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)

If the failing left ventricle could be given an effective push, other approaches to the treatment of heart failure would not be needed. We have inotropes only for short-term parenteral use. We have no safe inotrope for chronic oral use. The effect of digitalis is only feeble and the phosphodiesterase inhibitors seem to increase mortality from sudden death. Diuretics are dramatic for acute pulmonary oedema and the mainstay for chronic fluid retention but do not improve the pump and by reducing blood volume stimulate the renin angiotensin system to vasoconstriction, further fluid retention and hypokalaemia. Nitrates drop pre-load without reducing blood volume but tolerance is a problem and stroke volume does not increase. Reduction of afterload helps the failing ventricle to empty, the pull and output increases. The angiotensin converting enzyme inhibitors (ACEI) are now the cornerstone of heart failure treatment, reducing mortality in severe heart failure (CONSENSUS) and superior to standard vasodilator therapy (V-HeFT-2) at improving the survival of patients with mild to moderate heart failure. ACEI can reduce the incidence of ventricular ectopy and probably do this through improving left ventricular function, from decreasing sympathetic tone, reducing myocardial oxygen demand or increasing serum potassium but ACEI did not diminish the incidence of sudden death in the SOLVD trial despite reducing mortality. Disappointingly little improvement in exercise tolerance and persistence of chronic fatigue in heart failure concentrated attention on the periphery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The push, the pull and the periphery. 144 45

R 79595 (N-cyclohexyl-N-methyl-2-[[[phenyl (1,2,3,5-tetrahydro-2 oxoimidazo [2,1-b]-quinazolin-7-yl) methylene] amin] oxy] acetamide) and its isomers represent a novel class of compounds with phosphodiesterase (PDE) inhibitory and cardiotonic (positive inotropic) actions. The cardiac effects of this class of compounds were investigated in the hexobarbital-depressed heart-lung preparation of the guinea-pig. After induction of heart failure (reduction of cardiac output to 25% of the initial value) cumulative addition of R 79595 or its isomers R 80122 (E-isomer) and R 80123 (Z-isomer) concentration-dependently reversed the cardiac depressant effects of hexobarbitone-Na. With regard to reconstitution of contractility and cardiac function R 80122 (E-isomer) was 10 fold more potent than R 79595 (1:1 mixture of the isomers) and nearly 100 fold more potent than R 80123 (Z-isomer). Furthermore, the cardiotonic action of the most potent isomer (R 80122) was compared to the effects of several positive inotropic reference compounds. The order of cardiotonic potency was as follows: (-)-adrenaline > R 80122 = adibendan > digitoxin > milrinone = enoximone > theophylline. Adibendan (EC50 value: 6.7 +/- 1.8 x 10.-8 mol/l), which showed cardiotonic effects in the same concentration range as R 80122 (EC50 value: 6.1 +/- 1.3 x 10(-8) mol/l), was significantly (p < 0.01) less effective than R 80122 with respect to the maximally induceable increase in cardiac output (CO). The cardiotonic effects of R 80122 could be observed in the low concentration range of 3 x 10(-8) to 1 x 10(-6) mol/l, whereas enoximone (EC50 value: 1.2 +/- 0.1 x 10(-5) mol/l) and milrinone (EC50 value: 8.9 +/- 3.5 x 10(-6) mol/l) elicited positive inotropic effects at 100 fold higher concentrations. Digitoxin was 10 fold less and theophylline was 300 fold less potent than R 80122 with regard to reconstitution of heart function. The cardiotonic effects of R 80122 were not accompanied by an increase in heart rate as found with milrinone, theophylline or (-)-adrenaline in this model. Furthermore, the PDE inhibitory effect of R 79595 and its E-isomer R 80122 were investigated in partially purified isoenzymes from guinea-pig ventricles. The IC50 values of R 79595 and R 80122 on PDE I-IV were compared to the IC50 values of adibendan, milrinone, enoximone and theophylline. The selectivity of an inhibitor for PDE III was evaluated by division of its IC50 values on PDE I, II and IV by the IC50 value on PDE III. R 80122 was the most potent and selective PDE III inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cardiac effects of R 79595 and its isomers (R 80122 and R 80123) in an acute heart failure model. A new class of cardiotonic agents with highly selective phosphodiesterase III inhibitory properties. 147 Feb 28

R 80122 is a newly synthesized, selective phosphodiesterase III inhibitor. The cardiac and hemodynamic effects of this compound following intravenous administration were studied in closed-chest anesthetized as well as in conscious chronically instrumented dogs. The findings in the closed-chest anesthetized dogs indicate that R 80122 has positive inotropic and possibly moderate vasodilating properties [maximum increase in LV dp/dtmax/pd: 61%, and maximum decrease in systemic vascular resistance: 29% (a 12.5% decrease for the solvent)]. As a result, cardiac output maximally increased to 149% of the control value. The most striking effect of R 80122 was its positive lusitropic effect (maximal decrease in the time constant of relaxation [T] of 46%). This pronounced lusitropic effect of R 80122 can be regarded as beneficial, because of the increasing evidence that lusitropic defects play an important role in disorders related to heart failure. These effects of R 80122 were associated with only slight changes in arterial blood pressure. The effects of R 80122 lasted about 75 min after stopping the infusion. No ventricular arrhythmias were noted during and after infusion of the compound. The positive inotropic effects seen in anesthetized dogs were confirmed in conscious nonsedated dogs. It may be concluded that R 80122 has a clinically favorable cardiovascular profile for acute applications in heart failure, because its combined positive inotropic and positive lusitropic effects, and moderate vasodilating properties lead to a pronounced increase in cardiac output and only minimal changes in aortic blood pressure.
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PMID:Cardiac and hemodynamic effects of intravenous R 80122, a new phosphodiesterase III inhibitor, in anesthetized and awake dogs. 153 Mar 74

In human heart failure the positive inotropic and cAMP-elevating effects of both beta-adrenoceptor agonists and phosphodiesterase inhibitors are diminished. This has been explained at least in part by an increase in the inhibitory signal-transducing G protein (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the alpha subunits of Gi-1, Gi-2, Gi-3, and Gs in myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with 32P-labeled cDNAs demonstrated expression of Gi alpha-2, Gi alpha-3, and Gs alpha mRNA. In contrast, Gi alpha-1 mRNA was not detectable. To investigate whether the increased ratio of Gi/Gs might be due to altered gene expression, we compared mRNA levels of Gi alpha-2, Gi alpha-3, and Gs alpha in left ventricular myocardium from failing hearts with idiopathic dilated cardiomyopathy (n = 8) and ischemic cardiomyopathy (n = 6) and from nonfailing hearts from transplant donors (n = 8). Compared with nonfailing control hearts, the Gi alpha-2 mRNA was increased by 75 +/- 26% (p less than 0.05) in idiopathic dilated cardiomyopathy hearts and 90 +/- 26% (p less than 0.05) in ischemic cardiomyopathy hearts. Gi alpha-3 and Gs alpha mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Gi alpha-2 and Gi alpha-3 mRNA are the predominant Gi alpha mRNA subtypes in human ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. 155 Nov 95

Intensive interest and passion have been generated in the search for orally effective inotropes over the past few decades. Several extensive clinical evaluations of these agents have now been completed. Both beta-adrenergic agonists and phosphodiesterase inhibitors that exert cardiotonic action by increasing intracellular cyclic adenosine monophosphate produced dramatic short-term hemodynamic benefits in patients with advanced heart failure. However, patients who received long-term treatment with these agents had unfavorable outcomes, including a higher mortality and morbidity rate, and deleterious side effects. The principal mechanisms responsible for the limitations in its usefulness in long-term therapy may be related to increased energy expenditure and potential arrhythmogenic effects. In contrast to these pessimistic views, one quinolinone derivative has been shown to exert a positive inotropic action without a chronotropic effect. Patients with mild heart failure responded favorably to this agent in long-term therapy. The lack of an increase in heart rate might be the cause of this salutary effect. Concerns regarding the possible improvement in the prognosis of patients with heart failure due to the use of positive inotropic therapy still continue.
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PMID:What do the newer inotropic drugs have to offer? 157 92

The prognosis of patients with advanced chronic cardiac failure is very poor. Only investigations made in recent years provided evidence that this adverse prognosis can be influenced by conservative pharmacological treatment. Among many tested vasodilating substances positive data were obtained only with high doses of nitrates with hydralazine and in particular with inhibitors of the angiotensin converting enzyme which are the greatest advance in the treatment of chronic cardiac failure. Preparations of this group mitigate the symptomatology, increase load tolerance and improve the prognosis. So far they are indicated above all in severe forms of cardiac failure, however, the possibility to use them also in milder forms and in patients with myocardial infarction is intensively investigated. The basis of pharmacological treatment remain diuretics. The position of digitalis in the treatment of cardiac failure is revised at present; in a major proportion of patients, in particular those with a preserved sinus rhythm, its administration is useless. A number of other positively inotropic substances was tested, catecholamines as well as phosphodiesterase inhibitors (amrinone, milrinone, xamoterol, enoximone). Contrary to acute failure, their effect in chronic failure is controversial, data on an improved prognosis are lacking and some investigations reveal an adverse trend. Almost half the patients with cardiac failure die from a sudden death and it would thus be logical to use antiarrhythmic drugs. Here, too, however, data on an improved diagnosis are lacking. The results of hitherto accomplished studies were rather disappointing, the investigation with the most promising antiarrhythmic agent--amiodarone--is still under way.
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PMID:[Can pharmacotherapy in heart failure affect mortality?]. 159 10

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.
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PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 160 Sep 69

Intravenous phosphodiesterase inhibition with milrinone is known to have a beneficial effect on haemodynamics in chronic heart failure. Its effect on lower limb capacitance vessels has not been previously investigated. We have studied the effect of intravenous milrinone in 10 patients with severe chronic heart failure. Thirty minutes after commencement of treatment mean cardiac index had risen by 26% and pulmonary artery wedge pressure, systemic vascular resistance and right atrial pressure had fallen by 51, 24 and 89%, respectively (p less than 0.05 for all changes). These changes were maintained for the 2 h observation period with no evidence of tolerance and were accompanied by a 17% increase in venous volume (p less than 0.01) and a 42% increase in ejection fraction (p less than 0.001) at 30 min; at 120 min the improvement in ejection fraction had been maintained and a further increase in venous volume to 38% above baseline was evident. The increase in venous volume was strongly correlated with the decrease in mean pulmonary artery wedge pressure and mean right atrial pressure at 30 min and 2 h (r = -0.80 and -0.69 for mean pulmonary artery wedge pressure, r = -0.88 and -0.56 for mean right atrial pressure). Milrinone therefore has clinically important venodilating properties, in addition to its known effects as an arterial vasodilator and a positive inotrope.
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PMID:Acute effects of intravenous phosphodiesterase inhibition in chronic heart failure: simultaneous pre- and afterload reduction with a single agent. 161 97

The hemodynamic effects of dobutamine, milrinone, and a combination of both drugs were compared intra-individually in 14 patients with severe heart failure (NYHA III: n = 9; NYHA IV: n = 5). Dobutamine (maximum dose: 9 micrograms/kg/min) and milrinone (0.5 micrograms/kg/min) each induced a comparable increase in stroke volume index (21 to 29 resp. 21 to 30 ml/m2; mean values; p less than 0.001) and reduction in pulmonary capillary wedge pressure (29 to 22 resp. 28 to 21 mm Hg; p less than 0.001), as well as in systemic (1846 to 1218 resp. 1858 to 1276 dyn s/cm5; p less than 0.001) and pulmonary vascular (301 to 195 resp. 293 to 216 dyn s/cm5; p less than 0.001) resistances. The heart rate rose significantly after dobutamine (92 to 107 min-1; p less than 0.05), but did not change after milrinone (94 to 95 min-1; ns). Neither drug had a significant effect on systemic arterial pressures. The combination of milrinone and dobutamine induced a further significant rise in stroke volume index (37 ml/m2; p less than 0.01) when compared to either drug alone. The combination also caused an additional fall in pulmonary capillary wedge pressure (14 mm Hg; p less than 0.01), as well as in systemic (799 dyn s/cm5; p less than 0.001) and pulmonary (133 dyn s/cm5; p less than 0.001) vascular resistances. When compared to dobutamine alone, the combined therapy did not significantly change the heart rate and systemic arterial pressures. The combined administration of a beta-adrenergic agonist and a phosphodiesterase inhibitor induces beneficial hemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Additive effects of milrinone and dobutamine in severe heart failure]. 162 7

Therapeutic approaches to the management of heart failure have traditionally focused on shortterm hemodynamic and symptomatic goals, but present evidence suggests that most therapeutic decisions have long-term consequences. Treatment may change the rate of disease progression, modify the need for additional therapy, influence the number of hospitalizations, and alter the risk of death. However, there may be little relation between a drug's short-term effect on cardiac function or cardiovascular symptoms and its long-term effect on survival. Some therapeutic interventions favorably influence the outcome of patients with heart failure, even though they exert negative inotropic effects; others adversely affect the outcome of patients, even though they markedly improve cardiac performance. This discordance might be explained if the most important predictor of response to a therapeutic intervention in heart failure were the effect of the pharmacologic agent on neurohormonal systems rather than on hemodynamic variables. In general, drugs that decrease the effects of the sympathetic nervous system (digitalis glycosides) and the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors) reduce the risk of worsening heart failure. Conversely, drugs that potentiate the effects, or increase the activity, of the sympathetic nervous system (phosphodiesterase inhibitors) or the renin-angiotensin system (calcium antagonists) increase cardiovascular morbidity and mortality. These observations suggest that physicians should no longer focus on short-term hemodynamic or symptomatic goals in the treatment of heart failure but, instead, should manage patients to improve both the quality and quantity of life.
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PMID:Long-term strategies in the management of heart failure: looking beyond ventricular function and symptoms. 162 88


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