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)

Lung transplantation is now an accepted modality for treating end-stage lung disease. To better understand the factors limiting the survival of these patients, we reviewed the autopsy findings in 37 patients who received lung transplants. Between 1986 and 1995, 131 patients have undergone lung transplantation at our institution, including 4 patients with repeat transplantations. Of these, 48 (36.6%) died, 37 (77%) of whom had an autopsy. The autopsied patients were divided into three groups on the basis of post-transplantation interval: early (< 30 d), intermediate (31-365 d), and late (> 365 d). Of the 12 patients in the early group, 6 died of intra- and postoperative complications and 6 of bacterial infection with pneumonia in the transplanted lung. There were 18 patients in the intermediate group, of whom 11 died of infection (5 of cytomegalovirus, 5 of nonviral infections of the transplanted lung, and 1 of encephalomyelitis), 3 of post-transplantation lymphoproliferative disorder, 3 of chronic airway rejection, and one of unrelated cause. Of the seven patients in the late group, four died of chronic airway rejection, two of unrelated causes, and one of bacterial infection. Native lungs examined in 23 patients showed, in addition to the primary disease, bacterial pneumonia in 5, post-transplantation lymphoproliferative disorder in 3, cytomegalovirus in 2, and aspergillosis in 1. In this series of 37 autopsied patients, chronic rejection was the cause of death in 7 and was concomitantly seen in 3 patients (27%). In summary, the most common cause of death was infection (48%), followed by chronic rejection (19%), surgical complications (19%), post-transplantation lymphoproliferative disorder (7%), and unrelated causes (7%); rejection was not a major cause of death in the early and intermediate post-transplantation periods; in 30% of native lungs, significant pathologic findings were present in addition to the primary disease; and in the intermediate post-transplantation period, significant left ventricular hypertrophy occurred, which may be attributable to cyclosporine-induced hypertension but which needs to be further studied.
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PMID:Postmortem findings in lung transplant recipients. 883 58

Endothelin-1 (ET-1) has been implicated in the regulation of vascular tone in various pathological conditions. To examine the effect of in vivo overexpression of the peptide in rats, we prepared recombinant adenovirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escherichia coli lacZ (Ad.betaGal), each driven by cytomegalovirus early promoter. Ad.ET-1 or Ad.betaGal was injected into the caudal vein of rats and the animals were studied under anesthesia 96 h later. Hepatic overexpression of the virus-derived human ET-1 mRNA was accompanied by a 13-fold elevation of liver ET-1 content in the Ad.ET-1 group. Circulating plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.betaGal group. Mean arterial blood pressure was increased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.betaGal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) receptor antagonist FR 139317 reduced the blood pressure to levels seen in the Ad.betaGal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.betaGal group. Intravenous infusion of the ET(B) receptor antagonist BQ-788 caused a small but significant increase in blood pressure in both groups. These findings demonstrate that endogenous overexpression of preproET-1, accompanied by an elevation of plasma ET-1 concentrations to the levels seen in pathophysiological states, can cause systemic hypertension through the activation of the ETA receptor.
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PMID:Systemic hypertension induced by hepatic overexpression of human preproendothelin-1 in rats. 894 55

To provide a more definitive assessment of the efficacy and safety of tacrolimus therapy in comparison with cyclosporin, the extended follow-up of the European multicentre study is reported. Two-year Kaplan-Meier estimates indicated significant reductions in acute (tacrolimus 45.4%, cyclosporin 55.8%; P = 0.006), refractory (1.2% versus 6.4%; P = 0.003) and chronic rejection (2.0% versus 6.9%; P = 0.015) despite significantly lower steroid usage in patients receiving tacrolimus therapy. Patient and graft survival rates (80.6% versus 74.8% and 74.5% versus 70.0%, respectively) were also superior, although these failed to reach statistical significance. Safety profiles were comparable for most major categories (including renal, neurological and glucose metabolic disorders) and in certain aspects were more favourable for tacrolimus. Hypertension (28.0% versus 39.6%, P < 0.01) and cytomegalovirus infection (14.8% versus 22.3%, P < 0.01), two events with important long-term clinical consequences, were reported significantly less frequently. Hirsutism (0.0% versus 8.7%, P < 0.01) and gum hyperplasia (0.0% versus 2.3%, P < 0.05) were absent in patients receiving tacrolimus. Tacrolimus appears to provide effective and safe long-term immunosuppression.
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PMID:Two-year data from the European multicentre tacrolimus (FK506) liver study. 895 12

To produce a prolonged decrease in blood pressure, we have developed a nonpathogenic adeno-associated viral vector (AAV) with the antisense DNA for AT1-R. AAV has many advantages over other viral vectors. AAV does not stimulate inflammation or immune reaction. AAV enters nondividing cells and does not replicate. Therefore, it is an appropriate choice for gene therapy. Recombinant AAV was prepared with a cassette containing a cytomegalovirus promoter and the cDNA for the AT1 receptor inserted in the antisense direction. The cassette was packaged in the virion. Stable transfection of NG108-15 cells with the PAAV-AS (plasmid AAV) antisense to AT1-R produced a significant reduction in AT1 receptors. A single injection of the rAAV-AS (viral vector) was made in adult spontaneously hypertensive rats, either directly in the hypothalamus (1 microL) or in the lateral ventricles (5 microL). The result shows that there is a significant decrease of blood pressure (approximately 23 +/- 2 mm Hg) for up to 9 weeks after injection. Control injections of mock vector produced no change in blood pressure during the same time period in age-matched controls. In young spontaneously hypertensive rats (3 weeks), a single intracardiac injection of recombinant rAAV-AS reduced blood pressure and slowed the development of hypertension compared with controls (P < .01). The results suggest that a prolonged reduction in high blood pressure can be achieved with AAV vectors delivering antisense to inhibit AT1 receptors with a single administration.
Hypertension 1997 Jan
PMID:Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT1-R mRNA antisense. 903 30

The tissue kallikrein-kinin system has been postulated to play a role in blood pressure homeostasis and the pathogenesis of clinical hypertension. To demonstrate the potential therapeutic effects of somatic gene delivery in treating hypertension, we used spontaneously hypertensive rats (SHR) as a model. The gene encoding the human tissue kallikrein was used because of its powerful hypotensive action. The human kallikrein DNA constructs were placed under the control of the metallothionein metal response element, the cytomegalovirus promoter/enhancer or the Rous sarcoma virus 3'-LTR. The human tissue kallikrein DNA constructs were incorporated into adenoviral vectors via homologous recombination. The naked plasmid DNA constructs or adenovirus containing the kallikrein gene were first introduced into kidney 293 cells and the expression of human tissue kallikrein was identified by ELISA. The kallikrein gene was delivered into SHR via intramuscular, intravenous, portal vein, intraperitoneal, and intracerebroventricular routes. A single injection of naked human kallikrein DNA constructs caused a prolonged reduction of high blood pressure for up to 8 weeks. Adenoviral-mediated gene delivery results in high efficiency of human tissue kallikrein expression. Immunoreactive human kallikrein was detected in rat serum at the highest level at 1 day post gene delivery. Portal vein delivery of a reporter gene, AdCMV-LacZ, results in intense staining of beta-galactosidase in rat liver, suggesting that recombinant kallikrein is mainly produced in liver and secreted into the circulation. These results show that kallikrein gene delivery causes a sustained reduction of blood pressure in genetically hypertensive rats and provide important information for a potential gene therapy approach to human hypertension and related diseases.
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PMID:Kallikrein gene therapy: a new strategy for hypertensive diseases. 922 51

The tissue kallikrein-kinin system has been postulated to play an important role in blood pressure regulation. Kallikreins are serine proteinases that release potent vasodilating kinin peptides from precursor kininogens by limited proteolysis. Our recent studies show that systemic delivery of the human tissue kallikrein gene into adult spontaneously hypertensive rats (SHR) results in a sustained reduction of blood pressure for several weeks. The goal of this study is to evaluate whether early delivery of the kallikrein gene into newborn SHR could exert a suppressive effect on blood pressure phenotype during rat growth and development. A human tissue kallikrein cDNA construct, under the control of cytomegalovirus promoter (CMV-cHK), or vector DNA was injected subcutaneously into the necks of 2-day-old SHR. Blood pressures were monitored biweekly from 3 to 19 weeks by the tail-cuff method. A single injection of the human kallikrein cDNA construct caused a significant reduction of blood pressure (n = 6, p < 0.001) from 11 to 17 weeks after injection compared with control rats receiving vector DNA. Intravenous delivery of the human tissue kallikrein gene into adult SHR produced blood pressure lowering effects (n = 6, p < 0.001) that lasted for 6 weeks in male but not in female rats. The expression of human tissue kallikrein in rats was identified by reverse transcription polymerase chain reaction followed by Southern blot analysis and an ELISA specific for human tissue kallikrein. Kallikrein gene delivery did not cause any changes in body weight, urine volume, or water intake in the experimental animals compared with the control group. No antibodies to either human tissue kallikrein or its DNA were detected in rat sera 19 weeks postinjection. These results show that delivery of the kallikrein gene at an early stage of life has a protective effect against development of hypertension in adult SHR and that gender differences could be a factor in kallikrein gene therapy for the treatment of hypertensive disorders.
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PMID:Kallikrein gene therapy in newborn and adult hypertensive rats. 927 59

Mycophenolate mofetil (the morpholinoethyl ester of mycophenolic acid) inhibits de novo purine synthesis via the inhibition of inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effects involve both T and B cells, preventing antibody formation. Mycophenolate mofetil has immuno-suppressive effects alone, but is used most commonly in combination with other immunosuppressants. Mycophenolate mofetil, in combination with cyclosporin and corticosteroids, has been studied in large, randomised clinical trials involving nearly 1500 renal allograft transplant recipients. These trials demonstrated that mycophenolate mofetil is significantly more effective in reducing treatment failure and acute rejection episodes than placebo or azathioprine. Additionally, mycophenolate mofetil may be able to reduce the occurrence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse effect reported is gastrointestinal intolerance; haematological aberrations have also been noted. The reversible cytostatic action of mycophenolate mofetil allows for dose adjustment or discontinuation, preventing serious toxicity or an overly suppressed immune system. Cytomegalovirus tissue invasive disease and the development of malignancies are concerns that merit evaluation in long term follow-up studies. Mycophenolate mofetil does not cause the adverse effects typically associated with other commercially available immunosuppressant medications such as nephrotoxicity, hepatotoxicity, hypertension, nervous system disturbances, electrolyte abnormalities, skin disorders, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, lipid disorders and structural bone loss. Based on preliminary information, a positive benefit-risk ratio has been demonstrated with the use of mycophenolate mofetil in the prophylaxis of rejection in cadaveric renal allograft transplantation. Data from studies in other types of organ transplants are promising, but are too limited to draw clear conclusions. Long term follow-up studies are required to confirm these observations. Although mycophenolate mofetil is expensive, the beneficial effects on the reduction of rejection, treatment failure and related expenses suggest that it is most likely to be cost effective.
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PMID:Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection. 928 99

Endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. We explored the effect of a continuous supply of human endothelial NO synthase (eNOS) on the blood pressure of spontaneously hypertensive rats (SHR) by somatic gene delivery. A DNA construct containing the human eNOS gene fused to the cytomegalovirus promoter/enhancer was injected into SHR through the tail vein. A single injection of the naked eNOS plasmid DNA caused a significant reduction of systemic blood pressure for 5 to 6 weeks in SHR, and the effect continued for up to 10 to 12 weeks after a second injection. The differences were significant from 2 to 12 weeks postinjections (n=6, P<.01). In a separate experiment, L-arginine, the substrate of eNOS, was supplied in drinking water at a concentration of 7.5 g/L for 11 weeks after eNOS gene delivery. A maximal blood pressure reduction of 21 mm Hg in SHR was observed with eNOS DNA compared with that of control SHR injected with vector DNA (181.9+/-1.46 versus 202.7+/-2.79 mm Hg, mean+/-SEM, n=6, P<.01). Human eNOS gene delivery induces significant increases in urinary and aortic cGMP levels and urinary and serum nitrite/nitrate content (P<.05), while no significant differences in body weight, heart rate, water intake, food consumption, or urine excretion were observed. These results indicate that somatic delivery of the human eNOS gene induces a prolonged reduction of high blood pressure and raises the potential of using eNOS gene therapy for hypertension and cardiovascular diseases.
Hypertension 1997 Sep
PMID:Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery. 931 9

Tissue kallikrein has been shown to play a role in blood pressure regulation, and abnormalities in the kallikreinkinin system are considered to be a factor in the pathogenesis of hypertension. To elucidate the potential therapeutic effects of kallikrein gene delivery in hypertension, an adenoviral vector containing the human tissue kallikrein gene under the control of a cytomegalovirus promoter, Ad.CMV-cHK, was intravenously injected into spontaneously hypertensive rats (SHR). A single injection of Ad.CMV-cHK into SHR caused a sustained delay in the increase in blood pressure from day 2 to day 41 post injection, as compared to control rats receiving Ad.CMV-LacZ adenovirus. Adenovirus-mediated kallikrein gene delivery had no effect on the blood pressure of normotensive Wistar-Kyoto rats. Human tissue kallikrein mRNA was detected in the liver, kidney, spleen, adrenal gland, and aorta. Immunoreactive human tissue kallikrein can be detected in sera and urine of rats receiving kallikrein gene delivery. Human tissue kallikrein in rat serum was at the highest level 5 days post injection, and the level declined gradually. Urinary kinin and cGMP levels were significantly increased in rats receiving kallikrein gene delivery compared to Ad.CMV-LacZ control rats. These results show that adenovirus-mediated delivery of human tissue kallikrein results in high-efficiency expression and blood pressure reduction in SHR. Application of adenovirus-mediated systemic expression of the tissue kallikrein gene may provide a unique way of delivering the gene product into the vasculature and could have important therapeutic implications in treating hypertension.
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PMID:Gene therapy in hypertension: adenovirus-mediated kallikrein gene delivery in hypertensive rats. 935 25

Allograft vascular disease is the major cause of late cardiac graft failure. A multifactorial etiopathogenesis is supposed. Our study investigated factors associated with allograft vascular disease occurrence. After stratifying our series on the basis of potential risk factors, we calculated allograft vascular disease incidence rate in 267 grafts from 258 patients who underwent transplant between November 1985 and August 1996. Chi-square test was used for the identification of univariate risk factors to be included in a multivariate model. Multivariate analysis was based on a Poisson model. Seventy of the 267 grafts (26.2%) were diagnosed with allograft vascular disease. Heart disease other than idiopathic dilated cardiomyopathy, donor's age, number of mismatches for HLA-B = 2, presence of systo-diastolic hypertension, number of acute rejection positive endomyocardial biopsies > or = 7 and the association of human Cytomegalovirus and hepatitis C virus infections proved to be univariate risk factors, and were included in the Poisson multivariate model. The association of Cytomegalovirus and hepatitis C infections multiplied allograft vascular disease incidence rate by 3.9, systo-diastolic hypertension by 2.2, occurrence of 2 HLA-B mismatches by 2, a high number (> or = 7) of acute rejection positive-endomyocardial biopsies by 1.8, and heart disease other than idiopathic dilated cardiomyopathy by 1.8. The association of human Cytomegalovirus and hepatitis C virus infections, of HLA-B mismatches, of acute rejection-positive endomyocardial biopsies, as well as post-transplantation hypertension and native heart disease other than idiopathic dilated cardiomyopathy, proved to be positively associated with an increased risk of allograft vascular disease. Given the concordance of our data with those of numerous prior series, we are going to adopt a special surveillance angiographic protocol for patients with these factors.
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PMID:Factors increasing the risk of allograft vascular disease in heart transplant recipients. 935 48


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