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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a common trait of multifactorial determination imparting an increased risk of myocardial infarction, stroke, and end-stage renal disease. The primary determinants of hypertension, as well as the factors which determine specific morbid sequelae, remain unknown in the vast majority of subjects. Knowledge that a large fraction of the interindividual variation in this trait is genetically determined motivates the application of genetic approaches to the identification of these primary determinants. Success in this effort will afford insights into pathophysiology, permit preclinical identification of subjects with specific inherited susceptibility, and provide opportunities to tailor therapy to specific underlying abnormalities. To date, mutations in three genes have been implicated in the pathogenesis of human hypertension: mutations resulting in ectopic expression of aldosterone synthase enzymatic activity cause a mendelian form of hypertension known as glucocorticoid-remediable aldosteronism; mutations in the beta subunit of the amiloride-sensitive epithelial sodium channel cause constitutive activation of this channel and the mendelian form of hypertension known as Liddle syndrome; finally, common variants at the angiotensinogen locus have been implicated in the pathogenesis of essential hypertension in Caucasian subjects, although the nature of the functional variants and their mechanism of action remain uncertain. These early findings demonstrate the feasibility and utility of the application of genetic analysis to dissection of this trait.
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PMID:Genetic determinants of human hypertension. 756 73

Glucocorticoid-suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension caused by the inheritence of a chimaeric 11 beta-hydroxylase/aldosterone synthase gene. Affected individuals appear to have an increased risk of premature morbidity and mortality from stroke, but treatment with low doses of dexamethasone can completely reverse the biochemical and clinical features. We assessed the clinical and genetic features of 5 British kindreds with GSH, the largest collection outwith the United States, and determined the location of the crossover regions in the chimaeric gene of all 5 kindreds. All of the kindreds were of celtic origin, another feature peculiar to GSH. In total 19 out of 60 individuals screened by genotyping were found to possess the chimaeric gene and sequencing of the chimaeric gene revealed that all the crossover regions were within the exon 3- exon 4 region of, in keeping with previous studies, and three kindreds possessed indistinguishable chimaeric genes.
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PMID:Clinical, biochemical and genetic features of five extended kindred's with glucocorticoid-suppressible hyperaldosteronism. 758 11

1. Early diagnosis of Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-suppressible hyperaldosteronism) in asymptomatic, affected individuals is essential if death from stroke is to be prevented. 2. In 21 patients with FH-I (presence of the causative hybrid 11 beta-hydroxylase/aldosterone synthase gene confirmed by Southern blot testing), various biochemical parameters were compared as possible screening tests. Hypokalaemia and elevated plasma aldosterone each detected only two (10%) of the affected individuals. 3. Plasma renin activity 19 (90%) and aldosterone/renin ratio 18 (86%) were more reliable but not free from false negatives. 4. Levels of the urinary 'hybrid' steroid, 18-oxocortisol, were elevated (P < 0.01) in all 15 patients tested (138.2 +/- 17.4 micrograms/g creatinine, range 41.6 +/- 281.0 micrograms/g) with no overlap when compared with 11 normals (9.7 +/- 1.3 micrograms/g, range 2.8-17.4 micrograms/g). 5. We conclude that measurement of urinary 'hybrid' steroids is probably the most rapid and reliable biochemical screening test currently available for FH-I, with confirmation dependent on demonstration of the hybrid gene by genetic techniques.
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PMID:Hybrid gene or hybrid steroids in the detection and screening for familial hyperaldosteronism type I. 858 97

We have reported that aldosterone is synthesized and cytochrome P450aldo mRNA exists in the vasculature. To clarify the pathophysiological role of vascular aldosterone in hypertension, we compared aldosterone production in the mesenteric arteries of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats (WKY). The expressions of mRNA of cytochrome P450aldo, mineralocorticoid receptor, and alpha 1, Na,K-ATPase in the mesenteric arteries were compared between the two groups. Aldosterone concentration in the perfusate of the vasculature was measured by radioimmunoassay after purification with high-performance liquid chromatography. Cytochrome P450aldo and mineralocorticoid receptor mRNA levels were quantified by Southern blot analysis of the products of reverse-transcribed polymerase chain reaction. Levels of alpha 1 Na,K-ATPase mRNA were measured by Northern blot analysis. Vascular aldosterone and cytochrome P450aldo mRNA levels of 2-week-old SHRSP were significantly increased compared with those of age-matched WKY. However, vascular aldosterone in 4- and 9-week-old SHRSP did not differ from that in age-matched WKY. Expression levels of mineralocorticoid receptor mRNA in the vasculature of 4- and 9-week-old SHRSP were significantly increased compared with those in age-matched WKY. Concentrations of vascular alpha 1 Na,K-ATPase mRNA of 2-, 4-, and 9-week-old SHRSP also were significantly higher than those in age-matched WKY. These results suggest that vascular aldosterone contributes to the pathophysiology of hypertension in SHRSP in the early stage.
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PMID:Vascular aldosterone in genetically hypertensive rats. 903 78

Previous studies have shown that short-term high salt intake unmasks blunted plasma aldosterone suppression in stroke-prone spontaneously hypertensive rats (SHRsp). The aim of this study was to evaluate the response of aldosterone biosynthesis and production to a sustained exposure to the stroke-permissive Japanese-style diet (JD) in young stroke-prone and stroke-resistant SHRs. For this purpose, 6-week old male rats from both strains were divided into 2 dietary groups and received regular diet (SHR = 37, SHRsp = 32) or the JD and 1% saline to drink (SHR = 34, SHRsp = 30) for 4 weeks. All measurements were carried out at the end of the dietary periods. After JD, plasma aldosterone levels were significantly decreased in SHR (from 357.8 +/- 57 to 163.3 +/- 31.5 pg/ml, p < 0.05) but markedly increased in SHRsp (from 442 +/- 56.5 to 739 +/- 125.7 pg/ml, p < 0.05). Consistently, the adrenal aldosterone synthase expression was reduced by JD in SHR (p < 0.05), whereas it was even slightly raised by JD in SHRsp so that, at the end of JD, aldosterone synthase mRNA was 5-fold higher in SHRsp than in SHR. Urinary sodium excretion (mEq/24h) achieved lower levels in SHRsp, so that fractional excretion of sodium was 80.2 +/- 9% in SHR and 40.3 +/- 8% in SHRsp (p < 0.05) in balance studies performed at the end of JD. These different responses of mineralocorticoid biosynthesis and urinary sodium excretion to JD were not accounted for by different adaptations of the renin-angiotensin and atrial natriuretic peptide systems, of serum potassium levels, or of adrenal 11beta-hydroxylase expression in the two strains. Systolic blood pressure was comparable in both strains throughout the experiment. These results demonstrate enhanced aldosterone biosynthesis, associated with reduced urinary excretion of sodium in response to JD in SHRsp before the onset of stroke. This abnormality may play a role in the higher susceptibility to stroke of this model.
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PMID:Defective suppression of the aldosterone biosynthesis during stroke permissive diet in the stroke-prone phenotype of the spontaneously hypertensive rat. 1082 99

In familial hyperaldosteronism type I (FH-I), inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene causes ACTH-regulated aldosterone overproduction. In an attempt to understand the marked variability in hypertension severity in FH-I, we compared clinical and biochemical characteristics of 9 affected individuals with mild hypertension (normotensive or onset of hypertension after 15 yr, blood pressure never >160/100 mm Hg, < or = 1 medication required to control hypertension, no history of stroke, age >18 yr when studied) with those of 17 subjects with severe hypertension (onset before 15 yr, or systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg at least once, or > or = 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs. 6 of 13 females; P < 0.05). All 4 subjects still normotensive after age 18 yr were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, all six who died before 60 yr of age (4 by stroke) were males. Biochemical studies were conducted in 6 mild and 16 severe subjects. The 2 groups were similar in terms of urinary sodium excretion. Mild subjects tended, although not significantly, to have lower urinary 18-oxo-cortisol (mean +/- SD, 27.4 +/- 9.0 vs. 35.2 +/- 12.9 nmol/mmol creatinine x day), higher plasma potassium (4.0 +/- 0.3 vs. 3.6 +/- 0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency) plasma aldosterone levels (498 +/- 279 vs. 744 +/- 290 pmol/L). Upright (midmorning after 2-3 h of upright posture) plasma aldosterone levels were similar (mild, 485 +/- 150; severe, 474 +/- 188 pmol/L). In 1 normotensive female, upright PRA was much higher, and the upright aldosterone/PRA ratio was much lower than that in the other subjects. The remaining mild subjects had similar upright PRA levels (mild, 2.8 +/- 1.4; severe, 3.7 +/- 3.2 pmol/ L x min) and aldosterone/PRA ratios (mild, 199.5 +/- 133.4; severe, 200.6 +/- 150.9) as severe subjects. During angiotensin II (AII) infusion studies (n = 6 mild and 10 severe), performed during recumbency, aldosterone levels were lower in the mild group both basally (404 +/- 144 vs. 843 +/- 498 pmol/L; P < 0.05) and after 60 min AII (2 ng/kg x min; 261 +/- 130 vs. 520 +/- 330 pmol/L; P < 0.05). Aldosterone was unresponsive (rose by <50%) to AII in all subjects. Day curve studies (blood collected every 2 h for 24 h; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by AII in both groups. In conclusion, in this series of patients with FH-I, males had more severe hypertension, and the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension.
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PMID:Severity of hypertension in familial hyperaldosteronism type I: relationship to gender and degree of biochemical disturbance. 1085 45

Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [(14)C]deoxycorticosterone to [(14)C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.
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PMID:Cardiac aldosterone production in genetically hypertensive rats. 1104 Feb 25

Glucocorticoid remediable hyperaldosteronism (GRA) is a monogenic form of inherited hypertension caused by a chimeric gene originating from an unequal cross-over between the 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. GRA is characterized by high plasma levels of aldosterone (regulated by ACTH) with suppressed plasma renin activity and the production of two rare steroids, 18hydroxycortisol and 18oxocortisol. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Affected women have a high risk of developing preeclampsia during pregnancy. Here, we describe a 5-generation pedigree from Sardinia in which the presence of the chimeric gene is demonstrated in 4 generations. This family displays a mild phenotype with average blood pressure levels of 131/86 mm Hg for GRA+ patients. The occurrence of stroke is very low, and preeclampsia was not observed in 29 pregnancies from 8 GRA+ mothers. We investigated whether the cross-over site (between the CYP11B1 and CYP11B2 genes) or biochemical characteristics could explain this phenotype. The cross-over site was located at the end of intron 3, in the same region as described in other families. We found a significant correlation between blood pressure and 18hydroxycortisol, 18oxocortisol, and plasma aldosterone levels, but not with kallikrein. However, none of the biochemical or genetic parameters investigated could explain the mild phenotype of the family.
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PMID:Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation italian pedigree. 1210 22

The renin-angiotensin-aldosterone system has functions that may contribute to brain infarction (BI). In 459 matched pairs of white patients and control subjects, we measured plasma angiotensin-converting enzyme (ACE) levels, seven polymorphisms (angiotensinogen T174M and M235T, ACE I/D and 4656 2/3CT repeat [rpt], angiotensin II type 1 receptor A1166C and A153G, and aldosterone synthase CYP11B2), and evaluated 5-year poststroke mortality. Mean plasma ACE levels (+/-standard error) were significantly greater in patients than control subjects (37.5 +/- 0.9 vs 33.9 +/- 0.9), in patients with lacunar stroke, and in patients with no previous vascular (cerebrovascular or cardiovascular) history. The risk for BI increased with tertiles of plasma ACE, without an interaction with hypertension. After adjustments, the association disappeared except among patients with cardioembolic BI and those without previous vascular events. Among the polymorphisms, there was a weak association of BI with angiotensin II type 1 receptor 1166C, a weak protective effect with angiotensinogen 174M, and a strong association of angiotensinogen 235T with 5-year vascular mortality. These results suggest that renin-angiotensin-aldosterone system activity and genes contribute to cerebrovascular disease and poststroke vascular death in white patients.
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PMID:Renin-angiotensin-aldosterone system in brain infarction and vascular death. 1598 9

Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) catalyze the production of aldosterone and corticosterone, respectively, in the rat adrenal cortex. Recently, there has been some debate as to whether these corticosteroids are also produced in the hearts of rodents and humans, possibly contributing to the development of hypertrophy and myocardial fibrosis. To investigate this, we have used our established, highly sensitive real-time quantitative RT-PCR method to measure CYP11B1 and CYP11B2 mRNA levels in adrenal and cardiac tissue from several rat models of cardiovascular pathology. We have also studied isolated adult rat ventricular myocytes treated with angiotensin II and ACTH. Total RNA was isolated from the adrenal and cardiac tissue of 1) male Wistar rats with heart failure induced by coronary artery ligation and sham-operated controls; 2) stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats as controls; 3) cyp1a1Ren-2 transgenic rats and Fischer controls; 4) isolated adult Sprague-Dawley ventricular myocytes incubated with 11-deoxycorticosterone (DOC), DOC plus angiotensin II, or DOC plus ACTH. Adrenal CYP11B2 expression was significantly increased in transgenic rats compared with Fischer controls (1.3 x 10(9)+/- 1.2 x 10(9) vs. 2.1 x 10(7) +/- 7.0 x 10(6) copies/microg RNA; P < 0.05). There were no other significant differences in adrenal CYP11B2 or CYP11B1 expression between the model animals and their respective controls. Cardiac CYP11B1 and CYP11B2 mRNA transcript levels from all in vivo and in vitro groups were never greater than 100 copies per microgram total RNA and therefore too low to be detected reproducibly. This suggests that cardiac corticosteroid production is unlikely to be of any physiological or pathological significance.
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PMID:The aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes are not expressed in the rat heart. 1617 17


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