Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renin plays a major role in the control of blood pressure and water and electrolyte metabolism and it is clear that blocking of this system is particularly effective in the treatment of essential hypertension and heart failure. A large number of converting enzyme inhibitors have been synthesized. Converting enzyme inhibitors are remarkably active in heart failure and they reduce microalbuminuria and possibly maintain glomerular function. Blocking of the renin-angiotensin system by converting enzyme inhibitors is not accompanied by hypotension or reflex stimulation of the sympathetic nervous system. Converting enzyme inhibitors represent a major therapeutic advance in the field of cardiovascular and renal disease but the long-term effects of decreased angiotensin II levels are unknown. There are other ways to inhibit the renin-angiotensin system. The recent discovery of orally-active non-peptide angiotensin II antagonists opens a range of fascinating prospects. Another approach consists in inhibiting the reaction of renin on angiotensinogen, which is remarkably selective. Although it is too early to know whether these new approaches will be less active, more active or as active as current converting enzyme inhibitors, they may constitute a progress in relation to currently available treatments.
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PMID:New therapeutic prospects of renin-angiotensin system inhibition. 269 Nov 25

beta-Blocking drugs are widely used throughout the world and serious adverse reactions are relatively uncommon. Most of those which do occur are pharmacologically predictable and may be avoided by ensuring that patients who are to be given beta-blockers do not have a predisposition to the development of bronchospasm, cardiac failure or peripheral ischaemia. In some situations, the use of a beta 1-selective blocking drug may reduce the risk of a severe adverse reaction, but there is little evidence that other ancillary properties such as partial agonist activity are of relevance in this context. Long term experience with many of the beta-blockers in current use suggests that unpredictable major adverse reactions such as the practolol oculomucocutaneous syndrome are unlikely to be repeated, although some of these drugs may be associated with immunological disturbances and some have been implicated in the development of retroperitoneal fibrosis. beta-Blocking drugs appear to be associated with a number of subjective side effects including muscle fatigue, peripheral coldness and some neurological symptoms. These side effects are highly subjective and are therefore difficult to quantify and it is not known whether they are of major importance in terms of their effect upon patients' overall well-being. It cannot be assumed that simply because such side effects can be elicited that they do, in fact, matter. However, because beta-blockers are often prescribed for patients who have no symptoms and for whom the benefits of therapy are generally small, such side effects would be of considerable importance if they had an overall effect upon quality of life. There are theoretical reasons to suppose that the incidence and severity of such side effects may be related to the ancillary properties of the individual drugs, but there is little evidence that parameters such as beta 1-selectivity, or partial agonist activity are clinically important determinants of the severity of these side effects. Lipophilicity, however, may be associated with an increased incidence of neurological symptoms. beta-Blocking drugs may cause a variety of metabolic disturbances including an increase in serum VLDL-cholesterol concentrations. However, long term studies have not shown that such disturbances are associated with an increased risk of cardiovascular disease, indicating that such metabolic changes may not be of major importance in practice. beta-Blocking drugs may be involved in a number of interactions with other drugs, but few of these have been shown to be of clinical significance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse reactions and interactions with beta-adrenoceptor blocking drugs. 287 46

1. Beta-Blockers are of similar efficacy in the treatment of hypertension to other antihypertensive drugs of first choice; they have a wide spectrum of activity both alone and in combination. 2. Although beta-blockers first appear to worsen the haemodynamic changes of hypertension, subsequently peripheral resistance falls. The cardiovascular reflexes responsible for the responses of posture or other responses requiring normal functioning of alpha-mediated tone are not inhibited. 3. Important contra-indications are asthma and heart failure in susceptible subjects. Lipid soluble drugs have somewhat greater CNS side effects. 4. Triglyceride levels, notably an increase in VLDL and a fall in HDL occur from non-selective agents (less so from beta 1-selective agents) and there is a marginal effect from drugs with relatively high ISA. 5. In contrast to other antihypertensive drugs beta-blockers reduce the myocardial infarction rate in high risk patients (i.e. post-myocardial infarct). Results in primary prevention of mild hypertension have been less promising. 6. Those drugs which are lipid soluble and liver metabolized result in greater variation of plasma concentration after oral administration and some pharmacokinetic drug interactions. Once daily administration is possible with many beta-blockers. 7. beta-Blocking drugs have an established and proven place in the treatment of hypertension.
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PMID:Risk-benefits of antihypertensive drugs--beta-blockers. 290 32

1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life-threatening toxicity while beta-adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation. 2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201-106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction. 3. Activation of L-type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors. 4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction. 5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.
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PMID:Ion channel modulators as potential positive inotropic compound for treatment of heart failure. 788 74

Hypertension is a major risk factor for the development of heart failure. Mechanisms which maintain normal function in the short term in the pressure overloaded heart have longer term deleterious effects. These include left ventricular (LV) hypertrophy and chronic activation of the adrenergic and renin-angiotensin systems. beta-Blocking agents are capable of blocking the adrenergic system and, to some extent, the renin-angiotensin system. They are therefore attractive in treating hypertension, both for preventing the development of abnormalities and for reversing established LV dysfunction and hypertrophy. Trials in heart failure have shown that these agents prevent progressive myocardial dysfunction, prevent and reverse remodelling and improve intrinsic systolic function. Non-selective beta-blocking agents appear to offer greater anti-adrenergic effects than selective ones. However, more research is needed, including direct comparisons of different agents.
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PMID:Mechanisms of development of heart failure in the hypertensive patient. 1065 66

Cardiac hypertrophy involves the accumulation of extracellular matrix proteins, such as fibronectin, leading to increasing myocardial stiffness, ventricular dysfunction and heart failure. To better understand the possible role of extracellular matrix-evoked intracellular signalling in ventricular myocytes, we investigated the effect of fibronectin on myocyte hypertrophic responses using cell culture models. Cell size in myocytes cultured on fibronectin-coated dishes was three times larger than that grown on non-coated dishes. However, the number of cells on fibronectin-coated dishes was not changed throughout the experiment. Protein synthesis was significantly increased by fibronectin, as were synthesis of atrial and brain natriuretic peptides. Fibronectin also elicited actin reorganization, co-localization of beta 1 integrin and vinculin, formation of focal adhesions and tyrosine phosphorylation of focal adhesion kinase in myocytes. These fibronectin-mediated effects were inhibited in a dose-dependent manner by GRGDSP, a competitive antagonist of the fibronectin receptors; GRGDSP had no effect on cell number or viability. Blocking antibody for beta 1 and beta 3 integrin significantly suppressed fibronectin-induced secretion of natriuretic peptides. Myocyte hypertrophy was observed in myocyte-nonmyocyte co-culture that reflects more closely the myocyte environment in vivo. GRGDSP may also suppress the myocyte hypertrophic response in the co-culture. These findings demonstrate that the interaction of fibronectin and RGD-dependent integrins is involved in the hypertrophic responses of myocyte in vitro, and suggest that extracellular matrix proteins such as fibronectin are not merely passive adhesive molecules but are active participants in processes leading to myocyte hypertrophy.
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PMID:Outside-in signalling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes. 1077 82

Major changes in the treatment of heart failure have occurred in the last fifty years that have had a dramatic effect on its morbidity and mortality. Over two hundred years have passed since the demonstration of the benefit of digitalis in heart failure to the development of potent loop diuretics. The observation that vasodilators could improve both cardiac function and mortality led to the investigation of the Angiotensin Converting Enzyme Inhibitors (ACEI). Although these agents had significant vasodilator properties, their major benefit appears to be related to their ability to effect remodeling of the failing left ventricle. The most recent randomized clinical trials demonstrate that Beta Adrenergic Blocking agents can provide an incremental effect on both mortality and morbidity when added to therapy with ACEI. Although these agents have improved the outlook for the heart failure patient, they have had very little effect on the improvement of left ventricular function. Future research must be directed at methods to deal with this issue by either changing the contractile properties of the cardiomyocyte by pharmacologic or electrical therapy or by transplanting functional cells that can increase the number of functioning contractile units.
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PMID:Heart failure therapy at the turn of the century. 1124 63

Endothelin 1 is a vasoconstrictor and pro-hypertrophic peptide released by the endothelium, whose secretion increases in cardiac insufficiency in proportion to the haemodynamic alteration, notably the systolic pulmonary arterial pressure. It acts by binding to 2 receptors: receptor A, responsible for the vasoconstriction effect, and receptor B, which produces vasodilatation and permits the pulmonary clearance of the molecule present in the plasma. Blocking receptor A appears logical in view of the hormonal hypothesis which prevails in the pathophysiology of cardiac insufficiency, but the significance of blocking receptor B is under discussion. The immediate effect of receptor antagonists is vasodilatation, permitting a haemodynamic improvement in patients, but the benefit on dyspnoea or the evolution of the disease has not been established. Animal models show a beneficial effect of endothelin receptor antagonists on survival, which has not been confirmed by the first studies in humans. The latter are difficult to interpret: the increase in dosage should probably to be very progressive, the optimal dosage is difficult to determine and could be lower than the doses tested. Only the result of studies underway will indicate the place of these drugs in the therapeutic arsenal for cardiac insufficiency.
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PMID:[Endothelin receptor antagonists in heart failure]. 1193 59

Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca(2+) levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F(dia)) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca(2+) (EC(50): 3.27+/-0.24 x 10(-6) versus 2.69+/-0.15 x 10(-6) mol/L; P<0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca(2+) sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540+/-93%) and pharmacologically blocked sarcoplasmic reticulum (539+/-77%), and was also similar in presence of the L-type Ca(2+)-channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca(2+) sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca(2+) influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.
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PMID:Hydroxyl radical-induced acute diastolic dysfunction is due to calcium overload via reverse-mode Na(+)-Ca(2+) exchange. 1201 65

The role of aldosterone in the pathophysiology of congestive heart failure (CHF) has long been recognized. The recent RALES (Randomized Aldactone Evaluation Study) trial demonstrated early reduction in morbidity and mortality using spironolactone, an aldosterone receptor antagonist, in combination with angiotensin converting enzyme (ACE) inhibitor and loop diuretic, in patients with heart failure. This effect of spironolactone highlighted the importance of understanding the contributions of the renin-angiotensin-aldosterone system (RAAS) in the progression of CHF, and increased interest in the use of aldosterone antagonists. While ACE inhibitors have had the largest impact on adverse events in CHF, numerous studies have shown that these drugs fail to completely suppress aldosterone. Blocking the effects of residual aldosterone has now been demonstrated to affect prognosis in these patients. This review will discuss the role of aldosterone in the pathophysiology of CHF, with an emphasis on both known and potential therapeutic benefits of aldosterone antagonism.
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PMID:Aldosterone antagonists in congestive heart failure. 1218 62


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