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)

Prazosin, a quinazoline derivative, is a peripheral vasodilator used in the treatment of arterial hypertension and more recently, congestive heart failure (CHF). Prazosin is extensively metabolised by the liver and has high first-pass metabolism and low oral bioavailability. In normal healthy volunteers, the time of peak concentration occurs between 1 and 3 hours after oral administration, with wide interindividual variations. The extent of oral absorption seems to be similar for different pharmaceutical forms and is not influenced by the presence of food in the digestive tract. Oral bioavailability of prazosin ranges from 43.5 to 69.3% (mean 56.9%). Prazosin is highly (92 to 97%) bound to human plasma proteins (albumin and alpha 1-acid glycoprotein) and the extent of binding is independent of the plasma concentration of the drug in the range of 20 to 150 ng/ml. Preliminary studies in humans indicate that pathways for biotransformation of prazosin are similar to those observed in the rat and dog. Only 6% of prazosin is excreted unchanged, mainly in the urine. The two main metabolites (0-demethylated) are almost completely excreted in bile. The time course of disappearance of prazosin from plasma after intravenous injecton indicates that prazosin disposition should be described by a model containing at least 2 kinetically distinct compartments. The mean elimination half-life is about 2.5 hours. After intravenous administration, the steady-state volume of distribution has been calculated to be 42.2 +/- 8.9L and the total body clearance 12.7 +/- 1.3L/h. In hypertensive patients with normal renal function, prazosin kinetics do not differ significantly from normals. However, prazosin disposition is modified in chronic renal failure and in congestive heart failure. In both cases, the plasma free fraction of prazosin is increased and plasma elimination half-life is longer. Prazosin kinetics may be expected to be altered in patients with liver diseases. Pharmacokinetic data do not suggest a mechanism to explain the disappearance of the first-dose effect during continued administration of prazosin. Although more investigation is needed to define prazosin kinetics in congestive heart failure and chronic renal failure, the available information about prolongation of elimination half-life, decreased protein binding and increased peak plasma concentrations suggest that prazosin dosage should be titrated cautiously in such patients.
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PMID:Clinical pharmacokinetics of prazosin. 699 81

An aldosterone-stimulating factor (ASF) has been isolated from normal human urine and found to be a glycoprotein with a molecular weight of 26,000 daltons. ASF stimulated aldosterone production both in vivo and in vitro. ASF was found to be different from other known aldosterone secretogogues by the use of high performance liquid chromatography (HPLC). The retention time of ASF was different (17.0 minutes) from ACTH (retention time, 28.4 minutes), beta-lipotropin (retention time, 20.5 minutes), and angiotensin II. Proteolytic enzyme digestion and purification of ASF by HPLC yielded a smaller molecule (retention time, 22.0 minutes) with a molecular weight of 4000 daltons. This smaller molecule also stimulated aldosterone production in vitro. This showed that the structural requirement for steroidogenesis may be residing in a smaller molecule. ASF failed to produce hypertension in adrenalectomized rats. By immunofluorescence (using fluorescein conjugated antibodies), ASF was found to be localized in the anterior lobe of the pituitary gland. Data suggest that ASF, a new aldosterone-stimulating hormone that has not been described before, is secreted by the pituitary gland, and the adrenal gland appears to be the target organ for the biological activities.
Hypertension
PMID:Localization, purification, and biological activity of a new aldosterone-stimulating factor. 702 16

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two-compartment open model. Terminal half-life (t1/2 beta) was about 3 hr and apparent volume of distribution (Vd beta) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first-pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and alpha 1-acid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first-order kinetics with a linear correlation between dose and steady-state plasma concentration (P less than 0.001). There were substantial variations in plasma concentrations between patients and there were also day-to-day variations in concentration within the same patient.
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PMID:Prazosin kinetics in hypertension. 728 77

1. A human urinary thermostable glycoprotein (ABG-TsU) believed to be a homologue of the plasma aldosterone-binding globulin (ABG) was isolated and purified by differential ultrafiltration, ion-exchange chromatography and gel filtration to electrophoretic homogeneity; it showed a charge heterogeneity in electrofocussing. 2. ABG-TsU was administered intraperitoneally to male rats in small daily doses (7 microgram/day per rat). Sustained hypertension developed in 5--8 days. 3. The treated rats showed no changes in plasma electrolytes, aldosterone or plasma renin activity; however, a significant increase in heart weight was observed. 4. This hypertension appears to be adrenal dependent since it is prevented by bilateral adrenalectomy or administration of an aldosterone antagonist, but not by adrenalectomy when aldosterone is given concomitantly with ABG-TsU.
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PMID:Experimental essential hypertension in the rat? 731 37

Erythropoietin, a glycoprotein, is synthesized mainly in the kidney. With the destruction of renal tissue, erythropoietin production decreases; this is a major factor in the development of anemia in patients with renal failure. For about ten years now, recombinant human erythropoietin has been available for the treatment of renal anemia. All patients with renal insufficiency, independent of their plan for future renal replacement therapy, may benefit from erythropoietin. At what extent of anemia erythropoietin therapy should be started is still discussed and is certainly dependent on the degree of the patient's impairment by his anemia. Before beginning a therapy with erythropoietin, other forms of anemia observed in patients with renal failure, i.e. mainly iron deficiency, have to be excluded. A strict monitoring of hematocrit during treatment with erythropoietin is mandatory. Hypertension, seizures and cardiovascular complications have been observed with overdosing of erythropoietin. Special emphasis of this review is therefore put on the discussion of the dynamics of the erythropoietin-red cell system.
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PMID:[Erythropoietin, a milestone in the history of nephrology]. 748 78

Angiotensinogen has been assumed to be an acute-phase protein, because some forms of acute inflammation, eg, the injection of lipopolysaccharide or cellite or partial hepatectomy, increased the hepatic synthesis of angiotensinogen. In addition, the well-characterized nephrectomy-induced stimulation of angiotensinogen was thought to represent an acute-phase reaction. To evaluate this hypothesis, we examined changes in angiotensinogen secretion by the isolated perfused rat liver after the systemic administration of turpentine or lipopolysaccharide as well as in response to nephrectomy or sham nephrectomy. Comparison was made with the secretion of two typical acute-phase proteins, alpha 1-acid glycoprotein and alpha 2-macroglobulin, and with the secretion of the negative acute-phase protein albumin. All forms of experimental surgery stimulated the secretion of both control acute-phase proteins several-fold. In contrast, the response of angiotensinogen was not uniform; lipopolysaccharide and bilateral nephrectomy stimulated secretion twofold to threefold, sham nephrectomy had no effect, and turpentine decreased the secretion to 30% of the control level. A similar inhomogeneity was found in an additional experiment performed to analyze the direct effects of interleukin-1 or interleukin-6 on the secretion of angiotensinogen by freshly isolated hepatocytes. Interleukin-6 increased but interleukin-1 decreased the mRNA and secretion of angiotensinogen, whereas both cytokines increased the secretion of both acute-phase proteins. Because of this nonuniform behavior of angiotensinogen, it is premature to classify angiotensinogen as an acute-phase protein until a specific function for angiotensinogen during acute inflammation is known.
Hypertension 1994 Jan
PMID:Angiotensinogen: an acute-phase protein? 750 96

The leukocyte glycoprotein L-selectin mediates an early step in the recruitment of leukocytes to sites of inflammation. L-Selectin surface expression is rapidly down-regulated by inflammatory signals in vitro. In a prospective study, we found L-selectin expression on umbilical cord blood granulocytes and monocytes to be significantly decreased in newborn infants with acute bacterial infection compared with controls (p < 0.01). A significantly reduced L-selectin expression of both granulocytes and monocytes was also found to be associated with an increased neutrophil immature/total ratio (p < 0.01) but not with other laboratory markers of neonatal sepsis. There was no apparent impact of prematurity, low birth weight, gestational hypertension, or gestational diabetes on L-selectin expression. Although the mode of delivery did not affect granulocyte L-selectin expression, umbilical cord blood monocytes showed an increased L-selectin expression after emergency cesarean delivery compared with samples obtained after elective cesarean or vaginal delivery (p < 0.01). We conclude that acute systemic inflammation results in down-regulation of granulocyte and monocyte L-selectin expression in vivo similar to that observed in vitro.
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PMID:L-selectin is down-regulated in umbilical cord blood granulocytes and monocytes of newborn infants with acute bacterial infection. 753 4

Fibronectin (FN) is a dimeric glycoprotein found in the extracellular matrix of most tissues that serves as a bridge between cells and the interstitial collagen meshwork and influences diverse processes including cell growth, adhesion, migration, and wound repair. Multiple FN forms arise by the alternative splicing of a primary transcript originating from a single gene. The spatial and temporal alterations in FN expression in the myocardium has been studied in models of cardiac growth in vivo such as fetal development, and hypertrophy secondary to pressure overload. This review focuses on the differential expression of FN isoforms that are observed in different models of cardiac growth. Using a combination of qualitative and quantitative analyses it is shown that in the rat myocardium: (1) the FN phenotype is developmentally regulated, (2) the re-expression of the fetal FN isoforms is observed in different models of cardiac hypertrophy secondary to a sudden or progressive hypertension and (3) the changes in cardiac FN expression affect mostly the coronary artery smooth muscle cells.
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PMID:Fibronectin expression during physiological and pathological cardiac growth. 756 10

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epoetin alfa. A review of its clinical efficacy in the management of anaemia associated with renal failure and chronic disease and its use in surgical patients. 757 84

Angiotensinogen is a glycoprotein with intriguing structural similarities to the serine proteinase inhibitors but with only one known function: to act as a substrate in the enzymatic generation of angiotensin peptides. It is expressed as a constitutive protein by the liver and various other tissues, including the brain. It is in this tissue that the expression of angiotensinogen attains its most complex and controversial manifestations. In late gestation, an unfolding of cellular expression occurs, starting at an epicentre in the eppendymal and astroglia cells of the hypothalamus, which rapidly and sequentially spreads to sub-cortical and then cortical regions, concentrating at sites of electrolyte, fluid and pressure regulation. This initial burgeoning of astroglial angiotensinogen is trailed by a wave of neuronal expression in various limbic and sensorimotor regions of the brain. The predominance of AT2 receptors in these regions suggests that the RAS actions are mediated by AT2 receptors. The angiotensinogen found in the CSF and secreted by cultures of glia and neurones is similar to the two major molecular sizes found in plasma. However, by electrophoretic separation on the basis of charge imparted by differential glycosylation, it can be shown that glia and neurones secrete distinct forms. The expression of different forms is under hormonal regulation. If these structural forms are shown to affect function, then the resulting ramifications may extend to pathological conditions, such as hypertension. Primary cell cultures of astrocytes secrete angiotensinogen constitutively and in a region-specific manner related to the size of the sub-population of secretory cells. Neurone cultures secrete angiotensinogen at about 25% the rate of hypothalamic astrocytes. The use of RT-PCR shows that both cell types express angiotensinogen mRNA. There is still an unresolved mismatch between these data and in situ hybridization histochemistry which shows expression limited to astrocytes but it is suggested that changes to more appropriate techniques will resolve any outstanding discrepancies.
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PMID:Location and secretion of brain angiotensinogen. 764


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