years later, however, the occipital tumor recurred and was subtotally resected. Pathological diagnosis was astrocytoma grade 3. Postoperatively, LAK cells induced from her peripheral blood lymphocytes incubated with interleukin-2 and anti-CD3 antibody were injected into the tumor cavity via Ommaya's reservoir for eight times. At the end of the LAK therapy, the tumor regrew with massive hemorrhage in the tumor cavity causing intracranial hypertension. At the reoperation, thick granulation tissue covered the surface of the recurrent tumor and dense deposits of clot were noted around the tip of the Ommaya's tube. Histologically the superficial layer of the tumor was infiltrated with macrophages and lymphocytes, mostly CD3-positive T cells, accompanied with capillary hyperplasia. Viable astrocytoma cells were abundant beneath the granulation layer. It should be considered that in local LAK therapy granulation tissue formation with hypervascularization at the surface of the tumor cavity may lead to tumor bleeding as well as resistance to the treatment.
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PMID:[Recurrence with tumor bleeding in a patient with malignant astrocytoma during the treatment with intracranial injection of lymphokine-activated killer cells--a case report]. 839 64

The effects of recombinant human interleukin-2 covalently linked to polyethylene glycol (PEG-IL-2) or interleukin-2 (IL-2) on hypertension and in vitro suppressor T cell function in the spontaneously hypertensive rats (SHR) were investigated. Male young prehypertensive (4 weeks old) SHRs and adult (10 weeks old) SHRs with established hypertension were injected with low (5,000 units (u)/kg) or high (50,000-100,000 u/kg) dose of PEG-IL-2 or IL-2 as a single bolus or repeated injections. Systolic blood pressure was measured twice weekly using the tail-cuff technique. Systolic blood pressure in the PEG-IL-2 or IL-2 treated animals, irrespective of age, dose, or route of injection, did not differ significantly from that measured in vehicle-treated controls over a 10 week period. Mean arterial pressure measured by intra-arterial catheter was 159 +/- 7 mm Hg 10 weeks after treatment with repeated injections of 5,000 u/kg of PEG-IL-2 and 158 +/- 9 mm Hg in vehicle-treated controls. All rats injected with IL-2 had IL-2-specific IgG antibody in their sera. None of the PEG-IL-2 treated rats had any detectable anti-IL-2 antibodies in their sera. Thus, PEG-IL-2 showed far less immunogenicity than IL-2. Suppressor T (Ts) cells generated from adult SHR spleen cells failed to suppress pokeweed mitogen (PWM)-driven immunoglobulin G (IgG) synthesis. PEG-IL-2 or IL-2 supplementation both in vitro and in vivo restored the ability of adult SHR to generate Ts cells able to inhibit IgG synthesis. Our data suggest that PEG-IL-2 or IL-2 administration does correct a prominent defective Ts cell activity found in adult SHR, but that correction of this immune abnormality is not attended by an attenuation of hypertension.
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PMID:The effects of PEG-interleukin-2 and interleukin-2 on essential hypertension and cellular immune function in the spontaneously hypertensive rat. 846 27

The present experiments were designed to investigate the effect of interleukin-2 on the response to arachidonic acid in rings with and without endothelium from Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR) aortas. In control rings, arachidonic acid induced contractions of WKY aorta that were not different between preparations with and without endothelium. Incubation with interleukin-2 (10 units/mL) for 6 or 18 hours augmented the response to arachidonic acid in rings with, but not in those without, endothelium from WKY rat aortas. In the WKY aorta, both the endothelium-dependent and endothelium-independent contractions to arachidonic acid observed after incubation with interleukin-2 were abolished by indomethacin and ridogrel (a thromboxane-endoperoxide receptor antagonist and a thromboxane synthase inhibitor) but were not affected by dazoxiben (a thromboxane synthase inhibitor). Interleukin-2 did not augment the vascular reactivity of WKY aortic smooth muscle to activation of the thromboxane-endoperoxide receptor with U46619. In aortas from SHRs, arachidonic acid evoked endothelium-dependent contraction; interleukin-2 did not modify the response to arachidonic acid in preparations with and without endothelium. These data demonstrate that 1) endothelium-dependent contractions to arachidonic acid are observed in SHR but not in WKY rat aortas; 2) interleukin-2 induces endothelium-dependent contractions to arachidonic acid in the WKY aorta that are mediated by an augmented release of a metabolite of cyclooxygenase, different from thromboxane A2 but activating thromboxane-endoperoxide receptors; and 3) interleukin-2 does not affect the endothelium-dependent and endothelium-independent response to arachidonic acid in the SHR aorta.
Hypertension 1993 Mar
PMID:Interleukin-2 causes endothelium-dependent contractions to arachidonic acid. 847 37

Renal Cell Carcinoma is the third most common malignoma in urology. Only little is known about the etiology and risk factors; the age peak lies at 60 and twice as many men than women are affected. The clinical picture presents with a wide spectrum. Over one third of all tumours are detected accidentally by ultrasound or computed tomography in asymptomatic patients. Most common symptoms are hematuria and flank pain, the classical trials including in addition a palpable mass is rare and by mo means an early symptom. Paraneoplastic syndromes include unspecific (increased blood sedimentation rate, weight loss, fever) and endocrine symptoms (hypertension, polyglobulia, hypercalcemia). Diagnosis is based on imaging procedures. By means of sonography renal cysts may be separated from solid, space-occupying tumors. For the latter CT plays a decisive role for staging, therapeutic planning and prognosis. Further radiologic investigations (angiography, MRI) are indicated only in special situations. Rarely a biopsy is necessary for the distinction between renal cell carcinoma and metastases of other primary tumors. The only curative treatment of localized carcinoma is radical nephrectomy. Partial resection is indicated in cases of a single kidney, bilateral tumors and possibly also for tumors smaller than 4 cm in diameter. Radiotherapy is only initiated for palliation of painful skeletal metastases. In case of distant metastases--mainly pulmonary--nephrectomy should only be performed if systemic treatment is planned or if local complaints (pain, hematuria leading to anemia) exist. Chemotherapeutic drugs have no influence on survival. The effect of gestagens on life quality is questionable. Adoptive immunotherapy with cytokines (Interferon-alpha, interleukin-2) appears most promising. These substances, however, not yet been introduced into routine therapy should only be used in prospective studies. Furthermore, renal cell carcinoma is a potential candidate for gene therapy. After tumor nephrectomy follow-up investigations should be performed twice a year, because of the possibility of curative surgical treatment of late solid metastases. Prognosis of tumors restricted to the organ is good. Five year survival after operation is about 90%. However, is distant metastases exist already at the time of diagnosis 5 year survival drops to less than 10%.
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PMID:[Renal cell carcinoma--a current review]. 931 11

Renal cell carcinoma (RCC) continues to be a frustrating tumor for clinicians to manage and treat. Progress has been made in the identification of risk factors, particularly dietary risk factors. An increased risk has been seen with frequent consumption of fried meat and poultry. Citrus fruits, vitamin C, beta-carotene, and alpha-tocopherol have demonstrated a protective effect against RCC. Other factors that have been associated with the risk of RCC are smoking (which doubles the risk), obesity, hypertension, and exposure to asbestos and petroleum products. Response rates for systemic treatment of RCC continue to hover at about 20%; however, some nonchemotherapy treatments may provide palliation with few side effects. In addition, lower dose combinations of interleukin-2 and interferon alfa may be as beneficial as higher dose regimens, but with less toxicity. Molecular prognostic factors, including proliferation markers, karyometric analyses, oncogenes, and cell adhesion molecules and proteases are areas of intense investigation and may provide mechanisms for identifying patients who require more (or less) aggressive treatment.
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PMID:Renal cell carcinoma. 961 63

Tetrandrine, a purified traditional Chinese medicinal herb that acts as an immunosuppressant and a Ca2+ channel blocker, has been clinically used to treat patients with arthritis, silicosis and hypertension. Since T cells play a critical role as autoreactive and pathogenic population in autoimmune diseases, in this study, we examined the immunosuppressive effect of tetrandrine on human peripheral blood T cells. We showed that tetrandrine inhibited phorbol 12-myristate 13-acetate (PMA) + ionomycin-induced T cell proliferation, interleukin-2 secretion and the expression of the T cell activation antigen, CD71. Further investigation of the molecular mechanism demonstrated that tetrandrine inhibited the expression of the protein kinase C-dependent interleukin-2 receptor alpha chain and CD69 but not the expression of the Ca2+-dependent CD40 ligand and CD69. Interestingly, when tetrandrine and cyclosporin A were added together, significant synergism in the suppression of T cell activation was observed. Moreover, of the several tetrandrine analogues studied, hernandezine was the most potent inhibitor of protein kinase C signaling events. These results also suggest that the protein kinase C-inhibitory capacity of tetrandrine and its analogues may not be associated with their function as Ca2+ channel blockers. Lastly, we showed that, within therapeutic concentrations, tetrandrine and its analogues could induce cellular apoptosis, which is defective in autoimmune diseases. In conclusion, our findings provide novel information about the molecular mechanism of the immunosuppressive effect of tetrandrine and its analogues in human peripheral blood T cells.
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PMID:Plant alkaloid tetrandrine downregulates protein kinase C-dependent signaling pathway in T cells. 1007 15

Renal dysfunction is a frequently encountered adverse event following treatment with high-dose interleukin-2 (IL-2). Information about parameters predicting the severity of IL-2-associated renal function abnormalities is limited. In this study the role of possible risk factors in the development of high-dose IL-2-associated acute and long-term renal dysfunction was investigated. A total of 72 patients, who were treated with a regimen consisting of IL-2 (18 MIU m(-2) day(-1) by continuous infusion), interferon alpha (IFNalpha; 5 MIU m(-2) day(-1), intramuscularly) and lymphokine-activated killer (LAK) lymphocytes, were analysed. Serum creatinine measurements were performed daily during treatment, weekly between courses and monthly during follow-up. Pre-and posttreatment 24-h urine samples were collected for calculation of creatinine clearances. Renal dysfunction was observed in 97% of patients. Grade 1 dysfunction (according to WHO criteria) was observed in 20 patients (28%), grade 2 in 37 (51%), grade 3 in 13 (14%) and grade 4 in 0 (0%). Renal dysfunction was reversible in more than 90% of patients. Only 6 patients (8%) suffered a certain amount of permanent function loss. More severe acute renal dysfunction occurred in patients who were experiencing hypertension prior to treatment, those who suffered sepsis during treatment and in men than in women. Sepsis was also associated with irreversible function loss. Other variables such as age, performance status, diabetes mellitus, interval between nephrectomy and start of IL-2 therapy and hypotension during treatment were not important. In conclusion, with high-dose IL-2, renal dysfunction develops in almost every patient and such abnormalities are mostly reversible. Predictors for severe acute renal dysfunction are pre-existing hypertension, sepsis and sex. A septic episode also carries a risk of permanent damage.
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PMID:The role of possible risk factors for acute and late renal dysfunction after high-dose interleukin-2, interferon alpha and lymphokine-activated killer cells. 1047 8


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