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)

Enhanced Na+ and water reabsorption by proximal tubular epithelial cells plays an important role in the development of systemic hypertension associated with cyclosporine immunosuppression. Since such Na+ reabsorption is subserved by sodium-potassium adenosine triphosphatase (Na-K ATPase), the current study compared the acute effects of hydrocortisone (H), cyclosporine, and FK506 on cultured LLC-PK1 cell viability and on Na-K ATPase activity. Phospholipase-C (PL-C) activity was also investigated because of its possible regulatory effect on Na-K ATPase activity. Culture medium containing low (5 nM, 4.1 ng/ml) or high (10 nM) concentrations of FK506 plus cyclosporine at 415 microM (500 ng/ml) resulted in cell death, whereas cyclosporine concentrations of 83 microM plus 5 nM or 10 nM FK506, or isolated use of the two drugs at high dosages, did not affect cell viability. As compared with controls, cyclosporine increased Na-K ATPase activity, particularly with addition of H (P less than 0.01). In contrast, FK506 reduced the specific activity of both PL-cyclosporine and Na-K ATPase (P less than 0.001-0.01); addition of H to FK506 resulted in an even greater fall in both the enzyme activities (P less than 0.001). Na-K ATPase activity increased in cell homogenates briefly incubated with cyclosporine in the ATPase reaction mixture (P less than 0.05) while FK506 reduced such enzyme activity (P less than 0.05), suggesting a direct effect of these agents on pump activity. These data in LLC-PK1 cells pocessing proximal tubular epithelial cell characteristics indicate that the combined use of cyclosporine plus FK506 may be very deleterious to viability in such cells. The opposing effects of cyclosporine and FK506 on PL-cyclosporine and Na-K ATPase activities and the possible potentiating effect of H on such responses are speculated to affect Na+ and water homeostasis in a manner that may explain differences in systemic blood pressure due to these agents.
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PMID:Phospholipase-C and Na-K ATPase activation by cyclosporine and FK506 in LLC-PK1, cells. Possible implications in blood pressure regulation. 171 43

After liver transplantation for cancer, there is a high incidence of disease recurrence within 18 to 36 months for most tumors, although there are a small number of long-term survivors. An extended resection of the upper abdominal viscera with replacement by a liver-pancreas cluster is being tried in Pittsburgh for lesions which have not been successfully managed with liver transplantation alone. Despite a high incidence of graft reinfection after liver transplantation for hepatitis B virus (HBV) related disease, a significant proportion of patients achieve long-term survival. Hyperimmune globulin and interferon have been of little benefit in preventing reinfection. Clinical trials with a human monoclonal antibody to HBsAg are in progress. Transplantation for alcoholic liver disease has been considered controversial. However, survival after liver transplantation for Laennec's cirrhosis is comparable to survival after liver transplantation for other chronic, benign, and non-HBV related liver diseases. Sclerotherapy followed by liver transplantation is the treatment of choice for patients with acute hemorrhage from esophageal varices and end-stage liver disease. Sclerotherapy alone or followed by selective shunting is an appropriate alternative in patients with good hepatic reserve. Only 25% of infants with biliary atresia benefit from portoenterostomy. To meet the demand for small infants waiting for transplantation, several transplant programs have successfully expanded their efforts to use partial (reduced) liver grafts. Cyclosporine and low-dose prednisone remain the basis for immunosuppression after liver transplantation. However, nephrotoxicity and hypertension are frequent and troublesome side effects of cyclosporine. Triple and quadruple drug regimens have been increasingly popular in an effort to minimize cyclosporine toxicity. Phase 1 clinical trials with a new drug, FK506, recently began in Pittsburgh. Hyperacute rejection of the liver has been demonstrated in animal models and has been strongly suspected in recent clinical descriptions of acute hemorrhagic necrosis after liver transplantation. So far, only transplantation across an ABO incompatibility has been identified as a risk factor for hyperacute rejection. The new preservation solution developed by Belzer and associates at the University of Wisconsin has significantly extended the preservation time for liver grafts, and improved the quality of liver preservation.
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PMID:Changing perspectives on liver transplantation in 1988. 315 94

The safety and efficacy of conversion to FK506 after failing immunosuppression with cyclosporine was prospectively evaluated in 31 pediatric liver transplant recipients between April 1991 and March 1993. The patients, who ranged in age from 40 days to 14 years, accounted for 28 primary transplantations and 3 retransplantations. The initial immunosuppression regimen consisted of cyclosporine in combination with prednisone. The indications for conversion were acute or chronic rejection refractory to OKT3, Minnesota antilymphocyte globulin, or steroids (13 patients); hypertension (8 patients); inability to reach a therapeutic level of cyclosporine (6 patients); hirsutism (3 patients); and growth retardation (1 patient). After an average follow-up of 10 months (range, 2 to 25 months), 27 (87%) of the patients are alive and have functioning grafts. Of the 13 patients who were converted for refractory rejection, 9 are alive. Six of these 9 patients experienced a complete biochemical reversal of the rejection process within 3 months of conversion; 2 had a partial response to conversion, and 1 patient failed but underwent successful retransplantation. Three of the 4 patients who died did so without showing any improvement. The remaining 18 patients who were converted for various other reasons are alive and have functioning grafts. Of the 8 patients who developed hypertension on cyclosporine and prednisone, 6 experienced a resolution of this problem within 3 months of conversion. Three of the 18 children who underwent rescue therapy for reasons other than refractory rejection experienced rejection episodes after conversion to FK506. Two of these 3 children achieved resolution with either steroid therapy or an increased dosage of FK506, while the third child developed chronic rejection. The side effects of FK506 were generally minor and resolved by lowering the dose. Lymphoproliferative disease developed in 2 patients (6%). The present study suggests that FK506 is a relatively safe and effective rescue therapy for pediatric liver transplant recipients who have failed immunosuppression with cyclosporine. Longer follow-up is needed to assess the effect of FK506 on growth.
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PMID:FK506 conversion therapy in pediatric liver transplantation. 751 11

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

Hypertension is common after orthotopic liver transplantation and may be due, in part, to cyclosporin A-induced renal dysfunction and/or enhanced proximal tubular sodium reabsorption. To determine whether enhanced proximal tubular sodium reabsorption is central to the development of posttransplant hypertension, measurements of renal hemodynamics and fractional clearances of lithium and sodium were compared 1 month after orthotopic liver transplantation in previously normotensive patients receiving either cyclosporin A (N = 24) or FK506 (N = 18), an immunosuppressive agent that is structurally unlike cyclosporin A and that has a lower reported incidence of hypertension. Median prednisone doses were 20 and 13 mg/day in the cyclosporin A and FK506 groups, respectively (P < 0.05). At 1 month, mean arterial blood pressure was higher in the cyclosporin A versus the FK506 group: 108 +/- 2 versus 95 +/- 3 mm Hg (P < 0.05). GFR, RBF, and renal vascular resistance were not different between the two groups: 59 +/- 4 and 53 +/- 5 mL/min per 1.73 m2, 439 +/- 28 and 440 +/- 41 mL/min per 1.73 m2, and 22,429 +/- 1,822 and 22,977 +/- 3,506 dyne s/cm5 per 1.73 m2, respectively. Fractional lithium excretion was similar in the cyclosporin A and FK506 groups: 19.9 +/- 2.2 and 19.4 +/- 2.0% (P = not significant) although both values were lower than those of normal controls (25.5 +/- 1.1%) (P < 0.05). Fractional sodium excretion was 2.7 +/- 0.3 and 2.3 +/- 0.4% in the cyclosporin A and FK506 groups, respectively (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal sodium handling with cyclosporin A and FK506 after orthotopic liver transplantation. 754 91

Hypertension, which develops after organ transplantation during immunosuppression with cyclosporine (CSA), is often associated with a loss of nocturnal decrease in blood pressure. Few data correlate circadian blood pressure patterns before transplant with those observed at fixed time points after transplant, or address the role of alternate immunosuppressive agents such as FK506. FK506 is unrelated structurally to CSA and less often leads to hypertension early after transplant. The present study compared nocturnal blood pressure patterns in patients with end-stage liver disease (ESLD) before transplant to those of transplant recipients receiving either FK506 (0.15 mg/kg/day) plus prednisone or CSA (2 to 3 mg/kg/day) plus prednisone and azathioprine after orthotopic liver transplantation. Overnight ambulatory blood pressure profiles were studied in 13 pretransplant ESLD patients and in 34 patients (FK506: n = 13; CSA: n = 21) treated with different steroid doses (24 +/- 11 mg/day FK506; 34 +/- 3 mg/day CSA), according to protocol, 4 weeks (range, 2 to 7 weeks) after liver transplant. Mean blood pressure and heart rate values from awake and nocturnal 5-h time blocks were compared to 13 normotensive control subjects. Patients with ESLD were normotensive and maintained a normal nocturnal blood pressure fall (125 +/- 3/74 +/- 2 mm Hg awake; 109 +/- 3/60 +/- 2 mm Hg nocturnal). Awake ambulatory blood pressures were higher in CSA patients than in FK506 patients (148 +/- 3/95 +/- 2 v 128 +/- 3/78 +/- 2 mm Hg, respectively; P < .01), despite reduced glomerular filtration rates in both transplant groups. Both immunosuppressive regimens led to a loss of nocturnal blood pressure fall, as compared to ESLD patients or normotensive controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Loss of nocturnal blood pressure fall after liver transplantation during immunosuppressive therapy. 754 83

The new immunosuppressive agent FK506 was used with steroids to treat 22 pediatric patients who received living-related partial liver transplantation. Seventeen recipients survived and 5 died between one and 16 months after transplantation. Three of the 5 patients who died had required intensive care preoperatively. Autopsy findings showed no evidence of rejection. There was no episode of rejection that required retransplantation in any of the patients. Liver allograft dysfunction, which was suspected to be a rejection response, was encountered in 2 recipients with ABO-nonidentical but compatible grafts. However, their clinical and biochemical findings were ameliorated upon steroid pulse therapy or upon augmented FK506 administration without additional potent immunosuppressive agents. Steroid treatment has been discontinued in all surviving patients at 1-9 months after transplantation. Infectious complications encountered in 9 patients included 2 bacterial, 5 viral, and 2 fungal infections. One recipient died of fungal pneumonia. Abnormal increase of serum creatinine level was confined to the complicated patients. Hypertension was a temporary adverse reaction in the early postoperative period, and only one patient needed an antihypertensive drug at 2 months after transplantation. Acute pancreatitis with hyperamylasemia was observed in one patient who was treated successfully with reduction of FK506 administration. Tremor was observed in 8 patients, itching in 4, insomnia in 2, and vomiting in one. Hirsutism, gingival hypertrophy, and lymphoma were not observed. FK506 was highly effective in living-related partial liver transplantation not only in terms of immunosuppressive potential but also because it produced fewer adverse effects.
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PMID:Experience with FK506 in living-related liver transplantation. 767 28

Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflecting widespread vasoconstriction associated with CsA. FK506 is a novel alternative immunosuppressive agent, structurally unrelated to CsA. These studies compared systemic and renal vascular changes developing in the initial 4 weeks after liver transplantation in patients treated with FK506 (plus PRED) and CsA (plus PRED and AZA). We studied arterial pressure, cardiac index (pulsed doppler ultrasound), and systemic resistance index (SVRI) before and weekly after liver transplant in 32 patients treated with CsA (2 mg/kg initial dose plus PRED; median dose at week 4, 30 mg/day) and 14 patients treated with FK506 (0.15 mg/kg/day initial dose and PRED; mean week 4 dose, 12.5). Renal plasma flow and glomerular filtration rate (GFR) were measured by clearance of para-amino hippurate and 125-iothalamate. Renin activity, aldosterone, and urinary prostanoids were measured by RIA. Pretransplant pressures and hemodynamics reflected low SVRI and increased cardiac index typical of end-stage liver disease. After transplantation, SVRI and pressures rose in both groups, but after week 2, SVRI was lower in patients treated with FK506. This was associated with less prevalent clinical hypertension during the subsequent 4 months (4/14 FK506 (28%) vs. 25/32 (78%) CsA, P < 0.01). By contrast, renal blood flow and GFR fell in both treatment groups similarly, whereas renal vascular resistance rose. Urinary 6-keto-PG-F1-alpha was suppressed in all transplant recipients, but to a greater degree in FK506-treated patients. This value correlated directly to post-transplant GFR (r = 0.48, P < 0.001). These data indicate that FK506-based immunosuppression differs from CsA by inducing less systemic vasoconstriction and hypertension. Renal vasoconstrictive effects were at least as great as those seen with CsA, however, and indicate that nephrotoxicity will remain a common feature to both regimens.
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PMID:Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. 768 34

Cyclosporine A (CsA)-induced hypertension appears to be caused in part by neurogenic vasoconstriction, but the mechanism by which CsA activates the sympathetic nervous system is unknown. In T lymphocytes, the cellular target of CsA and the macrolide immunosuppressant FK506 (as complexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca(2+)-calmodulin-dependent phosphatase calcineurin. The presence of calcineurin and its colocalization with immunophilin in the brain led us to hypothesize that the phosphatase also mediates CsA-induced sympathetic activation. We now report that sympathetic activity and arterial pressure in rats are increased not only by CsA but also by FK506, which is structurally unrelated to CsA but inhibits the same calcineurin-sensitive T-cell signaling pathway. In contrast, sympathetic activity and blood pressure are not increased by rapamycin, which forms an immunophilin complex that does not bind calcineurin. Furthermore, CsA- and FK506-induced sympathetic activation is attenuated for drug analogues possessing modest changes in molecular structure in a way that closely parallels the ability of each analogue to inhibit calcineurin-mediated T-cell signaling. These results implicate an important role for extralymphoid (ie, neuronal) calcineurin in mediating immunosuppressive drug toxicity.
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PMID:Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. 768 70

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.
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PMID:Weaning of immunosuppression in long-term liver transplant recipients. 783 42


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