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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the adrenergic nervous system appears to play a crucial role in the genesis of fatal arrhythmias associated with the very early stages of acute myocardial infarction. The second messenger of beta-adrenergic catecholamine stimulation, cyclic adenosine monophosphate (AMP), has established arrhythmogenic qualities, acting by an increase in cytosolic calcium, which potentially has three adverse electrophysiologic effects. First, stimulation of the transient inward current by excess oscillations of cytosolic calcium can invoke delayed afterdepolarizations, so that triggered automaticity can develop in otherwise quiescent ventricular muscle. Second, cyclic AMP can evoke calcium-dependent slow responses in depolarized fibers, so that conditions for reentry are favored. Third, excess cytosolic calcium can cause intercellular uncoupling with conduction slowing. Focal changes in cyclic AMP and cytosolic calcium promote the development of ventricular fibrillation. Beta-adrenergic blockade can limit the formation of cyclic AMP in ischemic tissue. Furthermore, by reducing sinus tachycardia it can lessen cytosolic calcium overload. Hence, beta-adrenergic blockade helps to prevent ventricular fibrillation in the early stages of acute myocardial infarction and protects from sudden death in the postinfarction phase. In congestive heart failure, abnormalities of cytosolic calcium patterns exist with cytosolic calcium overload. It is proposed that the adverse effects of phosphodiesterase inhibitors on the mortality rate in patients with congestive heart failure can be explained by increased rates of formation of cyclic AMP and the development of calcium-dependent arrhythmias. Because calcium is the ultimate messenger of cyclic AMP-induced arrhythmias and because cytosolic calcium is increased in heart failure, it will be difficult to develop positive inotropic agents that are free of the risk of sudden death.
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PMID:Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. 135 May 97

Beta-adrenergic stimulants (Dobutamine and Dopamine) and recently introduced phosphodiesterase inhibitors (PDI) such as Amrinone, Milrinone, Enoximone and Piroximone are the principal inotropic agents for the treatment of acute cardiac failure. Most of the hemodynamic effects of these drugs are comparable, but peripheral vasodilatation is more marked with PDI. A potential advantage of the latter group is the lack of development tolerance, which occurs within 48 to 72 hours after beta-stimulants. On simultaneous administration, additive effects can be observed. Short term clinical results with PDI are good, especially in patients with postoperative cardiocirculatory failure, including cardiogenic shock. In contrast, long-term oral treatment with Amrinone, Milrinone and Enoximone in recent studies was disappointing. Efficacy was not superior to Digoxin, and unwanted side effects were frequent. Intermittent instead of continuous administration of positive inotropic agents should be evaluated in patients with severe congestive heart failure not responding to vasodilators and diuretics.
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PMID:[New positive inotropic drugs in acute and chronic heart failure]. 135 9

Considerable effort and resources have been directed at the development and study of positive inotropic drugs over the past 10-15 years. Much has been learned about the physiology and pharmacology of myocardial contraction, the application of agents to augment contractility, and, importantly, the general and specific limitations of positive inotropic therapy. Studies on acute inotropic intervention have now shown that a drug's ability to augment overall cardiac performance is heavily dependent on its effects on vasculature, vascular control, and ventricular-vascular coupling. The clinical research on new agents has served to remind us how difficult it is to formulate the "ideal" positive inotropic or cardiovascular support drug for the critical care setting. The vast effort to develop a chronically and orally administrable drug to replace or even supplement digitalis has generally been disappointing. The dopaminergic agents (e.g., ibopamine, levodopa) act primarily via vasodilation and their effectiveness and role in managing heart failure remain unresolved. The initial excitement about the phosphodiesterase III inhibitors (e.g., amrinone, milrinone, enoximone) has been tempered by the results of large well-designed trials indicating variable effectiveness and a prominent adverse effect profile. During long-term oral administration none of these agents has been shown to improve clinical status or exercise capacity beyond that achieved by digoxin, when administered either separately or in combination with digoxin. The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial, showing that repeated oral administration of milrinone can increase mortality in heart failure, is having a devastating effect on the further development of this class of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Current status of non-digitalis positive inotropic drugs. 135 56

We have described five phosphodiesterase (PDE) isozymes that can be found in cardiac and vascular smooth muscle of animals and humans. Much of the evidence for the role that these isozymes have in the regulation of cellular processes has been generated through, or awaits, the identification of selective and potent PDE inhibitors. While selective inhibitors of the cGMP-inhibitable (cGi)-PDE isozyme have been approved for use in the acute treatment of heart failure, selective inhibitors of the cGMP-PDE have not been extensively explored as potential candidates for the treatment of cardiovascular diseases. More potent selective inhibitors of the cGMP-PDE isozyme are needed to determine whether these pharmacological potentiators of EDRF and ANP will be useful in the therapy of angina, hypertension or heart failure.
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PMID:Cardiovascular cyclic nucleotide phosphodiesterases and their role in regulating cardiovascular function. 137 94

The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.
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PMID:Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. 138 Jun 7

The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.
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PMID:Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure. 138 27

The effects of enoximone (MDL 17043, Perfan, CAS 77671-31-9) on the activities of the phosphodiesterase (PDE) isoenzymes I-IV and on force of contraction were investigated in ventricular preparations isolated from failing (end-stage myocardial failure, NYHA IV) and non-failing human hearts. In both tissues four PDE isoenzymes (PDE I-IV) with similar properties were separated by DEAE-sepharose chromatography. The effects of enoximone on PDE I-IV activities did not differ between non-failing and failing human hearts. As compared to PDE I (IC50 2100 mumol/l) and II (IC50 2900 mumol/l) enoximone is a selective PDE III (cGMP-inhibited PDE, IC50 5.9 mumol/l) and PDE IV (cGMP-insensitive PDE, IC50 21.1 mumol/l) inhibitor. Milrinone, 3-isobutyl-1-methylxanthine (IBMX) and UD-CG 212 Cl, a derivative of pimobendan, were studied in the failing heart for comparison. Milrinone inhibited PDE I-IV activities similar to enoximone, revealing IC50 values for inhibition of PDE III and IV (1.2 and 3.3 mumol/l) which were about two orders of magnitude lower than that of PDE I and II (173 and 306 mumol/l). UD-CG 212 Cl was the most potent (IC50 0.05 mumol/l) and most selective PDE III inhibitor tested (IC50 for PDE I, II and IV were 175, 181 and 40.8 mumol/l, resp.), whereas IBMX inhibited PDE I-IV nonselectively (IC50 15.3, 26.2, 5.6, 5.8 mumol/l, respectively). In trabeculae carneae from nonfailing and failing human hearts enoximone increased force of contraction only marginally by 18.0 +/- 9.1% (n = 8) and 24.5 +/- 8.7% (n = 9) of the predrug value.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts. 138 15

Heart transplantation is a widely accepted therapy for end-stage myocardial failure in adults. However, few centers have experience in the treatment of newborns and children. The management of these children from the anesthesiologic viewpoint is demonstrated in our first 10 patients. Ages ranged from 5 days to 5 years; weights ranged from 2900 gm to 16 kg. The children suffered from hypoplastic left heart syndrome (n = 5) or cardiomyopathy (n = 5). Eight patients had to receive catecholamines (dobutamine) before surgery. In neonates cardiopulmonary bypass (CPB) with hypothermic cardiac arrest at 18 degrees C was used; in the older children continuous CPB at 24 degrees to 28 degrees C was performed. Inotropic support during and after weaning from CPB was necessary in all patients who received dobutamine (range, 2 to 10 micrograms/kg/min), epinephrine (range, 0.03 to 1.0 microgram/kg/min), or both. The phosphodiesterase inhibitor enoximone (1.0 mg/kg) was administered to five patients. Prostaglandin E1 was given to four patients, and it was necessary to give additional tolazoline to two patients. Heart transplantation is a challenge for anesthesiologists during the prebypass period as well as during the weaning and early postbypass periods. More experience is necessary to optimize the anesthetic management of these children.
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PMID:Anesthesia in pediatric heart transplantation. 138 52

Since the use of cardiac glycosides for heart failure therapy is limited by their narrow margin of safety, numerous efforts have been made to find and develop novel cardiotonic agents that are superior to the cardiotonic glycosides. Positive inotropic drugs acting on beta-adrenoceptors and inhibitors of cAMP phosphodiesterase have been extensively studied for the treatment of patients with heart failure. The main mechanism of these agents is elevation of cAMP tissue levels. Furthermore, Ca sensitizers such as sulmazol, pimobendan, MCI-154, END 53998 and DPI 201-106 are of interest, since such a mechanism of action may be beneficial for the failing heart. Recently, cardiotonic substances with a novel mechanism of action such as gingerol and xestoquinone have been isolated from natural sources. Natural products, purealin, goniodomin and okadaic acid, have proven to be valuable pharmacological tools for studies on cardiac muscle contraction.
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PMID:[Novel types of cardiotonic drugs]. 139 36

The efficacy of the phosphodiesterase inhibitor enoximone for reversal of severe postcardiotomy low cardiac output syndrome was investigated in 13 cases of cardiogenic shock refractory to conventional treatment consisting of beta-adrenergic agonists (n = 13) combined with vasodilators (n = 7), and intra-aortic balloon counterpulsation (n = 5). Following a bolus of 1 mg/kg enoximone, cardiac and stroke volume indices increased from 1.56 +/- 0.27 l/min/m2 and 16.3 +/- 3.3 ml/m2, respectively, to 2.72 +/- 0.67 and 27.8 +/- 7.1 (both p < 0.001). Mean arterial pressure fell, from 77 +/- 11 to 68 +/- 9 mmHg (p < 0.05), as did atrial filling pressures (LAP and RAP), LAP from 21.3 +/- 5.5 to 15.9 +/- 2.9 and RAP from 16.6 +/- 2.3 to 13.7 +/- 2.1 mmHg (both p < 0.01). The heart rate rose by only 5%. Enoximone therapy was maintained by a continuous infusion (5-7.5 micrograms/kg/min) for 40.6 +/- 8.6 hours (range 14-92). All hemodynamic parameters remained stable throughout treatment. Six patients died of sepsis and/or multiorgan failure but seven were discharged from hospital. Enoximone thus improved hemodynamic performance significantly in cardiogenic shock after open-heart surgery. It also has proved valuable in cardiac failure when conventional therapy was unsuccessful.
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PMID:Efficacy of phosphodiesterase inhibitor enoximone in management of postcardiotomy cardiogenic shock. 143 45


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