Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

19-Nordeoxycorticosterone (19-norDOC) is a powerful mineralocorticoid, which has been postulated to be involved in the pathogenesis of some forms of hypertension. The urinary excretion of 19-norDOC by female rats is up to 20 times that of males. To demonstrate the influence of the gonads on the excretion of 19-norDOC, we measured the excretion of 19-norDOC in intact and gonadectomized male and female rats with and without replacement with testosterone (40 mg testosterone enanthate s.c.) or estrogen (4 mg estradiol valerate s.c.) and in intact animals receiving the aromatase inhibitor, 10-propargyl androstenedione (10-pA) (10 mg s.c.). Orchiectomy produced a significant increase in the urinary excretion of 19-norDOC in males. Testosterone treatment decreased 19-norDOC excretion by castrated males to below intact values, while estrogen administration increased its excretion. Oophorectomy had no consistent effect on 19-norDOC excretion. In oophorectomized females, testosterone administration significantly suppressed 19-norDOC excretion and estrogen replacement increased excretion slightly. 10-pA had little effect on the excretion of 19-norDOC in intact rats of either sex. In conclusion, it appears that 19-norDOC production is inhibited by testosterone, but is affected only slightly by estrogens.
 ...
PMID:The effect of gonadectomy and aromatase inhibition on the excretion of 19-nordeoxycorticosterone in rats. 188 77

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess urinary 19-nordeoxycorticosterone compared with salt-resistant control rats (SR/Jr). 19-Nordeoxycorticosterone is a hypertensinogenic mineralocorticoid, but whether it contributes to the salt sensitivity of SS/Jr is unknown. This study sought to evaluate the contribution of 19-nordeoxycorticosterone to the salt sensitivity of SS/Jr by lowering its production with an aromatase inhibitor, 10-propargyl-androst-4-ene,3,17-dione (19-acetylenic-androstenedione, 19-AA). This aromatase inhibitor also preferentially inhibits nonaromatizing adrenal 19-hydroxylation, an essential step in the formation of 19-nordeoxycorticosterone. To test this hypothesis, inhibitor (120 mg) or vehicle pellets were implanted into male and female weanling SS/Jr at 42 days of age. A high salt diet (8% NaCl) was started and two additional pellets were implanted at 52 and 62 days of age. Systolic blood pressure was measured in all animals and urinary corticosteroids in males. Compared with vehicle, the inhibitor lowered blood pressure at 50 days of age (when it could first be measured) until 64 days of age in females and 71 days of age in males. Corticosterone and aldosterone levels were not different between 19-AA- and vehicle-treated SS/Jr. 19-Nordeoxycorticosterone levels, however, were mildly reduced with the inhibitor (0.05 less than p less than 0.10). After 28 days of high salt diet all 23 of the 19-AA-treated SS/Jr were alive, whereas almost one half of the control animals had died. These data demonstrate that 19-AA attenuates the hypertension in SS/Jr; this effect may be through reduction in 19-nordeoxycorticosterone production.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1991 Jun
PMID:Antihypertensive effects of an aromatase inhibitor in inbred salt-sensitive rats. 204 38

19-Nor-deoxycorticosterone (19-nor-DOC) is a mineralocorticoid that is increased in some forms of experimental and human hypertension. The pivotal step in 19-nor-DOC biosynthesis is adrenal P450 19-hydroxylase, but this enzyme has not been clearly distinguished from P450 11 beta/18-hydroxylase. This study attempted to specifically inhibit adrenal 19-hydroxylation of deoxycorticosterone (DOC) using a suicide aromatase inhibitor, 19-acetylenic androstenedione (19-AA). Purified bovine P450 11 beta/18/19-hydroxylase was incubated with excess substrate DOC, adrenodoxin, and adrenodoxin reductase in the presence of increasing doses of the inhibitor, 19AA. 11 beta-, 18-, and 19-hydroxylation were measured by quantification of corticosterone, 18-OH-DOC, and 19-OH-DOC respectively. Measurements of these products demonstrated that 11 beta- and 18-hydroxylation was not inhibited whereas 19-hydroxylation was inhibited as manifested by decreased 19-OH-DOC formation (p less than .05). The IC50 of 19-AA was approximately 10(-12) M. The specific inhibition of 19-hydroxylation suggests that the 19-hydroxylase may be an enzyme distinct from the P450 11 beta/18-hydroxylase. This further suggests that 19-nor-DOC biosynthesis may be under independent regulation and may be amendable to specific in vivo inhibition.
 ...
PMID:19-Hydroxylase inhibition of adrenal mitochondrial P450 11 beta/18/19-hydroxylase by a suicide inhibitor. 278 64

19-Nor-deoxycorticosterone is a newly recognized mineralocorticoid which has been associated with some forms of genetic, experimental, and human hypertension. To further examine this relationship, specific inhibitors of 19-nor-deoxycorticosterone biosynthesis must be developed. Since 19-hydroxylation is the pivotal step in both 19-nor-deoxycorticosterone biosynthesis and aromatization of androgens to estrogens, we evaluated an aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione on the inhibition of 19-hydroxylation in both rat and human adrenal mitochondria in vitro and 19-nor-deoxycorticosterone production and blood pressure in spontaneously hypertensive rats in vivo. Adrenal mitochondria from 48 male Sprague-Dawley rats and 1 patient with an aldosterone-producing adenoma were incubated in the presence of deoxycorticosterone substrate both with and without 4-hydroxyandrost-4-ene-3,17-dione. 4-Hydroxyandrost-4-ene-3,17-dione produced significant inhibition of 19-hydroxy-deoxycorticosterone production in both rat and human adrenal mitochondria, with a smaller and not significant inhibition of corticosterone and 18-hydroxy-corticosterone. 4-Hydroxyandrost-4-ene-3,17-dione given subcutaneously to spontaneously hypertensive rats lowered 19-nor-deoxycorticosterone by 69% and completely abolished hypertension compared to Wistar-Kyoto controls. These data demonstrate that 4-hydroxyandrost-4-ene-3,17-dione is a specific inhibitor of 19-hydroxylase, that it lowers 19-nor-deoxycorticosterone production and prevents hypertension in the spontaneously hypertensive rat. These studies reinforce the possible pathogenic significance of 19-nor-deoxycorticosterone in hypertension in spontaneously hypertensive rats.
 ...
PMID:Selective 19-hydroxylase inhibition by an aromatase inhibitor, 4-hydroxyandrostenedione. 320 87

Recent studies from this laboratory have demonstrated that 19-nor-deoxycorticosterone, a potent mineralocorticoid, has been excreted in excess in the urine of young spontaneously hypertensive rats (SHR). Although urinary 19-nor-deoxycorticosterone levels decline before the onset of hypertension, preliminary evidence suggests that 19-nor-deoxycorticosterone is further oxygenated to other steroid products in older SHR. Since 19-hydroxylation is the essential first step in the formation of 19-nor-deoxycorticosterone from deoxycorticosterone and since the mechanism-based aromatase inhibitor 10-propargyl-androst-4-ene,3,17-dione preferentially inhibits 19-hydroxylation, this agent was administered to weanling SHR to determine whether inhibition of 19-nor-deoxycorticosterone formation could modify or prevent hypertension. Accordingly, either 10 mg of 10-propargyl-androst-4-ene,3,17-dione or vehicle (control) was injected daily for several weeks in 4.5 week-old SHR. Injection of 10-propargyl-androst-4-ene,3,17-dione reduced urinary free 19-nor-deoxycorticosterone and retarded the development of hypertension compared with the effect of vehicle injection (p less than 0.05). Mean blood pressure levels in SHR receiving 10-propargyl-androst-4-ene,3,17-dione were lower than those in SHR receiving vehicle for each of the first 8 weeks of treatment (p less than 0.05). These data support the importance of 10-nor-corticosteroids in the pathogenesis of hypertension in SHR.
Hypertension 1987 Nov
PMID:Antihypertensive effects of an aromatase inhibitor in the spontaneously hypertensive rat. 366 63

A 45-year-old man presented with gynecomastia, hypertension and a large left adrenal mass. Further evaluation revealed elevated serum concentrations of estrogen, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, deoxycorticosterone, and aldosterone and increased 24-hour urinary 17-ketosteroid and free cortisol excretion. Removal of a 10 kg adrenocortical carcinoma led to normalization of the hormone concentrations and partial resolution of the gynecomastia. There was no clinical evidence of metastases. Incubation of tumor slices demonstrated that the tumor had an active aromatase and sulfotransferase. We estimated that about half the serum estrone arose from peripheral conversion of androstenedione. Feminizing adrenocortical carcinomas are rare and this case is unusual given the lack of clinical metastases and the probable dual source of estrogen from tumor as well as from the peripheral conversion of tumor-derived androgens.
 ...
PMID:Feminization as a result of both peripheral conversion of androgens and direct estrogen production from an adrenocortical carcinoma. 793 Mar 80

The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased secretion of mineralocorticoids other than aldosterone in genetic and experimental hypertension in rats. We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena.
 ...
PMID:19-Nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11 beta, 18, 19-hydroxylase activity. 848 38

2-Hydroxylation is one of the major metabolic pathways of estrogens and is believed to be catalyzed by a form of cytochrome P450. Recently it has been reported that estrogen 2-hydroxylase activity in human placenta is catalyzed by aromatase. Some investigators suggested the effect of catechol estrogen on human placental steroidogenesis which may be related to pregnancy-induced hypertension (PIH) through the inhibition of catechol-O-methyltransferase (COMT) activity. In order to better understand the interrelationship between placental aromatase and estrogen 2-hydroxylase activities in PIH patients, both activities were evaluated in the PIH placentas. Human placental microsomes obtained from PIH patients were incubated with [1 beta-3H]androstenedione or [2-3H]estradiol in the presence of NADPH. Aromatase and estrogen 2-hydroxylase activities were assessed by the tritium water method. The immunosuppression patterns of both activities due to monoclonal antiaromatase cytochrome P450 antibody (MAb3-2C2) were studied. Estrogen 2-hydroxylase activity was significantly higher in PIH placentas (4.7 +/- 0.9 pmol/min/mg protein, n = 7) than in normal placentas (3.0 +/- 0.7 pmol/min/mg protein, n = 7). When the PIH placental microsomes were subjected to immunosuppression by 1 to 100 micrograms IgG of MAb3-2C2, estrogen 2-hydroxylase activity was suppressed by 94 to 65% whereas aromatase activity was strongly suppressed by 72 to 17%, respectively. From our results of high estrogen 2-hydroxylase activity in PIH placentas, it is assumed that there is a different estrogen catalyzing mechanism in PIH placentas.
 ...
PMID:Aromatase and estrogen 2-hydroxylase activities of human placental microsomes in pregnancy-induced hypertension. 893 May 23

The efficacy and tolerability of the new selective aromatase inhibitor, anastrozole (Arimidex), was compared with megestrol acetate in the treatment of advanced breast cancer in postmenopausal women. In two independent prospective randomised trials, patients who progressed after prior tamoxifen therapy received anastrozole 1 or 10 mg once daily, or megestrol acetate, 40 mg q.i.d. The two studies were designed to allow the data to be combined to increase the statistical power of the analyses. It is the data from these combined analyses that are considered in further detail. After 6 months of follow-up, the proportion of patients gaining clinical benefit (complete response + partial response + stable disease > or = 24 weeks) was approximately one third of patients in all three groups. No significant difference was observed between either dose of anastrozole and megestrol acetate in the time to disease progression (130-153 days). All three treatments were generally well tolerated, but significantly more patients on megestrol acetate gained weight, and the weight gain in this group continued up to at least 9 months of follow-up. At a 12-month update of tolerability, of the commonly observed adverse events, a greater than 2-fold difference between treatment arms was observed for hypertension, weight gain, dyspnoea, vaginal haemorrhage, sweating and diarrhoea (all higher on megestrol acetate except for diarrhoea). Anastrozole is effective and well tolerated and on the basis of these data, 1 mg once daily is the recommended clinical dose in postmenopausal women with advanced breast cancer.
 ...
PMID:Clinical overview of anastrozole--a new selective oral aromatase inhibitor. 939 55

AME has been a crucial experiment of biology from which much has been learnt about corticosteroid hormone action and mineralocorticoid hypertension. 11 beta-HSD is an important pre-receptor pathway determining corticosteroid hormone action. Any tissue expressing 11 beta-HSD1 or 11 beta-HSD2 can clearly modulate glucocorticoid and mineralocorticoid action independent of circulating concentrations. A series of related enzymes operates in a similar fashion to determine hormone action for other members of the thyroid/steroid hormone receptor superfamily (e.g. 17 beta-HSD, 25-hydroxyvitamin D 1 alpha-hydroxylase, aromatase, 5'-deiodinase, 5 alpha-reductase). Endocrinologists have been obsessed with measuring the concentrations of a hormone in the circulation and making their decisions on the basis of these results, whether or not that hormone is involved in the pathogenesis of a disease process. Such an approach needs to be revised, with greater emphasis on considering the action of a hormone within a given tissue and, in turn, on the role of these enzymes in the pathogenesis of human disease.
 ...
PMID:Cortisol, hypertension and obesity: the role of 11 beta-hydroxysteroid dehydrogenase. 959 34


1 2 3 4 5 Next >>