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Hypertension in pregnancy is one of the main causes of maternal, fetal and newborn morbidity and mortality in civilised countries. Current recommendations of the European Society for Hypertension prefer definition of hypertension in pregnancy based on absolute values of blood pressure, i.e. systolic blood pressure > or = 140 mm Hg or diastolic blood pressure > or = 90 mm Hg. The most important task of classification of hypertension in pregnancy is to distinguish whether hypertension comes before pregnancy (the so called pre-existing hypertension) or whether it is a pregnancy-induced condition (the so called gestational hypertension). Pre-existing hypertension is diagnosed either before pregnancy or within the first 20 weeks of pregnancy. Gestational hypertension is characterised with poor blood circulation in many body organs, higher value of blood pressure usually being just one of the characteristic features. Non-pharmacological treatment of hypertension must be considered in pregnant women with systolic blood pressure 140-150 mm Hg or diastolic blood pressure 90-99 mm Hg. Salt restriction is not recommended, as well as weight reduction in obese women. Systolic blood pressure > or = 170 mm Hg or diastolic blood pressure > or = 110 mm Hg in pregnant women must be considered serious condition necessitating hospitalisation. Pharmacological therapy should include labetalol i.v. or metyldopa or nifedipin administered orally. Intravenous administration of dihydralazine is no longer a therapy of choice, for its use is connected with increased occurrence of adverse effects. The threshold values for commencement of anti-hypertension therapy are systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg in females with gestational hypertension without proteinuria or with pre-existing hypertension before commencement of 28th week of pregnancy. Drug administration to reduce hypertension is instituted after reaching the same threshold values in females with gestational hypertension and proteinuria or after occurrence of the symptoms any time during pregnancy, with the same threshold values of blood pressure in the case of pre-existing hypertension at the presence of accompanying diseases or organ malfunction and further in the case of pre-existing hypertension and gestational hypertension. In other cases drug treatment of hypertension is recommended at systolic blood pressure values of 150 mm Hg or diastolic blood pressure values of 95 mm Hg. Unless serious hypertension is involved, the drugs of choice include metyldope, labetalol, calcium channel blockers and beta-blockers. Calcium channel blockers are considered safe, unless administered concurrently with magnesium sulphate (risk of hypotension in the case of potential synergism). ACE inhibitors and angiotensine blockers II (AT1-blockers) are contraindicated in pregnancy. Treatment with diuretics is not substantiated, unless oliguria is present. I.v. magnesium sulphate is recommended for prevention of eclampsia and spasm treatment.
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PMID:[Hypertension in pregnancy]. 1672 58

The treatment and management of patients with arterial hypertension depends on the global cardiovascular risk of the individual patient. Thus, additional cardiovascular risk factors, the presence of target organ damage, cardiovascular or renal disease determine not only the initiation of therapy but also the choice of drug(s). Drug treatment is usually started with one compound, which is selected from 5 drug classes recommended for first-line therapy including ACE-inhibitors, AT1-antagonists, betablockers, calcium channel blockers, and diuretics. Depending on risk and additional disease individual target blood pressures are 140/90, 130/80 or 125/75 mmHg, respectively. If blood pressures at baseline exceeds target values more than 20/10 mmHg treatment may be started with initial or early combination therapy of two drugs. Overall, approximately two-thirds of patients require treatment with at least two drugs to achieve target blood pressure values.
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PMID:[Therapy of hypertension]. 1701 83

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage. However, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion present limitations for existing renin-angiotensin-aldosterone system inhibitors. A once-daily, orally effective, small-molecule renin inhibitor, aliskiren, is now available to address angiotensin production directly at its rate-limiting step. Studies in humans attest to an effective BP-lowering effect, a side effect profile no different from AT1 receptor blockers, and the option of combination therapies. A novel animal model of high human renin hypertension in the rat attest to target organ protection. Because angiotensin receptor blockade, angiotensin-converting enzyme inhibition, calcium channel blockade, and diuretic therapy all lead to sharp increases in plasma renin activity, aliskiren offers a novel circumvention.
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PMID:Direct renin inhibition with aliskiren in hypertension and target organ damage. 1769 10

We have previously found improved insulin sensitivity after antihypertensive treatment with an angiotensin II-receptor blocker as compared with a calcium channel blocker in hypertensives. In this study, we compare the effect of these 2 principal different vasodilating agents on levels of adipokines, inflammatory variables, and whole blood viscosity in the same hypertensive patients with cardiovascular risk factors. We test whether potential differences in these variables might explain the difference seen in insulin sensitivity. Twenty-one hypertensive patients (11 women, 10 men) with mean age of 58.6 years and blood pressure of 160 +/- 3/96 +/- 2 mm Hg entered a 4-week run-in period with open-label amlodipine 5 mg. Thereafter, they were randomized double-blindly to additional treatment with amlodipine 5 mg or losartan 100 mg; and after 8 weeks of treatment, all patients underwent laboratory testing. After a 4-week washout phase with open-label treatment, the participants were crossed over to the opposite treatment regimen for 8 weeks before final examination. No significant differences were seen in the blood levels of adiponectin (7814 +/- 870 vs 8090 +/- 967 ng/mL), leptin (961 +/- 122 vs 965 +/- 147 pmol/L), resistin (11.7 +/- 1.0 vs 11.3 +/- 0.7 ng/mL), plasminogen activator inhibitor 1 activity (23.9 +/- 2.2 vs 25.1 +/- 2.2 U/mL), tumor necrosis factor alpha (1.35 +/- 0.11 vs 1.72 +/- 0.28 pg/mL), and high-sensitivity C-reactive protein (3.09 +/- 0.84 vs 2.09 +/- 0.42 mg/L) between treatment with amlodipine 10 mg or losartan 100 mg + amlodipine 5 mg, respectively. Although no significant differences in whole blood viscosity and blood pressure were observed between the 2 treatment regimens, a consistent trend toward lower viscosity was found at all shear rates as vasodilatory treatment was intensified (baseline to amlodipine 5 mg to amlodipine 10 mg to losartan 100 mg + amlodipine 5 mg). Our data do not support that effects on adipokines, inflammatory markers, and whole blood viscosity could explain improved insulin sensitivity seen on AT1-receptor blockade.
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PMID:Improved insulin sensitivity by the angiotensin II-receptor blocker losartan is not explained by adipokines, inflammatory markers, or whole blood viscosity. 1795 96

Hypertension has been associated with several modifications in the function and regulation of the sympathetic nervous system (SNS). Although it is unclear whether this dysfunction is primary or secondary to the development of hypertension, these alterations are considered to play an important role in the evolution, maintenance, and development of hypertension and its target organ damage. Several pharmacological antihypertensive classes are currently available. The main drugs that have been clearly shown to affect SNS function are beta-blockers, alpha-blockers, and centrally acting drugs. On the contrary, the effects of ACE inhibitors (ACE-Is), AT1 receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics on SNS function remain controversial. These properties are pharmacologically and pathophysiologically relevant and should be considered in the choice of antihypertensive treatments and combination therapies in order to achieve, beyond optimal blood pressure control, a normalization of SNS physiology and the most effective prevention of target organ damage.
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PMID:Antihypertensive drugs and the sympathetic nervous system. 1803 57

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren has a low bioavailability (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h), which makes it suitable for once-daily dosing. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as standard doses of established AT1 receptor blockers (losartan, valsartan, and irbesartan), angiotensin-converting enzyme inhibitors (ramipril and lisnopril), hydrochlorothiazide, or long-acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, valsartan, irbesartan, or ramipril. However, the biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-NO-cGMP pathway. Blockade of the renin-angiotensin system with angiotensin I-converting enzyme inhibitors, AT1 receptor blockers, or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize renin-angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin-angiotensin system fully quiescent is a new possibility requiring further study. Preliminary results show that short-term administration of aliskiren has beneficial anti-albuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure.
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PMID:Direct renin inhibition: clinical pharmacology. 2223 43

We investigated the effects of chronic oral antihypertensive treatment on functional and structural capillary rarefaction in spontaneously hypertensive rats (SHR). Wistar Kyoto rats (WKY) were used as a normotensive control group. In untreated rats, intravital videomicroscopy showed that functional capillary density was lower in SHR skeletal muscle (WKY 395 +/- 17 and SHR 258 +/- 13 capillaries/mm, P < 0.01) and ear skin (WKY 391 +/- 18 and SHR 210 +/- 15 capillaries/mm, P < 0.01). A linear relationship was seen between skeletal muscle and skin capillary densities (r = 0.654, P < 0.0001). Histologic analysis showed that SHR had a lower capillary-to-fiber ratio in the skeletal muscle (WKY 1.74 +/- 0.08 and SHR 1.40 +/- 0.06, P < 0.01). Capillary volume density-to-fiber volume density ratio in the left ventricle of SHR was also reduced (WKY 0.55 +/- 0.09 and SHR 0.42 +/- 0.09, P < 0.01). The animals were treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril, the angiotensin II type I receptor (AT1) receptor antagonist losartan, the beta-blocker atenolol, or the calcium channel blocker nifedipine, resulting in similar reductions in systolic blood pressure (19.8%, 19.1%, 17.4%, and 18.2%, respectively, P > 0.05). Atenolol did not induce any change in functional capillary density of SHR. Losartan and nifedipine completely reversed functional capillary rarefaction in both muscle and cutaneous tissues, whereas enalapril significantly increased functional capillary density only in the skin. The skeletal muscle capillary-to-fiber ratio was normalized by enalapril, losartan, and nifedipine. Treatments with enalapril or losartan normalized the cardiac structural capillary rarefaction of SHRs, whereas atenolol and nifedipine had no effect. Our results suggest that different pharmacologic classes of antihypertensive drugs with similar effect on blood pressure differ in terms of their effect on the microcirculation.
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PMID:Effects of antihypertensive drugs on capillary rarefaction in spontaneously hypertensive rats: intravital microscopy and histologic analysis. 1842 84

The metabolic syndrome considerably increases the risk of cardiovascular and renal events in hypertension. It has been associated with a wide range of classical and new cardiovascular risk factors as well as with early signs of subclinical cardiovascular and renal damage. Obesity and insulin resistance, beside a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with proinflammatory properties, have been implicated in the pathogenesis. The close relationships among the different components of the syndrome and their associated disturbances make it difficult to understand what the underlying causes and consequences are. At each of these key points, insulin resistance and obesity/proinflammatory molecules, interaction of demographics, lifestyle, genetic factors, and environmental fetal programming results in the final phenotype. High prevalence of end-organ damage and poor prognosis has been demonstrated in a large number of cross-sectional and a few number of prospective studies. The objective of treatment is both to reduce the high risk of a cardiovascular or a renal event and to prevent the much greater chance that metabolic syndrome patients have to develop type 2 diabetes or hypertension. Treatment consists in the opposition to the underlying mechanisms of the metabolic syndrome, adopting lifestyle interventions that effectively reduce visceral obesity with or without the use of drugs that oppose the development of insulin resistance or body weight gain. Treatment of the individual components of the syndrome is also necessary. Concerning blood pressure control, it should be based on lifestyle changes, diet, and physical exercise, which allows for weight reduction and improves muscular blood flow. When antihypertensive drugs are necessary, angiotensin-converting enzyme inhibitors, angiotensin II-AT1 receptor blockers, or even calcium channel blockers are preferable over diuretics and classical beta-blockers in monotherapy, if no compelling indications are present for its use. If a combination of drugs is required, low-dose diuretics can be used. A combination of thiazide diuretics and beta-blockers should be avoided.
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PMID:The metabolic syndrome in hypertension: European society of hypertension position statement. 1880 11

Hypertension is the most common disease affecting humans. Statistical surveys indicate that approximately one billion individuals worldwide suffer from this serious condition. The spotlight of the present review is on the cardiac involvement in patients with hypertension and especially on the possibility that treatment of increased blood pressure may abolish the incidence of cardiac arrhythmia and particularly atrial fibrillation. Modern therapeutic approach based on the electrical and structural remodeling process in the hypertensive heart with a consequent administration of ACE inhibitors and AT1 receptor blockers represent new and more efficient option compared to other antihypertensive drugs, such as calcium channel blockers, beta-blockers and thiazide-type diuretics and might be useful in the prevention of atrial fibrillation and incidence of stroke.
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PMID:Does treatment of hypertension decrease the incidence of atrial fibrillation and cardioembolic stroke? 1932 99

Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca(2+)](i)) in a dose-dependent manner and activated the L-type Ca(2+) channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca(2+)](i) elevation was abolished in the presence of the ET(A) receptor blocker BQ123, but was not affected by the ET(B) receptor blocker BQ788. ET-1-induced an increase in [Ca(2+)](i), which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 micromol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca(2+)](i) increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca(2+) channel current and an increase of open-state probability (NPo) of an L-type single Ca(2+) channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca(2+) channel activation and Ca(2+)-induced Ca(2+) release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
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PMID:Endothelin-1 induces intracellular [Ca2+] increase via Ca 2+ influx through the L-type Ca2+ channel, Ca 2+ -induced Ca2+ release and a pathway involving ET A receptors, PKC, PKA and AT1 receptors in cardiomyocytes. 1938 62

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