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)

Mycophenolate mofetil (MMF) is an immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T and B lymphocytes. Standard primary immunosuppressive therapy after orthotopic liver transplantation (OLT) is based on a calcineurin-inhibitor (CNI): cyclosporine or tacrolimus. Renal failure with arterial hypertension, due to CNI side-effects, is a major cause of morbidity and mortality after OLT. Several studies have shown the efficacy of MMF to improve CNI-induced nephrotoxicity, blood pressure, and uric acid concentration in liver transplant patients with concomitant reduction or withdrawal of CNI. Predose plasma mycophenolic acid concentrations (MPA) are related to adverse events, drug dose, and clinical status. Blood level values outside the suggested MPA therapeutic range are associated with acute rejection episodes and side effects, which have been described in about half of the patients treated with MMF. Most authors have described gastrointestinal and hematological side-effects, whereas these appear usually dose related, responding quickly to reduction. MMF is potent and safe immunosuppressive agent, and replacement of CNI by MMF in liver transplant patients with renal dysfunction may improve not only kidney function but also other CNI-associated side-effects, such as hypertension and hyperuricemia, with a low risk of rejection.
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PMID:Use of mycophenolate mofetil in liver transplantation: a literature review. 1618 64

Obese Zucker rat (OZR) is a genetic model of obesity with noninsulin-dependent diabetes and hypertension. The OZR exhibit hyperinsulinemia, hyperlipidmia, and high circulating glucocorticoid levels. We have shown previously that long-term potentiation (LTP) is impaired in the CA1 region of the hippocampus of OZR. In the present work, although electrophysiological recording from anesthetized OZR hippocampus showed impaired LTP in the CA1, an intact LTP was recorded in the dentate gyrus (DG) region of the hippocampus of the same OZR. Thus, LTP is differentially impaired in the CA1 compared with the DG region of OZR hippocampus. Immunoblotting was used to investigate the molecular mechanism responsible for impairment of LTP in the CA1 but not in the DG region. Analysis revealed reduction in the levels of phosphorylated calcium-dependent calmodulin kinase II (P-CaMKII) and total CaMKII in the CA1 region of OZR. However, in the DG region, reduction was observed only in the levels of total CaMKII, with no change in P-CaMKII levels. The ratio of P-CaMKII to total CaMKII was increased in the DG but not in the CA1 area of hippocampus of OZR. Although unchanged in the CA1, calcineurin levels were significantly reduced in the DG of OZR. These findings suggest that the DG might possess a compensatory mechanism whereby calcineurin levels are reduced to allow sufficient P-CaMKII to produce an apparently normal LTP in the DG area of OZR hippocampus.
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PMID:Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in Obese Zucker rats: role of calcineurin and phosphorylated CaMKII. 1628 Jun 4

The spontaneously hypertensive rat (SHR) has been well established as a suitable model for studies of hypertension, but little is known about the processes of left ventricular (LV) hypertrophy and the changes in cardiac function in this model. The present study was designed to provide a noninvasive evaluation of the time-dependent alteration of cardiac function in male SHR at 4 to 24 weeks of age and age-matched Wistar-Kyoto rats (WKY). Echocardiographic studies were performed after blood pressure (BP) and heart rate (HR) were measured by a tail-cuff method. The body weight (BW) of SHR was lighter than that of WKY at all ages, and HR was consistently lower, with significantly elevated systolic BP from 4 weeks of age. In the echocardiographic study, LV mass at 4 weeks of age was similar between WKY and SHR, although the ratio of LV mass to BW was higher in SHR than WKY. The ejection fraction, fractional shortening (FS) and midwall FS did not differ between the two groups at 4 weeks, but after 8 weeks, these parameters were decreased in the SHR. The deceleration time was prolonged in SHR after 16 weeks and the E/A ratio was lowered at 12 weeks. We also analyzed the expression levels of calcineurin, which were found to be increased in both groups with age. These results suggest that calcineurin does not play a major role in the development of LV hypertrophy. Thus, in SHR, cardiac hypertrophy develops by 4 weeks of age, and systolic and diastolic dysfunction is evident at 2 to 3 months.
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PMID:Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. 1633 89

Sirolimus (SRL) is a new immunosuppressive drug approved for renal transplantation, but is being used increasingly in orthotopic liver transplantation (OLT). Compared with the calcineurin inhibitors, SRL has different mechanisms of action and side effects profile. Thus, this drug offers significant potential advantages over other immunosuppressive agents. SRL does not cause glucose intolerance, hypertension or renal failure, but it may cause dyslipidemia, hepatic artery thrombosis, thrombocytopenia, anemia, leukopenia, oral mucosa ulcers, edema, arthralgias and wound complications. SRL inhibits the signal of interleukin 2 at a post-receptor level, inhibiting lymphocyte proliferation and fibroblast proliferation. It also has antineoplastic and antifungal effects. We report a 10 years old girl who underwent OLT, experiencing a biopsy-proven recurrent acute rejection (AR) in spite of using three immunosuppressive agents (tacrolimus, mofetil micofenolate and steroids). She developed diabetes mellitus as a consequence of the immunosuppressive therapy. She was rescued with SRL, not experiencing AR again. Mofetil micofenolate, steroids and insulin could be discontinued and tacrolimus doses were reduced, without experiencing severe complications. SRL is a new and safe immunosuppressive agent for rescue in patients with OLT and recurrent AR.
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PMID:[Sirolimus for rescue of recurrent acute rejection and diabetes mellitus after liver transplantation: report of one case]. 1634 73

Endothelial dysfunction and damage are systemic processes that are recognised to play a central role in the pathogenesis of hypertension and atherosclerotic cardiovascular disease. Renal failure is associated with impaired endothelium dependent vasodilatation that is partly a consequence of increased circulating levels of asymmetric dimethyl arginine. Endothelial dysfunction persists, although it is improved, after renal transplantation. Statins appear to improve endothelial dysfunction, as does withdrawal of calcineurin inhibitors, although there is no evidence that these strategies improve patient or graft survival. The situation in transplant recipients is complicated by the fact that endothelial dysfunction (within the graft vasculature) may be a separate process contributing to chronic allograft nephropathy and to circulating levels of endothelial cells and their components, thus limiting the utility of circulating markers of endothelial damage in this population.
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PMID:Endothelial dysfunction in renal transplant recipients. 1638 45

The calcineurin inhibitors (CNIs) cyclosporine and tacrolimus are routinely used for immunosuppression following heart transplantation in conjunction with an antiproliferative agent with or without maintenance steroids. In randomized multicenter trials both agents showed similar efficacies to prevent rejection and death within the first year after transplant. Neither cyclosporine nor tacrolimus have been shown to prevent coronary allograft vasculopathy. Their use is limited by many side effects like kidney damage, hypertension, new-onset diabetes, and hyperlipidemia, although they may have different cardiovascular side effect profiles. The choice of CNIs seems to be currently dictated by their adverse effect profiles, by the results obtained for the individual patient, and possibly by institutional preference.
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PMID:Calcineurin inhibitors in heart transplantation. 1638 14

SLC12A cation/Cl- cotransporters are mutated in human disease, are targets of diuretics, and are collectively involved in the regulation of cell volume, neuronal excitability, and blood pressure. This gene family has two major branches with different physiological functions and inverse regulation: K-Cl cotransporters (KCC1-KCC4) mediate cellular Cl- efflux, are inhibited by phosphorylation, and are activated by dephosphorylation; Na-(K)-Cl cotransporters (NCC and NKCC1/2) mediate cellular Cl- influx and are activated by phosphorylation. A single kinase/phosphatase pathway is thought to coordinate the activities of these cotransporters in a given cell; however, the mechanisms involved are as yet unknown. We previously demonstrated that WNK3, a paralog of serine-threonine kinases mutated in hereditary hypertension, is coexpressed with several cation/Cl- cotransporters and regulates their activity. Here, we show that WNK3 completely prevents the cell swelling-induced activation of KCC1-KCC4 in Xenopus oocytes. In contrast, catalytically inactive WNK3 abolishes the cell shrinkage-induced inhibition of KCC1-KCC4, resulting in a >100-fold stimulation of K-Cl cotransport during conditions in which transport is normally inactive. This activation is completely abolished by calyculin A and cyclosporine A, inhibitors of protein phosphatase 1 and 2B, respectively. Wild-type WNK3 activates Na-(K)-Cl cotransporters by increasing their phosphorylation, and catalytically inactive kinase inhibits Na-(K)-Cl cotransporters by decreasing their phosphorylation, such that our data suggest that WNK3 is a crucial component of the kinase/phosphatase signaling pathway that coordinately regulates the Cl- influx and efflux branches of the SLC12A cotransporter family.
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PMID:WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatase-dependent pathway. 1644 21

Cells have the capability of defending themselves from various stressors by activating a genetic program with the production of substances known as heat shock proteins (Hsps) and their regulatory partners, the heat shock transcription factors. Hsps play a major role in systemic hypertension, coronary artery disease, carotid atherosclerosis, myocardial infarction and myocardial ischemia. In this review we discuss the interaction between Hsp70 and CaN which was carried out in our laboratory. We demonstrated that the cardiac Hsp70 stimulated a 2-fold increase in calcineurin (CaN) activity. In addition, the pull-down assay revealed that Hsp70 directly interacts with CaN. Furthermore, expressed cardiac specific Hsp70 was phosphorylated in vitro by cAMP-dependent protein kinase. The phosphorylated Hsp70 was unable to activate the phosphatase activity of CaN. For the first time we demonstrated that Hsp70 is phosphorylated by cAMP-dependent protein kinase and provides an on/off switch for the regulation of CaN signaling by Hsp70. This will lead to therapeutic benefit in human diseases such as atherosclerosis, cardiomyopathy, congestive heart failure, and ischemia.
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PMID:Interaction between heat shock protein 70 kDa and calcineurin in cardiovascular systems (Review). 1646 87

The relationship between the kidney and blood pressure control is complex. Monogenetic forms of hypertension have recently been identified that implicate specific mutations responsible for blood pressure control. The thiazide sensitive Na-Cl cotransporter (NCC) has been implicated in the control of blood pressure, however a direct link between the kidney NCC and blood pressure regulation is lacking. Here, we report a case of chimerism in which a kidney from a patient with Gitelman syndrome was transplanted into a non-Gitelman hypertensive recipient. After transplantation, postural hypotension resulted, necessitating discontinuation of all antihypertensive medications used for treatment of calcineurin-induced hypertension. This is the first reported case of acquired Gitelman syndrome after transplantation. Transplantation of a Gitelman "kidney" into a hypertensive recipient provides additional support for the role of the kidney NCC in blood pressure regulation. Furthermore, this case suggests the potential use of thiazide diuretics in the treatment of calcineurin-induced hypertension.
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PMID:Correction of renal hypertension after kidney transplantation from a donor with Gitelman syndrome. 1647 87

Adverse effects associated with calcineurin inhibitors may impact their clinical utility in some patients. This study characterizes the clinical outcomes of liver transplanted (LT) patients who experienced diabetes mellitus (DM) on tacrolimus-based regimen and were converted to cyclosporine-based therapy. Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Clinical and laboratory data related to the clinical course of the patients were recorded. Twenty-five patients were included after a median delay of 54 months after LT [seven women and 18 men, 51 years (range 30-69)]. There were 11 patients with insulin-treated DM (ITDM), 14 patients with noninsulin-treated DM (NITDM), and the glycemic control was poor (HbA1c > 6.5%) in 13/25 patients (52%). After a median follow-up of 20 months after conversion, there were four patients with ITDM, 17 patients with NITDM, and four patients without DM, and the glycemic control was poor in 3/25 patients (12%). Four patients returned to tacrolimus because of arterial hypertension or digestive side-effects. In conclusion, our results suggest that conversion from tacrolimus to cyclosporine in stable LT patients with DM is well tolerated and beneficial on glycemic control.
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PMID:Conversion from tacrolimus to cyclosporine in liver transplanted patients with diabetes mellitus. 1649 79


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