Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antihypertensive drug therapy can lower blood pressure and prolong life, but many hypertensive patients continue to develop further risk factors and to die prematurely of heart disease. Antihypertensive drugs can also interfere with the patient's quality of life, and many are not compatible with the concomitant medical conditions of the patient and the medications taken to treat them. For these reasons, the antihypertensive therapy selected should meet the specific and complete needs of each patient, not just treat the high blood pressure. An analysis of the drugs that inhibit the renin-angiotensin system suggests that several of these drugs have a more favorable therapeutic profile than other classes of hypotensive agents. The newly developed receptor-site-specific blockers are expected to be tolerated better by hypertensive patients and, consequently, to enhance their quality of life. The first of the new class of nonpeptide blockers of the AT1 receptor, losartan--which has no partial agonist activity--is likely to have the advantages of the angiotensin-converting enzyme inhibitors without their adverse effects, notably cough. In selected patients, the AT1-receptor blockers could become the drugs of first choice for the management of hypertension.
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PMID:Antihypertensive therapy targeted to the needs of the patient: focus on the renin-angiotensin system; older and newer agents. 763 60

The renin-angiotensin system is associated with a variety of pathophysiological processes in many organ systems, and is known to be involved in the normal regulation of blood pressure and in the pathogenesis of renovascular hypertension. Angiotensin II is a multifunctional hormone that manifests its properties by interacting with two major subtypes of cell surface receptors (AT1 and AT2). Angiotensin converting enzyme (ACE) inhibitors are able to modify the actions of the renin-angiotensin system, and are indicated for the treatment of hypertension and heart disease. The antihypertensive effects of ACE inhibiting drugs are related to their ability to block the conversion of the decapeptide, angiotensin I, to the potent pressor octapeptide, angiotensin II. ACE inhibitors have been implicated in fetopathies in humans and perinatal mortality in rats, rabbits, sheep and baboons. Human fetopathies were seen when ACE inhibitors were given around the 26th week of gestation. The major adverse effects in babies include: oligohydramnios, renal tubular dysgenesis, neonatal anuria, calvarial and pulmonary hypoplasia, mild to severe intrauterine growth retardation, persistent patent ductus arteriosus and fetal or neonatal death. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the fetal renin-angiotensin system and partly due to the ischemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrient delivery to the fetus. The purpose of this review is to briefly discuss the pathophysiological role of the renin-angiotensin system, the therapeutic uses of ACE inhibitors in pregnant patients and to focus primarily on the major fetotoxic effects of ACE inhibitors encountered in humans and animal models. I will also review our recent data which show that capozide (captopril + hydrochlorothiazide) not only produces oligohydramnios but also disturbs the balance of glucose and NaCl in the maternal plasma and amniotic fluid of the rat.
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PMID:An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. 940 46

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
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PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

The A II antagonists (RA II antagonists) are a new group of anti-hypertensive drugs with five years of clinical use. They were investigated after the knowledge of independent ways to get angiotensin II. They block AT1 receptor. It's possible that, after AT1 block, the high plasmatic levels of AII stimulate the AT2 receptors with vasodilation and anti-proliferative activity. We are waiting for the results of several big prospective studies with RA II antagonists on cardiovascular morbidity and mortality. At present time, the first indication for its use is the appearance of cough when taking ACE inhibitors. The association of ACE inhibitors and RA II antagonists can improve some clinical conditions like dilated hypertensive cardiopathy, nephropathy or refractory hypertension.
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PMID:[ACE inhibitors versus AR II antagonists. Their role in arterial hypertension]. 1130 10

Optimal management of pregnancies for patients with acquired heart disease requires exact knowledge of the hemodynamic influence of pregnancy-related cardiovascular adaptation processes on the heart disease. Maternal and fetal risks must be carefully considered and mutually weighed. Critical time periods, during which closely networked, interdisciplinary support for the patient is essential, are primarily during the 30th to 32nd week of pregnancy. This is the period in which maximum increases in heart rate, cardiac output, and plasma volume are observed. The peripartal phase represents another critical period. Owing to the mechanically related fixation of cardiac output, stenotic valvular diseases are generally tolerated much poorer than are valvular insufficiency defects. Therapeutic objectives are reduction in heart rate and--in cases of pulmonary-venous congestion--decrease in preload. Vaginal deliveries are possible with slight to moderate valvular stenosis; cesarean section is to be preferred in more severe cases. In patients with valvular insufficiency and normal left ventricular function pregnancy is usually well tolerated. Reduction in regurgitation is even often observed owing to pregnancy-induced decrease in peripheral vascular resistance. Since ACE inhibitors and AT1 antagonists are contraindicated during pregnancy, afterload reduction can be achieved by a combination of hydralazin and nitrates, or calcium antagonists. Peripartal cardiomyopathy is rare and is associated with a high degree of maternal mortality (25-50%). Apart from the necessary consideration of pregnancy-related contraindications, therapeutic principles do not differ from those for other forms of heart failure. Most patients exhibiting hypertrophic obstructive cardiomyopathy satisfactorily pass through their pregnancies. Individual cases have been described, however, of both pregnancy-related cardiac decompensation as well as sudden death. Aortal and coronary-arterial dissections represent rare, life-endangering complications for mother and fetus: these developments can occur among predisposed patients as a result of the hormonal and hemodynamic adaptation processes during pregnancy. Close interdisciplinary collaboration and tightly networked support for patients are the prerequisite for successful management of high-risk pregnancies involving maternal heart disease.
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PMID:[Pregnancy risks in acquired heart diseases]. 1137 39

Cardiovascular diseases including heart failure represent a common disease in patients referred for anesthesia. In most cases, heart failure is caused by left ventricular dysfunction due to coronary heart disease. The aims of the treatment of chronic heart failure are the relief of symptoms, the improvement of prognosis and the prevention of the progression of heart failure. The first-line treatment involves the underlying heart disease such as myocardial revascularisation procedures in coronary heart disease or the correction of valve diseases. The pharmacological therapy depends on the stage of heart failure and symptoms of the patient. Heart failure therapy includes ACE-inhibitors, betablockers, diuretics und digitalis. Nitrates can be prescribed in patients with symptomatic heart failure despite adequate therapy but calcium antagonists are not recommended. Repeated or prolonged treatment with positive inotropic agents like phosphodiesterase inhibitors or beta-adrenergic drugs increases mortality but this is commonly used in acute stages of heart failure refractory to treatment. Interactions of ACE-inhibitors or AT1- antagonists with anesthetic agents can lead to severe hypotension especially in hypovolemic patients. Whether those drugs should be continued perioperatively or not has been controversially discussed. The use of betablockers has a positive impact on cardiac morbidity and mortality during and early after surgery. Chronic treatment with diuretics can be associated with hypovolemia and an imbalance of electrolytes leading to hypotension and arrhythmia during anesthesia but careful evaluation prior to anesthesia can avoid such complications. The continuation of digitalis during anesthesia has been controversially discussed due to the various interactions with anesthetics.
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PMID:[Current treatment of chronic heart failure]. 1289 47

Mast cells are believed to be involved in myocardial tissue remodelling under pathophysiological conditions. We examined the effects of autoantibodies against G-protein-coupled receptors in sera of patients with heart diseases on myocardial mast cells in the cultured neonatal Sprague-Dawley rat heart cells. Cells collected at day 3 and 10 of the culture were preincubated with autoantibodies against alpha1-adrenoceptor and angiotensin II AT1-receptor, agonist phenylephrine and angiotensin II, and control IgG. The pretreated cultured cells were stained for selected mast cell markers tryptase, chymase and TNF-alpha. The cultured cells were also processed for observation with electron microscopy. The autoantibodies-treatment of the 3-day cultured cells caused both increased intensity of immunofluorescence (p < 0.05) and their enlarged diameters of the mast cells when compared to age-matched ones. In contrast, the fluorescence of preincubated 10-day-old mast cells was decreased compared with controls (p < 0.01). In control samples, the fluorescence of 10-day-old mast cells was significantly higher than that of 3-day-old ones (p < 0.001). Results of electron microscopy examination demonstrated there was an increased granulation of treated 3-day-old mast cells, while a degranulation of mast cells at day 10 of application. The results suggest the modulation effect of the autoantibodies against G-protein-coupled receptors on mast cells, indicating a potential functional link between the autoantibodies against G-protein-coupled receptors and the mast cells in progression of heart disease.
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PMID:Autoantibodies against G-protein-coupled receptors modulate heart mast cells. 1748 7

The emerging recognition that chronic obstructive pulmonary disease (COPD) is a complex disorder, characterized not only by local pulmonary inflammation, but also by systemic inflammation that might have an adverse impact on various extrapulmonary organs, such as the blood vessels and the heart, among others, emphasizes the need for new and more effective forms of therapy for this debilitating disorder. Fortunately, many of the 'standard' therapeutic options used to treat COPD have the potential to influence systemic inflammation. Moreover, several new therapeutic strategies aimed at controlling the underlying inflammatory processes of COPD more specifically are under development. Unfortunately, we still do not know whether treatment of lung inflammation decreases, for example, the risk of acute cardiac events, progression of atherosclerosis or thrombotic events. It is also unclear whether, alternatively, treatment of heart disease can affect the progression of lung disease. Nonetheless, initial data seem to indicate that drugs, such as statins, ACE inhibitors, AT1 receptor blockers and PPAR agonists, used to treat a co-morbid condition have the potential to benefit COPD patients.
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PMID:Treating systemic effects of COPD. 1789 27

The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to up-regulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage.
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PMID:Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. 1840 95

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
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PMID:Aliskiren--mode of action and preclinical data. 1844 51


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