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)

The only known action of renin is the hydrolysis of angiotensinogen into angiotensin I. Renin is synthesized as an inactive precursor, preprorenin. The processing of prorenin into active renin occurs after the clivage of a profragment, just after a dibasic pair of amino-acids. The renin profragment hinders the active site by its binding to the rest of the molecule. Circulating inactive renin is prorenin because it is recognized by antibodies produced against various parts of the renin profragment. Renin, like other aspartyl proteases, hydrolyses its substrate in its active center where two aspartyl residues are involved in the catalytic mechanism. The strong species specificity of renin lies in its interaction with its substrate through subsites which can be modelized by computer graphics. There is much promise in the inhibition of the renin angiotensin system at the level of the renin-angiotensinogen reaction. The i.v. infusions of human renin antibodies in primates produces a decrease in blood pressure which is parallel to that observed during inhibition of the angiotensin I converting enzyme. The magnitude of the blood pressure decrease depends on the intensity of the sodium depletion. Potent and specific pepstatin derived inhibitors have been synthesized which are able to inhibit primate renin in vitro and in vivo with a long duration of action. Other transition state analogs inhibitors have been administered parenterally in humans and similar results have been obtained. The concept of the treatment of hypertension by an anti-renin drug is becoming more and more a reality. However, it remains to find an orally active and a non-toxic compound which will compare well with the present converting enzyme inhibitors.
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PMID:[From the renin gene to renin inhibitors]. 353 35

Rat plasma contains two distinct forms of angiotensinogen (Ao-1 and Ao-2) that can be found in single animals in a distinct ratio. The ratio of Ao-1 to Ao-2 was determined by separation of Ao-1 and Ao-2 from 1 ml of plasma from individual rats on an SP-Sephadex C-50 column. Plasma from rats of three different strains, Wistar, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR), was investigated. In Wistar rats native plasma contained Ao-1 and Ao-2 in a ratio of 2.6:1. Twenty-four hours after nephrectomy, which increased the total Ao content 4.1-fold, this ratio was changed to 1.1:1. In native WKY and SHR the ratio of the two forms was similar to that in Wistar rats: 2.4:1 and 2.8:1, respectively. After nephrectomy the ratio of Ao-1 to Ao-2 was changed to 1.1:1 and 0.78:1 in WKY and SHR, respectively, while the total Ao content increased 4.9-fold and 8.2-fold in the two strains. Endogenous plasma renin inactivated the two forms of Ao, with a Km of 4.0 +/- 0.46 and 3.7 +/- 0.43 microM and a Vmax of 176 +/- 15.5 and 155 +/- 12.7 nM/hr, respectively. These results suggest that 1) Ao-1 and Ao-2 are synthesized in equimolar amounts, 2) the clearance of Ao-2 is faster than that of Ao-1 in control rats, and 3) under conditions of stimulated synthesis (i.e., after nephrectomy), the plasma content of Ao-2 increases faster than that of the more highly glycosylated form, Ao-1.
Hypertension 1987 Apr
PMID:Differences in pattern of plasma angiotensinogen in native and nephrectomized rats. 355 99

Angiotensinogen is the precursor of the most potent pressor substance, angiotensin. Angiotensinogen levels are increased in some forms of human hypertension. Its levels are modulated by various factors including glucocorticoids, estrogens, and prostaglandins. We have recently reported the isolation of a human angiotensinogen cDNA clone and provided evidence for the presence of its mRNA in rat liver, brain, and heart. In this communication we report the effect of dexamethasone and estradiol on angiotensinogen mRNA levels in rat liver, brain, and heart. Our results indicate that angiotensinogen levels are increased to different extents in these three tissues as a result of glucocorticoid or estrogen administration.
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PMID:Tissue specific hormonal regulation of the rat angiotensinogen gene expression. 357 22

The presence of angiotensinogen messenger RNA (mRNA) was assessed in total RNA extracted from hepatoma, glioma, neuroblastoma, and glioma-neuroblastoma hybrid cell lines. Total RNA from 1 X 10(7) cells was extracted, transferred to a membrane, and hybridized with a 32P-labeled, full-length (1650-base pair) rat angiotensinogen complementary DNA (cDNA). Angiotensinogen RNA sequences could be definitively detected only in hepatoma cells. Steroids were used in an attempt to increase the angiotensinogen mRNA level. Dexamethasone (2 X 10(-6) M) or 17 beta-estradiol (1 X 10(-7) M) was added to the cultures 18 to 24 hours prior to harvest. Dexamethasone treatment of the hepatoma cells resulted in a large increase in angiotensinogen mRNA, whereas estradiol had no effect. Steroids failed to induce detectable levels of angiotensinogen mRNA in total RNA from the other cell lines. That the RNA was intact was ensured by hybridizing duplicate Northern blots to a 32P-labeled actin cDNA. Actin mRNA sequences were detected in all cell lines. Blot hybridization of poly(A)+RNA resulted in the visualization of a weak angiotensinogen mRNA signal for a glioma cell line and a glioma-neuroblastoma hybrid line. However, the ability to detect angiotensinogen mRNA in a cell may depend on the phenotype expressed, which can be governed by culture conditions.
Hypertension 1987 Jun
PMID:Presence of angiotensinogen messenger RNA in various cultured cell lines. 359 87

Angiotensinogen (renin substrate) and its messenger RNA are known to accumulate in the rat brain. We have cloned rat preangiotensinogen cDNAs and used them as probes to measure the accumulation of preangiotensinogen messenger RNA sequences in eight regions of rat brain, as well as in liver and kidney. The brain regions examined were the cerebral cortex, hippocampus, striatum, cerebellum, diencephalon (including basal forebrain structures), midbrain, brainstem, and pituitary. On a tissue weight basis, the accumulation of preangiotensinogen RNA sequences was greatest in the liver, midbrain, and brainstem. The relative concentrations of messenger RNA were ranked as follows: liver, brainstem, midbrain greater than cerebellum, diencephalon greater than hippocampus greater than cortex, striatum, kidney greater than pituitary. Relative RNA concentrations from liver to kidney varied over a 16-fold range. Liver and brain preangiotensinogen RNA sequences were indistinguishable in size as measured by gel electrophoresis; however, the kidney sequences appeared some 100 nucleotides larger. Our data agree with previous measurements of angiotensinogen in the rat brain as assayed by renin-catalyzed angiotensin I release.
Hypertension 1986 Jun
PMID:Localization of preangiotensinogen messenger RNA sequences in the rat brain. 371 May 60

To examine the role of the macula densa in renin release, afferent arterioles alone or afferent arterioles with the macula densa attached were microdissected from rabbit kidney and incubated in Medium 199 for two consecutive 30-minute periods. Renin concentration in the medium was measured using partially purified rabbit angiotensinogen. Renin release rate over 1 hour from a single arteriole (or an arteriole with macula densa) was calculated and expressed as nanograms of angiotensin I generated per hour per arteriole (or arteriole with macula densa) per hour incubation (ng of ANG I X hr-1 X Af-1/hour). Basal renin release rate from afferent arterioles was 0.69 +/- 0.13 ng of ANG I X hr-1 X Af-1/hour (mean +/- SEM, n = 9) and remained stable for 60 minutes. Basal renin release rate from arterioles with macula densa was 0.25 +/- 0.03 ng of ANG I X hr-1 X Af + MD-1/hour (n = 9), which was significantly lower (p less than 0.025) than that from afferent arterioles alone. When furosemide (1.5 X 10(-3) M) was added to afferent arterioles alone, no significant change in renin release was observed (percent change from control; 24.8 +/- 29.9%; p greater than 0.05, n = 6). When furosemide was added to arterioles with macula densa attached, however, renin release increased by 387 +/- 46% (n = 7; p less than 0.001). After pretreatment with indomethacin, a cyclooxygenase inhibitor, furosemide still increased renin release from 0.17 +/- 0.03 to 0.60 +/- 0.10 ng of ANG I X hr-1 X Af + MD-1/hour (n = 4; p less than 0.05); however, indomethacin pretreatment reduced both the basal renin release rate and the absolute change in renin release induced by furosemide. We conclude that (1) the macula densa inhibits renin release in this preparation, (2) the macula densa plays a central role in furosemide-induced renin release, and (3) while the prostaglandin system is not essential for furosemide-induced renin release, it may be a modulating factor.
Hypertension
PMID:Role of the macula densa in renin release. 388 38

Amongst 40 patients undergoing cardiac transplantation between 1981 and 1984 and treated with cyclosporin A, 23 had hypertension. Fifteen of these patients, aged 39 years (16-57 years), without cardiac failure, treated with 8 +/- 3 mg kg-1 d-1 of cyclosporin A and 0.27 +/- 0.1 mg kg-1 d-1 of prednisolone were studied on average 288 days after transplantation (63-788 days). Blood pressure in the out-patients department of these 15 patients was 164 +/- 14/112 +/- 13 mmHg, in the absence of any antihypertensive treatment for more than 15 days, with a urinary sodium of 104 +/- 48 mEq/d and a urinary potassium of 55 +/- 13 mEq/d (mean +/- standard deviation). Two abnormalities accompany the raised blood pressure: a reduced creatinine clearance of 63 +/- 30 ml min-1 and an increased plasma volume of 445 +/- 686 ml (p less than 0.05) with reference to Hurley's norms (1975). By contrast, urinary excretion of VMA and metanephrines were invariably normal. Plasma renin activity (PRA) was normal in a lying position (1.02 +/- 0.42 ng ml-1 h-1) and after orthostatic stimulation (2.55 +/- 1.31 ng ml-1 h-1). Renin release was not stimulated by acute inhibition of converting enzyme (1.11 +/- 0.70 ng ml-1 h-1). Plasma aldosterone (110 +/- 52 pg ml-1), plasma angiotensinogen (924 +/- 213 ng/ml) and converting enzyme activity (30 +/- 6 mU ml-1) were normal. In these patients with a denervated heart, the orthostatic position increased heart rate from 85 +/- 11 to 93 +/- 12 beats/min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Arterial hypertension in heart transplant patients treated with cyclosporin]. 393 36

The renal renin-angiotensin system plays an important role in the control of renal hemodynamics and in the etiology of some types of hypertension. Angiotensinogen is the prohormone for angiotensins I and II. In the present communication, we report for the first time the presence of mRNA coding for angiotensinogen in the kidney. Indeed, the intrarenal location appears to be predominantly in the renal medulla. Additionally, an investigation of the effect of uninephrectomy on the intrarenal angiotensinogen mRNA suggests that regulation of mRNA levels in the kidney does occur.
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PMID:Intrarenal localization of angiotensinogen mRNA by RNA-DNA dot-blot hybridization. 394 13

The present experiments were designed to document changes in the regional distribution of angiotensinogen in the rat brain with the development of hypertension in spontaneously hypertensive rats (SHR) relative to age-matched normotensive Wistar-Kyoto rats (WKY). Levels of angiotensinogen were measured in discrete brain nuclei and cerebrospinal fluid from rats at 4, 7, and 16 weeks of age and in cerebrospinal fluid obtained by cisternal puncture at 7 and 16 weeks. Age-dependent changes in angiotensinogen were found, with levels higher in both strains at 4 weeks of age compared with 7 or 16 weeks. In contrast, plasma levels of angiotensinogen were essentially the inverse of the brain levels, low at 4 weeks and higher at 7 and 16 weeks. Levels in a number of regions adjacent to the rostral third ventricle from the 4-week-old SHR (prehypertensive phase) were significantly elevated relative to the WKY (p less than 0.05), while levels in the amygdala and posterior hypothalamus were significantly lower in the SHR (p less than 0.05). In 7-week-old rats (evolving phase), levels in nine brain regions were significantly elevated in the SHR relative to the WKY and included the nucleus tractus solitarii (p less than 0.01). Unlike the prehypertensive and evolving phases, in 16-week-old rats (maintenance phase) only two brain areas, the nucleus of the diagonal band and the lateral hypothalamus, had significantly elevated levels in the SHR (p less than 0.05). Cerebrospinal fluid levels of angiotensinogen did not correlate well with brain levels of angiotensinogen.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:Angiotensinogen levels in the brain and cerebrospinal fluid of the genetically hypertensive rat. 403 46

Among 25 patients with benign, essential hypertension, and an equal number with other benign forms of hypertension, without serious cardiac, renal, or cerebrovascular impairment, 41 cases failed to reduce aldosterone excretion rates into the normal range (less than 5 mug/day) on a daily intake of 300 mEq of sodium. The hypertensive patients excreted slightly less than the normal fraction of labeled aldosterone as acid-hydrolyzable conjugate. Secretion rates were significantly higher in the hypertensive patients than in normotensive controls taking the high-sodium intake. On a 10 mEq sodium intake, the increase in excretion and secretion rates of aldosterone in the hypertensive patients could be correlated with plasma renin activity (PRA). The patients with the least increase in PRA had subnormal increase in aldosterone secretion and excretion, while unusually large rises in aldosterone secretion accompanied high PRA, especially in the cases with increased plasma angiotensinogen induced by oral contraceptives. The persistence of inappropriately high aldosterone secretion in most hypertensive patients during sodium loading could be related to a higher PRA than that found in normotensive controls under comparable conditions. In other hypertensives, whose PRA was unresponsive to sodium depletion, there was no significant correlation between PRA and aldosterone output, and no known stimulus to aldosterone production was detected. Five obvious cases of hyperaldosteronism were found among the 16 low-renin patients. The cause of the nonsuppressible aldosterone production in the other low-renin cases remains to be determined.
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PMID:Abnormally sustained aldosterone secretion during salt loading in patients with various forms of benign hypertension; relation to plasma renin activity. 431 84


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