Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the renin-angiotensin system by sodium deficiency is associated with reciprocal changes in the expression of angiotensin II receptors in adrenal glomerulosa and vascular smooth muscle cells. The effects of dietary sodium changes on the expression of brain angiotensin receptor subtype 1 (AT1) mRNAs were examined in rats maintained on normal, low, and high sodium intake for 3 weeks. Plasma aldosterone and renin activity were elevated in rats maintained on a low salt diet compared with normal rats and were reduced in rats maintained on a high salt diet. These results are consistent with previous findings on the effects of altered dietary sodium on the renin-angiotensin system. The expression of AT1A and AT1B receptor subtype mRNAs was determined by quantitative reverse transcriptase-polymerase chain reaction during changes in sodium intake. The results revealed that sodium deprivation enhanced the expression of AT1B receptors in decorticated brains by 164% compared with high sodium intake. Conversely, high sodium diet increased the expression of AT1A receptors by 155% in the brain compared with low sodium intake. These data suggest that AT1A and AT1B receptors play reciprocal roles in central mechanisms for the control of fluid homeostasis. Further analysis of the molecular biology of angiotensin II receptor regulation in the brain may provide new insights into the interplay between the renin-angiotensin system and blood pressure regulation and also into the role of angiotensin II in the pathogenesis of essential hypertension.
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PMID:Regulation of angiotensin II receptors in rat brain during dietary sodium changes. 750 98

Losartan potassium (losartan) is the first of a new class of antihypertensive agents that specifically blocks the type 1 angiotensin II receptor. The efficacy and safety of losartan have been assessed in double-blind, controlled clinical trials conducted in approximately 3700 patients with uncomplicated mild, moderate and severe essential hypertension. Overall, losartan, whether administered alone or in combination with a low dose of hydrochlorothiazide (HCTZ), was effective and well-tolerated in these clinical trials, with an incidence of adverse experiences similar to that of placebo. The antihypertensive effects of losartan 50 mg once daily were similar to those of 20 mg once daily of the angiotensin-converting enzyme (ACE) inhibitor enalapril. The antihypertensive effects of losartan 50 to 100 mg once daily were similar to those of the calcium channel blocker felodipine 5 to 10 mg and to those of the beta-adrenergic blocker atenolol 50 to 100 mg once daily. Losartan was shown to have a smooth antihypertensive profile throughout the 24 h period following dosing, which mirrors the diurnal variability of blood pressure. The addition of 12.5 mg HCTZ to 50 mg losartan produced an additional significant antihypertensive response. There were no clinically meaningful differences in the antihypertensive effect of losartan when assessed by demographic subgroups of age or sex; there is a smaller antihypertensive response in Black patients. The most common patient-reported, drug-related, clinical adverse experience, with an incidence greater than that of placebo, was dizziness (2.4% versus 1.3%). The overall rate of patient withdrawal from losartan therapy due to clinical adverse experiences was lower than that of placebo (2.3% versus 3.7%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy and safety of losartan. 766 15

Although the activity of the renin-angiotensin system is known to decrease with age, the antihypertensive efficacy of angiotensin-converting enzyme (ACE) inhibitors has been demonstrated in the elderly. To examine the role of the renin-angiotensin system in hypertension in the elderly, we evaluated the antihypertensive response to enalapril and to TCV-116, an angiotensin II type-1 receptor antagonist, in elderly patients with essential hypertension. A single oral dose of enalapril (10 mg) increased plasma renin activity (PRA) and reduced the angiotensin II concentration, whereas a single oral dose of TCV-116 (4 mg) increased both PRA and the angiotensin II concentration. Blood pressure was significantly reduced by these drugs from 4 h after administration. Basal levels of PRA and angiotensin II declined with age. However, the changes in blood pressure produced by either TCV-116 or enalapril did not correlate with age. These results suggest that the activity of the renin-angiotensin system in plasma declines with age, and that the extrarenal renin-angiotensin system may play a role in hypertension in the elderly.
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PMID:Role of the renin-angiotensin system in hypertension in the elderly. 788 95

Activation of the renin-angiotensin system both systemically and locally seems to be of importance for cardiovascular hypertrophy and remodelling. The octapeptide angiotensin II definitively plays a central role. In the reversal, for example, of left ventricular hypertrophy, so far the most important independent risk factor for an adverse outcome, blocking of the renin-angiotensin system with ACE inhibition has been shown to be particularly effective. In cardiac tissue, however, ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed, indicating that other enzymatic pathways can be of importance. From a theoretical point of view a more complete blockade of the angiotensin II type 1 receptor would offer a more effective attenuation of the unfavourable effect of angiotensin II. Experimentally, losartan, a novel selective angiotensin II receptor type 1 antagonist has been shown to decrease cardiac hypertrophic response in models of both hypertension and volume cardiac hypertrophy as well as reverse hypertrophy in spontaneously hypertensive rats. TCV-116, another selective angiotensin II antagonist, also effectively reverses cardiac hypertophy and interstitial fibrosis in the rat. The only report so far regarding the effect of angiotensin II blockade on cardiac hypertrophy in essential hypertension suggests a more favourable short-term effect on cardiac hypertrophy for the same blood pressure reduction with losartan compared with atenolol in a small population of mild to moderate hypertensives. In the perspective of the well-established positive effects of ACE inhibition on the remodelling process in the remaining viable myocardium after myocardial infarction, involving myocyte hypertrophy, interstitial fibrosis and progressive dilatation, it is reassuring that angiotensin II blockade has been shown to perform equally well as ACE inhibition after experimental coronary ligation. In summary, the development of cardiovascular hypertrophy in hypertension is a serious prognostic indicator and selective angiotensin II blockade is a new anti-hypertensive treatment modality with promising properties, especially for prevention and reversal of cardiac hypertrophy including pathological fibrosis and cardiac remodelling after myocardial infarction. Thus, taking into account the shortcomings of today's anti-hypertensive treatment to achieve normalisation of excessive cardiovascular morbidity and mortality, as well as the seemingly great importance of the renin-angiotensin system for hypertension-induced functional and structural abnormalities, a therapy based on a specific All antagonist could offer obvious advantages in a high risk hypertensive patient with cardiovascular hypertrophy. This hypothesis will be investigated in a large prospective trial (Losartan Intervention For End-point reduction in hypertension: The LIFE Study).
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PMID:Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review. 858 80

The renin-angiotensin system plays a crucial role in the development and establishment of the hypertensive state in the spontaneously hypertensive (SH) rat. Interruption of this system's activity by pharmacological means results in the lowering of blood pressure (BP) and control of hypertension. However, such means are temporary and require the continuous use of drugs for the control of this pathophysiological state. Our objective in this investigation was to determine if a virally mediated gene-transfer approach using angiotensin type 1 receptor antisense (AT1R-AS) could be used to control hypertension on a long-term basis in the SH rat model of human essential hypertension. Injection of viral particles containing AT1R-AS (LNSV-AT1R-AS) in 5-day-old rats resulted in a lowering of BP exclusively in the SH rat and not in the Wistar Kyoto normotensive control. A maximal anti-hypertensive response of 33 +/- 5 mmHg was observed, was maintained throughout development, and still persisted 3 months after administration of LNSV-AT1R-AS. The lowering of BP was associated with the expression of AT1R-AS transcript and decreases in AT1-receptor in many peripheral angiotensin II target tissues such as mesenteric artery, adrenal gland, heart, and kidney. Attenuation of angiotensin II-stimulated physiological actions such as contraction of aortic rings and increase in BP was also observed in the LNSV-AT1R-AS-treated SH rat. These observations show that a single injection of LNSV-AT1R-AS normalizes BP in the SH rat on a long-term basis. They suggest that such a gene-transfer strategy can be successfully used to control the development of hypertension on a permanent basis.
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PMID:Chronic control of high blood pressure in the spontaneously hypertensive rat by delivery of angiotensin type 1 receptor antisense. 879 Apr 39

Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing the pathophysiological damage. The duration and initiation of treatment, site of administration, and agent used all appear to influence the reversal of the pathophysiological alterations associated with hypertension. We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor antisense (AT1R-AS) attenuates the development of high BP in the spontaneously hypertensive (SH) rat model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of other pathophysiological changes induced by the hypertensive state. Intracardiac delivery of AT1R-AS in neonates prevented the development of hypertension in SH rats for at least 120 days. Contractile experiments demonstrated an impaired endothelium-dependent vascular relaxation (acetylcholine) and an enhanced contractile response to vasoactive agents (phenylephrine and KCl) in the SH rat renal vasculature. In addition, the voltage-dependent K+ current density, which is believed to contribute to smooth muscle resting membrane potential and basal tone, was decreased in renal resistance artery cells of the SH rat. AT1R-AS treatment prevented each of these renal vascular alterations. Finally, AT1R-AS delivery prevented the pathological alterations observed in the SH rat myocardium, including left ventricular hypertrophy, multifocal fibrosis, and perivascular fibrosis. These observations demonstrate that viral-mediated delivery of AT1R-AS attenuates the development of hypertension on a long term basis, and this is associated with prevention of pathophysiological changes in SH rats.
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PMID:Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy. 1551 57

Essential hypertension is characterized by a near normal cardiac output but an increase in total peripheral resistance. In turn, total peripheral resistance is controlled directly by the diameter of the small arteries and arterioles like those in the kidney. The dynamic regulation of renal vessel diameter is governed by the contractile state of the vascular smooth muscle cells that line the vessel walls. This review addresses the role of a number of different ion channels to initiate and maintain the contractile state of the vascular smooth muscle cells in hypertension and the potential prevention of hypertension through gene therapy. These specific channels include Ca2+, K(Ca), Kv, and Cl- channels. In hypertension, it has been reported that increased activity of Ca2+ channels and decreased activity of Kv channels are responsible for the increased contractile tone and resting membrane potential observed in dissociated vascular smooth muscle cells from the spontaneously hypertensive rat. In contrast, increased activity of K(Ca) channels in vascular smooth muscle cells of the SHR has been hypothesized to dampen or brake the activity of Ca2+ and Kv channels. Finally, recent evidence suggests that introducing angiotensin II type-1 receptor antisense into prehypertensive rat pups prevents the onset of pathophysiological alterations observed in hypertension including K+ channel alterations. These results suggest that gene therapy may be a useful pharmacological and physiological tool to combat hypertension.
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PMID:Ion channels in vascular smooth muscle: alterations in essential hypertension. 964 36

The renin-angiotensin system is central to the pathophysiology of a number of cardiovascular disorders. Most obviously this is so with renin secreting tumours, but the system is of central importance in other disorders such as scleroderma renal crisis and most cases of malignant hypertension. Activation of the renin-angiotensin system in unilateral renal artery stenosis is pivotal to the development of hypertension and the disturbances in electrolyte and volume balance -- most particularly in the hyponatraemic-hypertensive syndrome. Likewise, stimulation of the renin-angiotensin system is an important contributor, amongst many other systems, to the pathophysiology of cardiac failure. In diabetic nephropathy, the renin-angiotensin system is often suppressed as gauged by circulating levels of renin, yet it appears to make an important contribution to the progressive decline in renal function. Much less clear is the role of the renin-angiotensin system in essential hypertension insofar as it contributes to the level of blood pressure, to the development of left ventricular hypertrophy, and in the evolution of complications such as stroke and myocardial infarction. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors has contributed to our understanding of the role of this system in cardiovascular disease. The advent of selective angiotensin II type-1 receptor blockers will further increase knowledge in this area.
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PMID:The importance of the renin-angiotensin system in cardiovascular disease. 965 50

Gene coding for the main components of the renin-angiotensin system have been characterized and localized: angiotensinogen (AGT, chromosome 1q42), renin (REN, chromosome 1), angiotensin I-converting enzyme (ACE, chromosome 17), angiotensin II receptors (AT1R, chromosome 3 and AT2R, chromosome X). A positive linkage and association have been found between AGT and essential hypertension. M235T is also associated with plasma AGT concentration. In vitro studies suggest that a polymorphism (G-6A) which is in complete linkage disequilibrium with M235T and which is located in the promoter close to the start of transcription might explain this association with high blood pressure. The ACE I/D polymorphism explains about 30 to 40 per cent of the variance of plasma ACE levels. Although the ACE gene itself does not seem to play a role in blood pressure level, the corresponding chromosomal region has been linked to blood pressure in both spontaneously hypertensive rats and humans. In tissues, an increased ACE activity may explain the association between the ACE I/D polymorphism and coronary heart disease, left ventricular hypertrophy, neointimal proliferation in vessels and progression of diabetic and IgA nephropathy.
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PMID:[Genetic polymorphisms in the renin-angiotensin system]. 977 26

Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT1) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT1 gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166-->C allele of the AT1 gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT1 gene locus influences the risk of essential hypertension in the Finnish population.
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PMID:Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. 1008 97


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