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

The pathophysiological understanding and management of acute and chronic heart failure have changed dramatically in the past decade. Since the early 1980s, a major effort has been made to develop nonglycosidic, noncatecholamine agents that combine inotropic and vasodilating properties, in order to treat myocardial dysfunction unresponsive to current therapy. Within this context, increasing attention has been paid to the role of intracellular cyclic adenosine monophosphate (cAMP) in myocardial contractility. The pharmacologic use of catecholamines to stimulate beta-receptors activates adenylate cyclase, which in turn leads to an increase in intracellular levels of cAMP. In addition, phosphodiesterase 3 (PDE 3) inhibition may prevent the degradation of cAMP, thus maintaining high intracellular levels of the substance. Intravenous amrinone has been shown clinically to improve hemodynamic status remarkably in the patient experiencing a low cardiac output syndrome, by increasing CO while decreasing filling pressures and pulmonary arterial pressures, without increasing myocardial O2 demand. This report will review several studies of different types of patients and explain the effects of amrinone alone and in combination with the more traditionally used catecholamines. It must be stressed that amrinone, in spite of its dual action of inotropy and vasodilation, should not be considered a rival to catecholamines but rather an enhancer of them, which clinicians should consider using in the early stages of therapy in many different settings.
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PMID:Historical perspectives and update of amrinone. 252 Oct 46

In heart failure a decrease in cardiac beta-adrenoceptors presumably due to endogenous down-regulation by the elevated catecholamines is a general phenomenon. Thus, attempts have been made to assess beta-adrenoceptor function in patients with chronic heart failure in order to monitor the functional state of cardiac beta-adrenoceptors. The model most widely used is that of circulating lymphocytes that contain a homogeneous population of beta 2-adrenoceptors coupled to the adenylate cyclase/cyclic AMP system. The biochemical and pharmacological properties of beta 2-adrenoceptors present in lymphocytes are quite comparable to those of beta 2-adrenoceptors in the human heart, but clearly different from those of human cardiac beta 1-adrenoceptors. Furthermore, beta-adrenoceptor agonists and antagonists regulate lymphocyte beta 2- and cardiac beta 1- and beta 2-adrenoceptors in a subtype-selective fashion: while non-selective agonists (independent of exogenously applied or endogenously elevated) and antagonists affect both cardiac beta 1- and beta 2- as well as lymphocyte beta 2-adrenoceptors, beta 1-selective agonists and antagonists influence only cardiac beta 1-, but not cardiac and lymphocyte beta 2-adrenoceptors. Finally, direct comparison of lymphocyte and cardiac beta-adrenoceptor densities revealed that changes in lymphocyte beta 2-adrenoceptors are significantly correlated with changes in cardiac beta 2-adrenoceptors, but not related to changes in cardiac beta 1-adrenoceptors. Since beta 1-adrenoceptors predominate in all parts of the human heart, the use of lymphocyte beta 2-adrenoceptors as a tool for predicting the status of cardiac beta-adrenoceptors is, therefore, quite limited.
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PMID:Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes? 255 8

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) 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. Drugs such as milrinone have a wider therapeutic index than the cardiac glycosides. 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 PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.
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PMID:Pharmacology of positive inotropic phosphodiesterase III inhibitors. 255 11

Cardiac alpha- and beta-adrenoceptors and the positive inotropic effects of several adenylate cyclase dependent and independent agents have been measured in papillary muscle strips from patients without, as well as with moderate and severe heart failure. The number of beta-adrenoceptors was found to be decreased depending on the degree of heart failure. This does not apply to alpha-adrenoceptors, which remain unchanged. The antagonist affinity of adrenoceptors for the different ligands did not change in heart failure. Maximal increases in force of contraction were measured after raising Ca++ up to 15 mM in the muscle strips. In healthy human myocardium, isoprenaline, dobutamine, IBMX or cardiac glycosides increase force of contraction to the same maximal values as Ca++ does. However, in cardiac tissue from heart failure patients, positive inotropic agents which increase intracellular cAMP or are cAMP-dependent are less effective than Ca++. Furthermore, the results seem to indicate a homologous (agonist specific) downregulation of receptors in moderate heart failure and a heterologous downregulation in severe heart failure. Thus, many well known positive inotropic drugs lose their effectiveness just when they are needed most: in severe heart failure.
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PMID:Positive inotropic stimulation in the normal and insufficient human myocardium. 255 70

To investigate whether heart failure alters beta-adrenergic receptors on skeletal muscle and its associated vasculature, the density of beta-adrenergic receptors, isoproterenol-stimulated adenylate cyclase activity, and coupling of the guanine nucleotide-binding regulatory protein were compared in 18 control dogs and 16 dogs with heart failure induced by 5-8 wk of ventricular pacing at 260 beats/min. Hindlimb vascular responses to isoproterenol were compared in eight controls and eight of the dogs with heart failure. In dogs with heart failure, the density of beta-receptors on skeletal muscle was reduced in both gastrocnemius (control: 50 +/- 5; heart failure: 33 +/- 8 fmol/mg of protein) and semitendinosus muscle (control: 43 +/- 9; heart failure: 27 +/- 9 fmol/mg of protein, both P less than 0.05). Receptor coupling to the ternary complex, as determined by isoproterenol competition curves with and without guanosine 5'-triphosphate (GTP), was unchanged. Isoproterenol-stimulated adenylate cyclase activity was significantly decreased in semitendinosus muscle (control: 52.4 +/- 4.6; heart failure: 36.5 +/- 9.5 pmol.mg-1.min-1; P less than 0.05) and tended to be decreased in gastrocnemius muscle (control: 40.1 +/- 8.5; heart failure: 33.5 +/- 4.5 pmol.mg-1.min-1; P = NS). Isoproterenol-induced hindlimb vasodilation was not significantly different in controls and in dogs with heart failure. These findings suggest that heart failure causes downregulation of skeletal muscle beta-adrenergic receptors, probably due to receptor exposure to elevated catecholamine levels, but does not reduce beta-receptor-mediated vasodilation in muscle.
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PMID:Skeletal muscle beta-receptors and isoproterenol-stimulated vasodilation in canine heart failure. 255 23

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.
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PMID:Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. 256 29

The stimulant effects of adrenaline and noradrenaline on contractile force and adenylate cyclase, mediated through beta 1 and beta 2-adrenoceptors, are analysed in isolated atrial and ventricular myocardium of man. The tissues were obtained from patients without advanced heart failure undergoing heart surgery. Usually, both adrenaline and noradrenaline stimulated adenylate cyclase predominantly through ventricular and atrial beta 2-adrenoceptors. Because the relative density of beta 2-adrenoceptors is usually smaller than that of beta 1-adrenoceptors, stimulation of one beta 2-adrenoceptor leads to the production of up to 10 times more cyclic AMP molecules than does stimulation of one beta 1-adrenoceptor. Adrenaline and noradrenaline maximally enhance contractile force through both atrial and ventricular beta 1-adrenoceptors. Adrenaline can also maximally enhance contractile force through atrial beta 2-adrenoceptors. In the ventricle, adrenaline increases force via beta 2-adrenoceptors by up to 60% of its maximal beta 1 response. Noradrenaline can increase atrial and ventricular contractile force through beta 2-adrenoceptors but only at high concentrations. Unexpectedly, in atria from patients treated with the beta 1-selective antagonist atenolol, contractile responses to adrenaline are markedly and selectively augmented through activation of beta 2-adrenoceptors. In atria from atenolol-treated patients equi-inotropic concentrations of adrenaline and noradrenaline acting through beta 2 and beta 1-adrenoceptors, respectively, cause similar increases of cyclic AMP and of cyclic AMP-dependent protein kinase activity.
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PMID:A comparison of the effects of adrenaline and noradrenaline on human heart: the role of beta 1- and beta 2-adrenoceptors in the stimulation of adenylate cyclase and contractile force. 257 19

Isolated guinea pig hearts were perfused with Krebs buffer in the absence or presence of 10 microM adenosine for 60 to 120 min followed by a 15 min washout with adenosine-free buffer. The effects of isoproterenol on left ventricular dP/dt and heart rate were then determined. Perfusion with adenosine for a minimum of 90 min followed by washout resulted in a 40% depression of the dose-response curve of left ventricular dP/dt to isoproterenol. This depressed inotropic responsiveness persisted for at least 1 hr after cessation of adenosine perfusion. The heart rate response to isoproterenol was unaffected. Also, adenosine perfusion had no effect on ouabain inotropism. Measurement of adenosine in coronary effluent and in ventricular tissue by radioimmunoassay verified that no residual elevated adenosine remained following perfusion and washout. Moreover, isoproterenol-induced release of adenosine into the coronary effluent did not differ between control and adenosine-treated hearts. Addition of 100 microM theophylline, an adenosine receptor antagonist, to the adenosine containing buffer during perfusion prevented the depressed response to isoproterenol. In membrane fractions prepared from ventricles, beta receptors were assessed by (-) [125] iodocyanopindolol binding and neither the density of these receptors nor their affinity for agonists or antagonists was altered by adenosine perfusion. However, activation of adenylate cyclase by isoproterenol (10 microm) was significantly depressed in membranes from adenosine perfused hearts. These findings are consistent with a receptor mediated action of adenosine to produce persistent depression of catecholamine inotropism. Such an effect may be important in heart failure where myocardial levels of adenosine are elevated and circulating levels of catecholamines are high.
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PMID:Persistent desensitization of the heart to the inotropic action of isoproterenol by adenosine. 260 56

The influence of long-term verapamil administration on the consequences of Trypanosoma cruzi infection in mice was studied with regard to animal mortality, morbidity, myocardial pathologic features and myocardial beta-adrenergic adenylate cyclase activity. Verapamil administration dramatically decreased the mortality rate from 60% to 6% during the 70 day period of infection. Three clinical stages of infection were evident. In the acute stage (17 days after infection with maximal parasitemia), verapamil treatment not only decreased the incidence of myocardial disease (fibrosis and inflammation), but also protected myocardial beta-adrenergic adenylate cyclase activity. In addition, there was no increase in total body weight, which was regarded as an index of right-sided heart failure. In the subacute stage (30 to 60 days after infection), administration of verapamil continued to decrease myocardial disease and preserve beta-adrenergic adenylate cyclase activity. In addition, verapamil ameliorated the morbidity and mortality associated with this stage of infection. The chronic stage of infection was characterized by a decrease in myocardial disease and in beta-adrenergic adenylate cyclase activity. Thus, independent of the state of infection, long-term verapamil treatment enhanced beta-adrenergic adenylate cyclase activity. In addition, verapamil ameliorated the morbidity associated with infection. Although the relation among these various effects of verapamil in the setting of T. cruzi infection remains to be determined, collectively the results suggested that verapamil administration attenuated the consequences of T. cruzi infection.
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PMID:Verapamil ameliorates clinical, pathologic and biochemical manifestations of experimental chagasic cardiomyopathy in mice. 267 Oct 96

The effects of congestive heart failure on the physiological and biochemical functions of the cardiac beta-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic beta-receptor density, measured by [3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the beta-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, beta-receptor down-regulation is chamber-specific, occurring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occurred in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by beta-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.
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PMID:Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. 282 36


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