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

The large prospective studies on adverse effects of oral contraceptives have unanimously revealed an increased risk of thromboembolic diseases, which seem to be associated with the dose of ethinylestradiol (EE). According to the recommendations of several medical committees, the dose of EE has, therefore, been more and more reduced; in some countries there are now ovulation inhibitors containing 20 micrograms EE. Since serious reactions, which have a relatively low incidence, are highly underreported (less than 10%), it is difficult to prove dose-dependent differences in the rates of cardiovascular diseases. There is, however, virtually no doubt that not only the incidence of thromboembolic diseases and stroke, but also that of benign liver tumours and gall bladder diseases is increased in relation to the EE-dose. A series of metabolic serum parameters, e.g. serum binding proteins, coagulation and fibrinolysis factors, angiotensinogen, is changed by EE in a dose-dependent manner which is, however, limited when the effects are receptor-mediated. Higher doses of EE have been shown to facilitate fibrin deposits on vascular subendothelium. The pharmacological effects of EE are to a large extent dependent on the dose, e.g. the irreversible reactions of EE and other ethinylated steroids with hepatic enzymes which are involved in the metabolism of steroids, drugs and toxic compounds. After long-term treatment with combinations containing 50 micrograms EE, in half of the women, abnormal liver function tests with pathological morphological alterations have been found. As combinations with low EE doses and a sufficiently effective progestogen component do not differ from higher dosed oral contraceptives in their contraceptive safety and cycle control, there are no indications for pills containing 50 micrograms EE, except the normophasic sequential preparations for women with sustained irregular bleedings when taking low dose combinations.
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PMID:[Ovulation inhibitors: the significance of estrogen dose]. 208 34

The brain renin-angiotensin system (RAS) has been suggested as contributing to the pathogenesis of spontaneous hypertension in rats. Brain angiotensinogen- and angiotensin II (AII)-sensitive neurons were therefore investigated in stroke-prone spontaneously hypertensive rats (SHR-sp) and in Wistar-Kyoto (WKY) rats with and without treatment by captopril (CAP). Angiotensinogen was decreased in the anterior hypothalamus but increased in the cortex, the hippocampus, and cerebellum of SHR-sp. There were no differences between SHR-sp and WKY rats concerning the angiotensinogen content of posterior hypothalamus, brain stem, and septum. The sensitivity of the septal neurons to microiontophoretically applied AII was elevated, however, in SHR-sp as compared to WKY rats with regard to threshold and maximal response for AII-evoked neuronal discharges. The excitation characteristics did not change with the age of animals in both WKY rats and SHR-sp. The treatment of SHR-sp with CAP (50 mg/kg/day per os) starting in weanlings kept animals normotensive and reduced the high sensitivity of septal neurons to AII. Simultaneously angiotensinogen content was increased in the anterior hypothalamus and suppressed in the hippocampus. The same treatment of WKY rats reduced blood pressure somewhat and increased the angiotensinogen content in the anterior hypothalamus without affecting the neuronal sensitivity to AII. Thus, malfunction of the brain RAS may participate in the hypertension of SHR-sp, since converting enzyme blockade with CAP inhibited the blood pressure rise, augmented the angiotensinogen content of the anterior hypothalamus, and decreased the sensitivity of AII receptors in the brains of these rats.
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PMID:Influence of captopril treatment on angiotensin II receptors and angiotensinogen in the brain of spontaneously hypertensive rats. 631 52

Several interventions known to alter plasma renin substrate in rats such as nephrectomy (NX), adrenalectomy (ADX) and glucocorticoid treatment changed the angiotensinogen content in the cerebrospinal fluid (CSF) in the same direction. However, peripheral and central angiotensinogen could be dissociated from each other by ADX and NX in combination, as well as by chronic converting enzyme blockade. The regulation of brain angiotensinogen was further investigated in stroke-prone spontaneously hypertensive rats (SHR-sp) in comparison with normotensive Wistar Kyoto (WKY) rats. The angiotensinogen levels of the anterior hypothalamus and of the septal area showed strain and age-related differences. Chronic converting enzyme blockade, which kept SHR-sp normotensive, stimulated angiotensinogen in the anterior hypothalamus of both SHR-sp and WKY rats, but suppressed plasma renin substrate. A specific radioimmunoassay (RIA) for renin substrate of rat plasma also recognized the CSF angiotensinogen, and a linear correlation existed between direct and indirect measurements. In conclusion, angiotensinogen in the central nervous system appears to be immunologically similar to plasma angiotensinogen. Its regulation is not directly related, however, to circulating renin substrate, although adrenal steroids stimulate both central and peripheral angiotensinogen. A differential regulation of angiotensinogen in the brain of SHR-sp as compared to WKY is evident and could be linked to blood pressure control.
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PMID:Regulation of angiotensinogen in the central nervous system. 635 57

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

There is considerable evidence from clinical and experimental studies that blood pressure is lowered by converting enzyme inhibitors (CEIs) irrespective of whether the plasma renin-angiotensin system (RAS) is stimulated. New insights into the molecular biology of the RAS--in particular, the gene expression of renin and angiotensinogen in various tissues--support the view that the antihypertensive properties of CEIs may be mediated, at least in part, by interaction with tissue RAS. To investigate this possibility further, stroke-prone spontaneously hypertensive male rats (SHRSP) were treated orally for 28 days with different CEIs or a peripheral vasodilator to study the effects of the various drug treatments on the gene expression of the RAS in selected tissues. Different effects of different CEIs on tissue gene expression suggest localized action and some degree of organ specificity of the drugs. The experiments involved: (1) untreated controls; and rats treated with either (2) 50 mg/kg of captopril; (3) 10 mg/kg of lisinopril; (4) 10 mg/kg of cilazapril; (5) or 30 mg/kg of the vasodilator hydralazine with 10 rats/group. All of the study drugs reduced systolic blood pressure to normotension. Cardiac hypertrophy and the heart:body weight ratio were significantly decreased only in the CEI-treated animals, and kidney renin mRNA was increased by the CEIs whereas hydralazine had no effect on heart weight or kidney renin mRNA. Plasma renin activity increased in parallel with kidney renin mRNA levels. Liquid hybridization and Northern blotting assays revealed drug-specific regulation of the angiotensinogen mRNA level in the adrenal gland, with cilazapril producing the most marked stimulation of adrenal angiotensinogen gene expression. Both lisinopril and cilazapril suppressed hypothalamic angiotensinogen mRNA. There were no significant changes in angiotensinogen gene expression observed in the kidney or liver with any of the CEIs. In conclusion, these data show that CEIs interact differentially and drug-specifically with tissue RAS, and have class-specific effects on cardiac hypertrophy.
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PMID:Converting enzyme inhibitors differentially affect expression of genes of the renin-angiotensin system. 761 28

The components of the renin-angiotensin system have been implicated in the development of primary hypertension in humans and genetically hypertensive rats. In humans a mutation in the angiotensinogen gene and elevated plasma angiotensinogen levels have been linked to primary hypertension. Although we had previously excluded a linkage of blood pressure to the angiotensinogen gene in the stroke-prone spontaneously hypertensive rat (SHRSP), elevated angiotensin II (Ang II) levels in this strain compared with the normotensive reference, the Wistar-Kyoto rat (WKY), prompted us to investigate further into the origins and effects of altered Ang II regulation using a range of physiological, biochemical, molecular, and genetic approaches. Ang II plasma levels determined by radioimmunoassay were confirmed to be significantly elevated in SHRSP compared with WKY. Sequence comparison among the two rat strains revealed a mutation in the coding region of the angiotensinogen gene that results in an isoleucine-to-valine substitution in SHRSP at amino acid position 154 (I154V). We performed a cosegregation analysis in an F2 intercross cohort bred from SHRSP and WKY from the University of Heidelberg (SHRSPHD and WKYHD) to address the following questions: (1) whether this or another mutation of the angiotensinogen gene may be casually related to the observed differential Ang II plasma levels, (2) whether Ang II plasma levels may be correlated with blood pressure or organ hypertrophy, and (3) whether genetic linkage to the renin or angiotensin-converting enzyme (ACE) gene loci (the two classic regulatory enzymes of the renin-angiotensin system) may provide an explanation for elevated Ang II plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered angiotensinogen amino acid sequence and plasma angiotensin II levels in genetically hypertensive rats. A study on cause and effect. 763 35

Recently, evidence has been presented for genetic linkage between the angiotensinogen gene and primary hypertension in humans. In the present study we examined whether a similar linkage between blood pressure and the angiotensinogen gene locus can be demonstrated in a widely used animal model of primary hypertension, the stroke-prone spontaneously hypertensive rat (Heidelberg colony, SHRSPHD). In 115 F2 hybrids bred from SHRSPHD and a normotensive reference strain, the Wistar-KyotoHD (WKYHD) rat, systolic and diastolic blood pressures and heart rate were determined by indwelling arterial catheters in the presence and absence of dietary sodium loading. In addition, left and right ventricular heart weight was measured. Using a newly developed polymorphic marker assay for the angiotensinogen gene based on polymerase chain reaction amplification of an exon 2 fragment and subsequent restriction endonuclease digestion, we performed a cosegregation study in this cohort. No evidence for cosegregation between the angiotensinogen gene locus and blood pressure or any other phenotypic parameter assessed was found. Although the SHRSP serves as a valuable model of hypertension, our data emphasize that disease-relevant genetic loci in humans and rats cannot be assumed to coincide.
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PMID:Unlike human hypertension, blood pressure in a hereditary hypertensive rat strain shows no linkage to the angiotensinogen locus. 791 49

The role of angiotensin (ANG II) at the tissue level, particularly in the brain, remains imperfectly defined. We measured angiotensinogen (A degrees) mRNA in the brain stems, sensory and sympathetic ganglia, and blood vessels of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHR-SP) by quantitative, liquid hybridization. We micro-injected ANG II and glutamate into the brain stems of these rats to gain insight into the functional significance of our findings. A. mRNA was found in the dorsolateral, dorsomedial, and ventrolateral pons, as well as in the dorsolateral, dorsomedial, and ventrolateral medulla of both strains. A degrees mRNA was 8-10 pg/micrograms total mRNA higher (p < 0.05) in the dorsomedial medulla (nucleus tractus solitarii) in WKY and SHR-SP (28.27 +/- 1.26 and 33.50 +/- 1.42 pg/micrograms RNA respectively) than in the other areas. SHR-SP had higher values (27.22 +/- 1.77 vs. 21.53 +/- 0.57 pg/micrograms mRNA) than WKY (p < 0.05) in the dorsolateral pons (locus coeruleus). A. mRNA was also identified in the optic nerves and chiasm, trigeminal and coeliac ganglia, arteries and veins. Injections of glutamate and ANG II into the dorsomedial, dorsolateral, and ventrolateral medulla increased blood pressure, while ANG II in the dorsal medial pons did not. We conclude that A degrees mRNA is produced to different degrees in brain stem areas which participate in blood pressure regulation. Medullary structures show more response to local ANG II than pontine structures. A degrees mRNA is located in sensory neural tissues as well as sympathetic ganglia. A degrees mRNA is present in both arteries and veins. These findings underscore the scope and complexity of ANG production in tissues.
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PMID:Angiotensinogen mRNA and pressor reactions to angiotensin in brain stem areas of spontaneously hypertensive rats. 837 11

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of association between angiotensinogen polymorphism (M235T) and cerebrovascular disease and carotid atheroma. 852 90

Primary human hypertension is a polygenic disorder. It is the prevalent cause of cardiovascular disease leading to cardiac failure, stroke, chronic renal failure and, ultimately to death. Several genes are involved in cardiovascular control mechanisms and their genetics are complex. Experimental models which are well defined are needed to clarify the role of individual genes. The generation of the hypertensive transgenic rat line TGR (mREN2)27 bearing the murine Ren-2 gene cloned from the DBA/2J mouse strain provides a monogenic model of hypertension in which the genetic basis (the additional renin gene) is known. These rats develop severe hypertension, which reaches 200 mm Hg and higher at 8 weeks of age in the heterozygous animal. Homozygous rats develop even higher blood pressures than heterozygous animals, which is paralleled by a higher mortality rate in homozygous rats. Animals develop pathomorphologic alterations which are characteristic for systemic hypertension. The transgenic rats are characterized by unchanged or even suppressed concentrations of active renin, angiotensin I (ANG I), ANG II, and angiotensinogen compared to transgene-negative littermates. In contrast, plasma levels of inactive renin (prorenin) are much higher in TGR (mREN)27 rats than in control animals. In the kidneys, renin is suppressed, probably mediated through negative feedback inhibition, in other tissues, especially in the adrenal gland, murine Ren-2 mRNA is expressed at very high levels. The cascade of pathophysiologic events which finally lead to hypertension is not fully understood in this rat model. Treatment with ACE inhibitors or angiotensin II receptor antagonists such as losartan is extremely efficient, which could mean that hypertension in this model is mediated through ANG II. Since the the renin-angiotensin system (RAS) in the kidneys is suppressed, other ANG II generating sites must be considered. This favors the concept of extrarenal RASs in this model.
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PMID:The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. 873 83


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