Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood vessels are remodeled in hypertension both structurally and functionally. The changes that occur in their structure, mechanical properties, and function contribute to blood pressure elevation and to complications of hypertension. We studied the remodeling of small arteries in experimental animals and humans. Smooth muscle cells of small arteries are restructured around a smaller lumen, with significant remodeling of the extracellular matrix and collagen and fibronectin deposition. Interestingly, there is no evidence of net growth of the vascular wall (which results in so-called eutrophic remodeling), particularly in the milder forms of human essential hypertension. Hypertrophic remodeling and increased small artery stiffness may be found in more severe forms of hypertension. Almost all hypertensive patients have vascular structural remodeling. However, only some exhibit endothelial dysfunction. This is particularly true in mild hypertension, in which endothelial dysfunction is less common. A 1-year treatment of hypertensive patients with angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long acting calcium channel blockers corrected small artery structure and, to variable degrees depending on the agents used, impaired endothelial function. In contrast, beta blockers did not improve structure, function, or mechanics of vessels. When beta-blocker-treated patients were switched to an AT1 receptor antagonist, small artery structure and impaired endothelial function were corrected. The vascular protective action of some antihypertensive agents may contribute to improve outcome for hypertensive patients, although this is presently unproven.
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PMID:Effect of antihypertensive treatment on small artery remodeling in hypertension. 1271 May 31

Data derived from a 10 years research program of our team demonstrate that many categories of antihypertensive drugs like beta-adrenergic blockers, alpha1-adrenergic blockers, ACE inhibitors, AT1-receptor antagonists and calcium-entry blockers increase plasma atrial natriuretic peptide (ANP) levels after a medium-term treatment of patients suffering from moderate essential hypertension. ANP always increases despite the drop of the arterial pressure and the fact that the left atrial and ventricular diameters remain unchanged or slightly reduced. These findings indicate that the increase of ANP plasma levels is not the result of a mechanical overload in the left cardiac chambers but the result of a pharmacological action. In conclusion, ANP is a universal factor contributing to the antihypertensive action of many drugs.
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PMID:Atrial natriuretic peptide contributes to the antihypertensive action of many drugs. 1450 65

Hypertension is a very common condition and the most important risk factor for the occurrence of cardiovascular events. The hyperactivity of the renin-angiotensin-aldosterone system is considered a cardiovascular risk factor in subjects with essential hypertension. The intrinsic vascular abnormality in which the renin-angiotensin-aldosterone system is clearly the milieu for the development of the pathologic changes in blood vessel walls is one of the causes of the establishment of hypertension. Many drugs with different mechanisms of action have been used for the treatment of hypertension and its vascular complications. Nevertheless, the utilities of many drugs are limited by their adverse effects. Continuous research in the search for new pharmacological agents for the treatment of hypertension has led to the development of angiotensin II receptor type AT1 blockers. The most important functions mediated by AT1 receptors include: vasoconstriction, induction of the production and release of aldosterone, renal reabsorption of sodium, cardiac cellular growth, proliferation of vascular smooth muscle, increase of peripheral noradrenergic action and the central activity of the sympathetic nervous system, stimulation of vasopressin release, and inhibition of renin release from the kidney. The angiotensin II receptor type AT1 blockers inhibit the interaction of angiotensin II with its AT1 receptor. These agents lower blood pressure without producing cough as a side effect since, unlike the angiotensin-converting enzyme inhibitors they do not influence the levels of bradykinin or substance P. Hence, these drugs are suitable for the treatment of hypertensive patients who require therapy with a drug blocking the effect of angiotensin-converting enzyme but cannot use angiotensin-converting enzyme inhibitors due to cough as a side effect.
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PMID:Role of angiotensin II AT1 receptor blockers in the treatment of arterial hypertension. 1462 77

Essential hypertension is a very heterogeneous disease and different pressor mechanisms might interact to increase blood pressure. It is therefore not surprising that antihypertensive drugs, given as monotherapy, normalize blood pressure in only a fraction of hypertensive patients. This is, for instance, the case for diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-lowering effect may be enhanced when two classes are coadministered. Also, combination therapy serves to counteract counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and that act to limit the efficacy of the antihypertensive medication. For example, the compensatory rise in renin secretion induced by sodium depletion may become the predominant factor sustaining high blood pressure. Simultaneous blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1-receptor blocker, makes this compensatory hyper-reninemia ineffective and allows maximum benefit from sodium depletion. The combination of a blocker of the renin-angiotensin system and a low dose of a diuretic increases the effectiveness, but not at the expense of tolerability compared with the individual components administered alone. Fixed-dose combinations containing an ACE inhibitor or an AT1-receptor blocker and a diuretic are therefore likely to become increasingly used not only as second-line therapy but also as first-line treatment.
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PMID:Combination therapy with ACE inhibitors/angiotensin II receptor antagonists and diuretics in hypertension. 1503 Feb 96

Recent studies have shown that F2-isoprostane levels-a marker for lipid peroxidation-are increased in human renovascular hypertension but not in essential hypertension. Angiotensin II specifically stimulates F2-isoprostane production through activation of the AT1 receptor. The objective was to determine whether there is a relationship between the level of oxidative stress evaluated by measuring urinary F2-isoprostanes levels and polymorphisms of genes involved in the renine angiotensin aldosterone system (RAAS) regulation. The population studied included 100 subjects, 65 of whom were healthy normotensives; the other 35 were suffering from untreated, essential hypertension. The polymorphisms studied concern the genes encoding angiotensin I-converting enzyme (ACE/in16del/ins), angiotensin II receptor type I (AGTR1/A+39C[A+1166C] and AGTR1/A-153G), angiotensinogen (AGT/M235T), and aldosterone synthase (CYP11B2/T344C). Oxidative stress was evaluated by measuring urinary F2-isoprostanes levels. The characteristics of the population were as follows: men/women = 46/56; age = 50 +/- 10 years; BMI = 24 +/- 3 kg/m2; SBP = 131.7 +/- 17.2 mm Hg; DBP = 84.6 +/- 10.4 mm Hg. In univariate analysis, urinary F2-isoprostane levels were significantly lower in the presence of the G allele of AGTR1/A-153G (56 +/- 17 vs 76 +/- 39 pmol/mmol creatinine; P < 0.001, and P < 0.01 after Bonferroni correction for 10 tests). In multivariate analysis, taking into account BP, age, gender, BMI, plasma glucose, and total cholesterol, the G allele of AGTR1/A-153G is linked independently to urinary F2-isoprostanes level (P < 0.01). Our data suggest that F2-isoprostane level depends at least in part on the A-153G polymorphism of the angiotensin II AT1 receptor gene. The clinical and prognostic relevance of this polymorphism requires further investigation.
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PMID:F2-Isoprostane level is associated with the angiotensin II type 1 receptor -153A/G gene polymorphism. 1568 14

Antihypertensive medications belong to different pharmacological classes. Besides blood pressure lowering properties, many substances, particularly ACE inhibitors and AT1-receptor antagonists but also in part calcium antagonists and aldosterone receptor antagonists, exert additional anti-inflammatory and antifibrotic effects as well as protective effects on endothelium. Delay of disease progression in chronic kidney disorders by inhibition of the renin-angiotensin system also as the result of blood pressure independent effects has been documented in clinical trials. On the other hand, in patients with essential hypertension without end-organ damage, it remains unclear whether the clinically proven blood pressure independent effects of antihypertensive agents are also clinically relevant. However, in clinical studies ACE inhibitors and AT1-receptor antagonists reduce the de novo occurrence of the diabetic metabolic state. Inhibition of the renin-angiotensin system decreases the incidence of diabetic nephropathy. This contribution presents currently available data on possible blood pressure independent effects of antihypertensive agents.
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PMID:[Blood pressure independent effects of antihypertensive agents]. 1580 Jul 76

The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.
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PMID:The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. 1582 64

The effect of antihypertensive therapy on arrhythmias is controversial. An initial study in patients with chronic heart failure indicated that losartan, an angiotensin II receptor antagonist, may possess antiarrhythmic properties. However, the effect of AT1 receptor antagonists on arrhythmias of subjects with good systolic function has never been evaluated. Thirty-nine men with primary hypertension (18 without left ventricular hypertrophy [LVH], and 21 with LVH, aged 48.2 +/-8.6 and 50.5 +/-6.0 years, respectively), 15 healthy normotensive subjects (47.9 +/-8.5 years), and 14 highly trained athletes (34.1 +/-1.6 years) were studied. Transthoracic echocardiography and 24-hour Holter ambulatory monitoring were performed at baseline (without treatment). Hypertensive patients underwent the same examinations after 8 months of losartan administration. The prevalence and complexity of ventricular arrhythmias, and the frequency of supraventricular arrhythmias were increased in hypertensive patients with LVH compared to normotensive controls and athletes, at baseline. A similar significant reduction of blood pressure (BP) was noted in both groups of patients (p < 0.001). The LVH was reduced in hypertensives with LVH (the left ventricular mass index by 12%, the interventricular septum by 8.1%, the posterior wall by 7%, all p < 0.01). However, the arrhythmias did not change in either group of patients, even if all hypertensives were considered as 1 group. In conclusion, an 8-month course with losartan was effective in lowering BP and reducing LVH. However, the increased arrhythmias, which were registered in hypertensive patients with LVH at baseline, did not change.
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PMID:Losartan controlled blood pressure and reduced left ventricular hypertrophy but did not alter arrhythmias in hypertensive men with preserved systolic function. 1607 26

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
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PMID:Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. 1614 58

To assess the effects of valsartan and amlodipine on the haemodynamics of forearm circulation in hypertensive patients undergoing isometric stress. A total of 24 patients with essential hypertension were subjected to a double blind-cross-over study. The artery left arm flow (strain gauge plethysmography), distensibility of digital arteries (piezoelectric plethysmography) and blood pressure were measured. District resistance was calculated as the ratio between mean arterial pressure and blood flow. The tests were performed at basal conditions (T0) and after 8 days (T8) of therapy with valsartan (160 mg) or amlodipine (10 mg), at rest and during handgrip (HG); treatments were inverted after 15 days of washout. Valsartan and amlodipine reduced blood pressure after 8 days (P<0.05), handgrip increased systolic and diastolic values and heart rate at T0 and only a slight raising in diastolic values at T8. The recovery time of pressure values was longer in hypertensives treated with amlodipine (P<0.05). The forearm flow increased after HG (at T0 an T8) and increased even further after valsartan (P<0.005). Valsartan increased arteriolar distensibility, expressed by the ratio between time to peak and total time (PT/TT) calculated on the sphygmic wave. Amlodipine did not affect PT/TT ratio, whereas it reduced local resistance (T8 vs T0, P<0.05). The reduction effect of valsartan on resistance was detectable also during handgrip, on the contrary amlodipine did not control the increase. Inhibition of AT1 is able to reduce haemodynamic modifications elicited by isometric stress in hypertensive patients.
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PMID:Haemodynamic effects of AT1 inhibition and Ca2+-channel blockade in hypertensive patients during isometric stress. 1631 6


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