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)

Recent discoveries in molecular biology have much clarified the regulation and function of steroid-converting enzymes. Most progress has been made in the area of cytochromes, which regulate the side chain cleavage of cholesterol (P-450 SCC) and the 17 alpha-hydroxylase and 17,20-desmolase (or 17,20-lyase) activities (P-450 17 alpha), as well as in 3 beta-hydroxysteroid dehydrogenase. Nevertheless, there are some discrepancies between fundamental knowledge and clinical experience, which are difficult to understand: why is it for example possible that cases with 'pure' 17 alpha-hydroxylase or 17,20-desmolase deficiency exist, when there is only one cytochrome regulating both steps? After a brief review of clinical and biochemical findings in the various defects of testosterone biosynthesis, a case is discussed, which is of interest in this respect. This XY patient with female external genitalia, who has been shown to have compound heterozygous mutations, had 'pure' 17,20-desmolase deficiency up to adolescence, but additional 17 alpha-hydroxylase deficiency with hypertension developed thereafter. From this observation, it has to be concluded that as yet unknown, possibly age-dependent modulating factors exist, which influence the activity of the cytochrome. Also the estrogen replacement given to the patient might have played a role in this change.
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PMID:Recent aspects of steroid biosynthesis in male sex differentiation. Clinical studies. 130 38

Cases of sexual immaturity and male pseudohermaphroditism due to disorders such as androgen resistance, 5 alpha-reductase deficiency, cholesterol desmolase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, and testicular and ovary dysgenesis can easily be distinguished from 17 alpha-OHD. None of these disturbances result in hypertension. In the only other form of juvenile hypertension due to congenital adrenal hyperplasia, 11 beta-OHD, androgen excess leads to female pseudohermaphroditism and precocious puberty in the male patient. Patients with dexamethasone-suppressible hyperaldosteronism present with no sexual abnormalities. A diagnosis of 17 alpha-OHD can be readily assumed in the female patient with primary amenorrhea, hypertension, and hypokalemia. The absence of aldosterone, a measurement that is readily available, establishes this diagnosis even without the measurement of DOC.
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PMID:17 alpha-hydroxylation deficiency. 187 98

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46,XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450c17, Northern blot analysis demonstrated abundant amounts of RNA in these tests that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450c17. These results suggest that these patients have a point mutation in the gene for P450c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.
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PMID:Combined 17-hydroxylase and 17,20-desmolase deficiencies: evidence for synthesis of a defective cytochrome P450c17. 249 25

Adrenal function was assessed in control rats and in rats treated for 2 and 4 weeks with 17 alpha-methylandrostenediol (MAD; 17 alpha-methyl-5-androstene-3 beta-diol), a synthetic androgen known to produce hypertensive cardiovascular disease. In both groups and at both time periods, a circadian rhythm of blood corticosteroid concentrations was observed. The high point for serum corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC), and 11-deoxycorticosterone (DOC) concentrations occurred at the beginning of the dark period (1800 hours), and the low point occurred at the onset of the light period (0600 hours). Serum concentrations of DOC were always found to be higher in MAD-treated rats as compared with controls. The serum concentrations of B and 18-hydroxy-DOC were lower than control values at 1800 hours but higher than control concentrations at 0600 hours. The in vitro 11 beta- and 18-hydroxylation of DOC was markedly reduced with MAD treatment. In contrast, cholesterol side-chain cleavage activity was higher in animals treated with MAD. These in vitro findings correlated with spectral studies that showed a decreased binding of DOC to cytochrome P450(11) beta and increased binding of cholesterol to cytochrome P450scc. These studies suggest that MAD treatment selectively decreases 11 beta- and 18-hydroxylation in adrenal mitochondria, and this results in an increased serum concentration of DOC, a hypertensinogenic steroid. This effect of MAD on peripheral serum DOC concentration is most readily observed in quiescent animals at the high point of the circadian rhythm.
Hypertension
PMID:Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension. 741 67

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11 beta (11 beta-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rodent models for studying steroids and hypertension: from fetal development to cells in culture. 779 17

The major regulator of mineralocorticoid production in the adrenal is angiotensin II produced by the action of renal renin. The discovery that the rodent adrenal also synthesizes renin and angiotensinogen suggests there is autocrine regulation of mineralocorticoid synthesis. The transgenic rat [TGR(mREN2)27] expresses the Ren-2d gene predominantly in the adrenal. Despite suppressed kidney and plasma renin, these animals develop fulminant hypertension between 5 and 15 weeks of age. Corticosteroid concentrations are significantly elevated during hypertension development. We assessed steroidogenesis in TGR(mREN2)27 rats by analyzing the expression of the mRNAs for three steroidogenic enzymes: P450scc, the rate-limiting step of steroidogenesis; P450c11 beta, which converts deoxycorticosterone to corticosterone in the zona fasciculata/reticularis; and P450c11AS, which converts deoxycorticosterone to aldosterone in the zona glomerulosa. P450c11AS mRNA, but neither P450c11 beta nor P450scc mRNA, was overexpressed in the adrenal gland of TGR(mREN2)27 rats. In situ hybridization with specific probes for P450c11 beta and P450c11AS mRNA localized the former exclusively to the zona fasciculata and the latter to the zona glomerulosa. In TGR(mREN2)27 rats, the size of the adrenal and number of P450c11AS-expressing zona glomerulosa cells were about twice those of a normal Sprague-Dawley rat. Both animals respond to corticotropin similarly; corticotropin had no effect on the expression of P450scc and P45011 beta mRNAs, rendered P450c11AS mRNA undetectable, and simultaneously altered the morphology of the adrenal cortex, resulting in a lack of zona glomerulosa-like cells. Thus, the local renin-angiotensin system has a major effect on the basal expression of P450c11AS mRNA, but little effect on the corticotropin-regulated expression of P450scc, P450c11 beta, and P450c11AS mRNAs.
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PMID:Role of adrenal renin in the regulation of adrenal steroidogenesis by corticotropin. 827 56

A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin activity and the aldosterone concentration were low, while the DOC concentration was high (6.10-10.3 ng/ml; normal range 0.03-0.33). Plasma cortisol, androgens, and estrogens as well as urinary 17-OHCS and 17-KS were within normal limits. Furosemide administration and two hours upright posture resulted in a 3-fold increase in plasma DOC, but the administration of ACTH, dexamethasone, or angiotensin III had no effect on plasma DOC. Following resection of a right adrenal tumor weighing 70 g, the hypertension and hypokalemia disappeared. DOC content in the tumor was high. On light microscopic examination, the tumor was encapsulated, composed of cells with clear cytoplasm and large nuclei and there were extensive areas of fibrosis and infiltration of lymphocytes. According to Weiss's criteria, the tumor was considered to be an adrenocortical adenoma. Immunohistochemically, P450scc, 3 beta HSD, P450C21 and P45011 beta were positive with heterogeneity of intra-tumoral expression. No immunoreactivity for P45017 alpha in this adenoma was detected. This is different from a previous report in which a relatively small number of cells in DOC-secreting adrenocortical carcinoma were positive for P45017 alpha.
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PMID:A case of deoxycorticosterone-producing adrenal adenoma. 857 86

Blood pressure is reportedly elevated in the spontaneously hypertensive rat (SHR) neonate, the etiology of which remains unclear. Aberrations in the hypothalamic-pituitary-adrenal axis have been implicated, as it is well accepted that excess corticosteroids are associated with hypertension. We examined aspects of adrenocortical activity in the neonatal SHR 1 to 21 days old and its normotensive genetic control, the Wistar-Kyoto rat (WKY). We found a fourfold greater abundance of P450scc mRNA in adrenals of SHR versus WKY day 1 neonates, and increasing but comparable abundance of adrenal P450c11B mRNA on neonatal days 1 to 21. The pattern of P450c11AS mRNA expression was distinctly different in the adrenals of SHR and WKY neonates; the relative abundance of this mRNA in SHR increased 15-fold over the 21-day period examined, whereas that in WKY remained fairly stable. RT-PCR for the presence/abundance of adrenal P450c11B3 mRNA showed absence in day 1 SHR and WKY, comparable abundances on neonatal days 7 and 14, and a distinctly greater abundance in the day 21 SHR adrenals. Peripheral corticosterone levels were threefold greater in the day 1 SHR neonate; aldosterone levels were elevated in both the SHR and WKY day 1 neonate. Thereafter, corticosterone and aldosterone levels were comparable on days 7, 14, and 21, although the anticipated depression in circulating corticosterone levels typical of the stress hyporesponsive period was noted in both SHR and WKY neonates. Although patterns of adrenocortical activity differ in the newborn SHR and WKY rat, our findings do not support an etiologic role for corticosteroids in the reported hypertension of the SHR. However, observed differences in corticosteroid profiles may augment or have a permissive effect upon the etiologic factor(s).
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PMID:Adrenocortical activity in the newborn spontaneously hypertensive rat. 1034 90

There is increasing evidence that the intrauterine milieu and corticosteroid exposure play a role in the etiology of hypertension. We examined adrenocortical gene expression and circulating corticosteroids in the d 21 fetal spontaneously hypertensive rat (SHR) and its normotensive genetic control, the Wistar-Kyoto (WKY) rat. By RNase protection assays, we found no differences in the relative abundances of mRNAs for P450scc and P450c11beta, and barely detectable P450c11AS mRNA in the adrenals of fetal SHR and WKY rats. P450c11B3 RNA was undetectable by reverse transcription polymerase chain reaction in both SHR and WKY fetuses. The zonal expression of P450c11 mRNA was comparable in SHR and WKY fetuses by in situ hybridization histochemistry. There were no significant differences in peripheral levels of aldosterone and corticosterone by radioimmunoassay in fetal SHR and WKY rats. Based upon the absence of distinct differences in the aspects of adrenocortical activity examined, it is unlikely that they are integral in the programming of hypertension in this model.
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PMID:Adrenocortical activity in fetal SHR and WKY rats. 1062 95

Factors responsible for hypertension in the spontaneously hypertensive rat (SHR) remain under investigation. As in human pregnancy complicated by essential chronic hypertension, the hypertension of the pregnant SHR subsides and returns postpartum. Because corticosteroid excess can cause hypertension, we examined several aspects of adrenocortical activity as potentially affecting the reported blood pressure profiles of nonpregnant, term pregnant, and postpartum SHR, using normotensive Wistar-Kyoto (WKY) rats as controls. We found that corticosterone levels were comparable in nonpregnant SHR and WKY rats, and unaffected by pregnancy. No differences were detected postpartum. Although pregnancy was accompanied by significant increases in plasma aldosterone levels, no interbreed differences were observed, which remained the case postpartum. Single adrenal cell secretion of aldosterone and corticosterone, as detected by reverse hemolytic plaque assay, yielded similar results in the pregnant and postpartum rat. Hormone responses to dietary manipulations in the nonpregnant and pregnant SHR and WKY suggest an important role for ACTH, and a lesser one for AII in the regulation of corticosteroids. In situ hybridization histochemistry, using a probe that detects both P450c11beta and P450c11AS mRNA, revealed comparable message density and zonal distribution in adrenals from pregnant and nonpregnant SHR and WKY rats. Breed- and pregnancy-dependent differences in adrenal expression of P450scc, P450c11beta, and P450c11AS were noted. In summary, our findings suggest that although some discrepancies exist in the aspects of adrenocortical activity examined, they are unlikely to be etiologic in the blood pressure profile observed in nonpregnant, pregnant, and postpartum SHR.
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PMID:Corticosteroid dynamics in the nonpregnant, pregnant, and postpartum spontaneously hypertensive rat. 1082 44


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