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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular ANG II receptor density of 33 and 45%, respectively. There were no changes in the affinity of ANG II in either tissue or in adrenal receptor density. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. Dexamethasone administration produced similar downregulation of glomerular ANG II receptor and was unaccompanied by a change in electrolyte balance or blood volume. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.
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PMID:Corticosteroids decrease glomerular angiotensin receptors. 382 86

The relationship between blood pressure and the characteristics of renal mineralocorticoid receptors was studied in glycyrrhizinic acid (GR) or deoxycorticosterone (DOC) induced hypertensive rats. The apparent maximum binding (Bmax) of aldosterone to renal mineralocorticoid receptors was 3.1 +/- 0.2 X 10(-13) mol/mg cytosol protein and the dissociation constant (Kd) was 1.6 +/- 0.5 nM. GR treatment reduced the concentration of cytosol mineralocorticoid receptors (Bmax) but did not affect the Kd. In unilaterally adreno-nephrectomized rats, GR induced hypertension and hypokalemia as seen in DOC treated rats. After the discontinuation of GR, blood pressure was normalized with concomitant recovery of free cytosol mineralocorticoid receptors in 14 weeks. On the contrary, in DOC treated rats, the characteristics of mineralocorticoid receptors in kidney were already normal one week after the cessation of DOC treatment. However, blood pressure remained high up to 15 weeks. These findings suggest that the persistence of hypertension after GR discontinuation might be caused by a long-standing effect of GR on renal mineralocorticoid receptor mechanisms.
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PMID:The characteristics of renal mineralocorticoid receptors in glycyrrhizinic acid or deoxycorticosterone-induced hypertensive rats. 623 15

Previous evidence shows that salt-sensitive (S) rats have a net increase in plasma mineralocorticoid activity due to 18-hydroxy-11-deoxycorticosterone and decreased urinary kallikrein excretion compared to salt-resistant (R) rats. Since mineralocorticoids stimulate urinary kallikrein excretion, these results are inconsistent. This inconsistency was explained by the fact that, while R rats responded normally to treatment with deoxycorticosterone (DOC) by an increase in urinary kallikrein excretion, S rats showed no change in urinary kallikrein even when treated with 10 mg of DOC/day for 24 days. S and R rats responded identically to DOC with changes muscle electrolytes and relative hypertrophy of the renal distal tubule. Other measures of chronic mineralocorticoid response in S rats beside kallikrein were, therefore, intact. It was found that S rats were capable of responding to Na deficient diet with an increase in urinary kallikrein comparable to R rats. It was argued, therefore, that mineralocorticoid receptor mechanisms and distal-tubular cell responsiveness are intact in S rats. Mild glomerular and tubular scarring was found in S rats and the severity of renal lesions was increased by DOC treatment in S rats. These lesions correlated well with blood pressure and proteinuria. No such lesions were present in control or DOC treated R rats. It was suggested that failure of urinary kallikrein to respond to DOC in S rats may be a secondary phenomenon resulting from renal damage.
Hypertension
PMID:Anomalous response of urinary kallikrein to deoxycorticosterone in Dahl salt-sensitive rats. 691 11

The bioactivity of 5 alpha-reduced sex steroids such as 5 alpha-dihydrotestosterone has increased interest in an analogous role for 5 alpha-reduced mineralocorticoids in hypertensive syndromes. In view of its relatively high mineralocorticoid receptor affinity despite relatively low electrolyte-altering effects, 5-alpha-dihydro-11-deoxycorticosterone, or 5 alpha DHDOC (2) was compared to 11-deoxycorticosterone acetate (DOCA) for blood pressure-altering ability by continuous subcutaneous infusion into uninephrectomized saline-drinking Sprague-Dawley male rats, at doses selected on the basis of relative mineralocorticoid receptor affinity. After three weeks of treatment, DOCA significantly raised blood pressure, body weight, heart and kidney weight, and produced a discernible increase in fluid intake; 5 alpha DHDOC failed to affect any of these parameters commonly influenced by mineralocorticoids. We conclude that 1) the ability of 5 alpha DHDOC to affect blood pressure was not predicted by its relatively high affinity for the mineralocorticoid receptor, and 2) these data do not support a role for 5 alpha DHDOC in mineralocorticoid hypertension, although differences in protein binding and clearance could affect its blood pressure-altering activity.
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PMID:5 alpha-Dihydro-11-deoxycorticosterone: effect on blood pressure in the rat. 722 41

Uninephrectomized rats maintained on 1.0% NaCl to drink and infused with aldosterone (0.75 microgram/h) for 8 wk have previously been shown to develop hypertension, cardiac hypertrophy, and cardiac fibrosis. In the present study we have shown that K+ supplementation (1.0% NaCl plus 0.4% KCl drinking solution) alters neither the interstitial nor the perivascular fibrotic response to mineralocorticoid treatment. Second, rats receiving 0.75 microgram/h 9 alpha-fluorocortisol, a mineralocorticoid and glucocorticoid agonist, respond with hypertension and cardiac fibrosis without cardiac hypertrophy. Finally, intracerebroventricular infusion of the mineralocorticoid receptor antagonist RU-28318 blocks blood pressure elevation, but not cardiac hypertrophy or fibrosis, when aldosterone is coinfused peripherally. We conclude that the myocardial fibrosis observed in response to chronic mineralocorticoid elevation and salt loading is a humorally mediated event independent of hypokalemia, hypertension, and cardiac hypertrophy. It remains to be determined whether the fibrosis observed in the presence of excess salt represents a direct (e.g., cardiac) effect of mineralocorticoid hormones or one mediated via a primary action on classical epithelial aldosterone target tissues (e.g., kidney).
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PMID:Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. 748 78

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP 1 production. Collagen synthesis, determined by 3H-proline incorporation and MMP 1 activity determined by degradation of 14C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10(-11) -10(-6) M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, dexoycorticosterone (DOC), or the prostaglandin, PGE2. Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type 1 or mineralocorticoid receptor antagonists, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hormonal regulation of cardiac fibroblast function. 755 72

In the present study the aldosterone-18-glucuronide and tetrahydroaldosterone values in 24 hour urine collections of healthy nonpregnant women, women with normal pregnancies and women with pregnancy induced hypertension (PIH) were compared. In pregnancy an elevated excretion of both aldosterone metabolites was found. The Q-ratio (aldosterone-18-glucuronide/tetrahydro-aldosterone+aldosterone-18-glu cur onide) was also increased compared to healthy nonpregnant women. The elevated Q-ratios point out to increased formation of aldosterone-18-glucuronide. This predominantly renal metabolite may reflect greater availability of aldosterone molecules for interaction with mineralocorticoid receptor in the kidney.
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PMID:Increased aldosterone-18-glucuronide/tetrahydroaldosterone ratios in pregnancy. 758 81

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kb in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-hydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase, but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.
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PMID:Cloning of cDNA encoding an NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase in sheep kidney. 758 2

The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of human hypertension thought to result from a deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme normally converts cortisol to inactive cortisone and is postulated to thus confer specificity for aldosterone upon the mineralocorticoid receptor. We have analysed the gene encoding the kidney isozyme of 11 beta HSD and found mutations on both alleles in nine of 11 AME patients (eight of nine kindreds). These mutations markedly affect enzymatic activity. They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension.
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PMID:Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. 767 Apr 88

The activities of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) and 5 beta-reductase were analyzed in 39 normotensive controls and 128 patients with essential hypertension. The activity of 11 beta-HSD was obtained by dividing the 24-hour urinary tetrahydrocortisone by the sum of tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF), whereas the activity of 5 beta-reductase was obtained by dividing the 24-hour urinary THF by aTHF. The activity of 5 beta-reductase was significantly lower in essential hypertensives compared with normotensive controls (P < 0.05). However, the activity of 11 beta-HSD did not differ between normotensive controls and essential hypertensives. A positive correlation between the activities of 11 beta-HSD and 5 beta-reductase was observed in essential hypertensives (r = 0.60, P < 0.01). Neither 11 beta-HSD nor 5 beta-reductase activity correlated with indices of renal mineralocorticoid receptor activation, which were assessed by determination of plasma potassium and urinary excretion of sodium as well as potassium. Taken together, these results suggest that disturbances of one of the inactivation pathways of cortisol may contribute to the pathogenesis of hypertension.
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PMID:The activities of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase in essential hypertension. 770 42


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