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)

Inhibition of calcineurin-mediated signaling in T lymphocytes is a major mechanism of cyclosporine A (CsA)-induced immunosuppression, and previous rat studies have suggested that inhibition of calcineurin-mediated signaling in central neuronal pools involved in blood pressure regulation plays an important role in causing acute CsA-induced hypertension. However, a central neural mechanism is difficult to reconcile with other data suggesting that CsA-induced hypertension is due to activation of renal and other subdiaphragmtic visceral afferents that reflexively increase efferent sympathetic nerve activity. Accordingly, we now have revised our hypothesis to suggest that CsA stimulates renal afferents by a calcineurin-dependent process. To test this new hypothesis, in anesthetized rats we recorded arterial pressure and multifiber afferent renal nerve activity from the cut distal end of the renal nerve before, during, and after intravenous infusion of either CsA (5 mg/kg over 20 min, n = 8), FK506 (0.15 mg/kg, n = 7), another potent calcineurin inhibitor that is structurally unrelated to CsA, or rapamycin (0.15 mg/kg, n = 4), a structural analog of FK506 that has no effect on calcineurin. We found that renal afferent discharge was increased markedly by intravenous FK506, as well as CsA, but unaffected by rapamycin (or vehicle), indicating calcineurin mediation. After infusion of either calcineurin inhibitor, afferent renal nerve activity remained elevated for up to 2 h, paralleling the prolonged increase in blood pressure. Thus, the major new conclusion of this study is that, in contrast to what has been assumed previously, calcineurin inhibitors enhance sympathetic neurotransmission by a novel action localized to visceral sensory nerve endings rather than to nerve cell bodies or central synapses. In the rat, calcineurin-dependent activation of renal afferents appears to be the primary mechanism producing the large blood-pressure-raising effect of CsA. Because the data suggest that the major side-effect of CsA and FK506--hypertension--is inexorably linked to calcineurin inhibition in extralymphoid tissue, development of agents that selectively inhibit calcineurin only in T lymphocytes could eliminate this important secondary form of hypertension.
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PMID:Calcineurin inhibitors cause renal afferent activation in rats: a novel mechanism of cyclosporine-induced hypertension. 1098 50

We report a case of cerebral hemorrhage associated with cyclosporin A (CsA)/FK506-related encephalopathy that developed in a 16-year-old woman after allogeneic bone marrow transplantation. Hematopoietic engraftment occurred on day 15, and the patient developed systemic convulsions after CsA was replaced by FK506 for the treatment of acute graft-versus-host disease (GVHD). Based on magnetic resonance imaging, laboratory findings and cerebrospinal fluid studies, she was diagnosed as having CsA/FK506-related encephalopathy with cerebral hemorrhagic infarction. Although she recovered completely after discontinuation of FK506, she developed convulsions again 15 days after re-administration of FK506. A computed tomography scan showed cerebral hemorrhage. She died of respiratory failure. Vascular damage induced by immunosuppressive drugs and enhanced by acute GVHD seemed to be the cause of the cerebral hemorrhage. Since hypertension, which was present during both of the central nervous system events, seemed to have contributed to the development of the cerebral hemorrhage, it is proposed that CsA and FK506 should be reduced or discontinued when patients who have risk factors of hypertension become hypertensive even if they have no symptoms of neurotoxicity.
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PMID:Fatal cerebral hemorrhage associated with cyclosporin-A/FK506-related encephalopathy after allogeneic bone marrow transplantation. 1110 Jul 53

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.
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PMID:Liver transplantation for alcoholic cirrhosis. 1111 78

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.
Hypertension 2002 Aug
PMID:AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. 1215 8

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

Autoimmune diseases characterized by activation of immune effector cells and damage of target organs are currently treated with a combination of several disease-modifying antirheumatic drugs (DMARDs) that preserve different immunomodulatory mechanisms. Such a combination treatment strategy not only provides synergistic effects but also reduces side effects from individual drug. Tetrandrine (Tet), purified from a creeper Stephania tetrandra S Moore, is a bis-benzylisoquinoline alkaloid and has been used to treat patients with silicosis, autoimmune disorders, and hypertension in Mainland China for decades. The accumulated studies both in vitro and in vivo reveal that Tet preserves a wide variety of immunosuppressive effects. Importantly, the Tet-mediated immunosuppressive mechanisms are evidently different from some known DMARDs. The synergistic effects have also been demonstrated between Tet and other DMARDs like FK506 and cyclosporin. These results highlight Tet a very potential candidate to be considered as one of DMARDs in the treatment of autoimmune diseases, especially rheumatoid arthritis. This review summarizes evidence-based in vivo and in vitro studies on this potential Chinese immunosuppressive herb.
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PMID:Immunomodulatory effects and mechanisms of plant alkaloid tetrandrine in autoimmune diseases. 1246 46

Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.
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PMID:Response of refractory colitis to intravenous or oral tacrolimus (FK506). 1627 9

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.
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PMID:Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation. 1283 78

A number of studies have reported a lower atherogenic lipid profile in liver transplant recipients under tacrolimus (FK506) than in those under cyclosporine A (CyA) immunosuppression. This has mainly been attributed to the steroid-saving effect of FK506. However, the effects of converting CyA to FK506 monotherapy on lipid metabolism have not been specifically investigated. In 20 patients with stable graft function, immunosuppressive monotherapy was switched from CyA to FK506 because of CyA-related side-effects (hypertension, nephrotoxicity, hypercholesterolaemia). Serum lipid levels were measured before and 3, 6 and 12 months after conversion. In 5 patients, a modification of immunosuppression became necessary during the study period (4 were reconverted to CyA, 1 to glucocorticoids). In the remaining 15 patients on FK506 monotherapy, 12 months after conversion, a slight decrease in mean serum cholesterol, a slight increase in LDL, but a significant decrease in mean serum HDL were observed, resulting in a significant increase in Chol/HDL and LDL/HDL ratios. Conversion of immunosuppressive monotherapy from CyA to FK506 had no beneficial effect on the atherogenic lipid profile in this selected study population of long-term liver transplant survivors.
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PMID:Impact of changing immunosuppressive monotherapy from Cyclosporin A to Tacrolimus in long-term, stable liver transplant recipients. 1450 23

The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. To this end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid cells to identify small molecules that inhibit NFAT nuclear import. Interestingly, we found that the majority of these small molecules suppress NFAT signaling by interfering with "capacitative" or "store-operated" calcium mobilization, thus raising the possibility that such mobilization processes are relevant targets in immunosuppression therapy. Further, these small molecules also show dose-dependent suppression of cytokine gene expression in T cells. Significantly, the IC(50) of CsA in primary T cells was reduced by the addition of suboptimal concentrations of these compounds, suggesting the possibility that such small molecules, in combination with CsA, offer safer means of immunosuppression.
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PMID:Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. 1518 84


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