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)

Rapid ventricular pacing (RVP) is used as an experimental model of congestive heart failure (CHF). The purpose of this study was to determine the energy status of the dog myocardium after the development of CHF via chronic RVP. The myocardium had a significantly lower (P < 0.05) energy charge (EC) during CHF (0.63 +/- 0.01) than in sham-operated controls (0.82 +/- 0.02). This was due to significant differences in concentrations in ATP (-48%), ADP (29%), and AMP (275%) in the RVP group. However, the total adenine nucleotide pool was not different between groups. Myocardial lactate concentration was also similar. Glycogen was significantly lower (P < 0.05) by 20% at peak CHF. The adenine nucleotides were similar among the different myocardial layers (endo-, mid-, and epicardium). The administration of enalapril (an inhibitor of angiotension-converting enzyme) to decrease vascular resistance had no effect on the myocardial energy status of CHF dogs. These findings suggest that the lower EC in CHF animals is not the result of subendocardial ischemia. Also, lower EC is not associated with endogenous glycogen depletion or increased lactate concentration. The energy status of the myocardium in RVP-induced CHF is unlike that seen in ischemia-induced heart failure. This suggests that CHF in RVP is not vascular in origin.
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PMID:Energy status of the rapidly paced canine myocardium in congestive heart failure. 149 Sep 44

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

The functional integrity of the beta-adrenergic stimulatory pathway in a rabbit model of heart failure induced by long-term adriamycin treatment was investigated. Adriamycin-induced cardiomyopathy was produced in 46 rabbits by injecting 0.75 mg/kg of adriamycin, three times per week, for a period of 11 weeks. Biochemical studies performed on isolated membrane preparations revealed a 40 and 55% decrease in basal adenylyl cyclase activity in the left and right ventricles of the adriamycin treated rabbits, respectively. Furthermore, the Vmax of forskolin stimulation was significantly lower in both ventricles with no change in Kact. The Vmax of 5'-guanylylimidodiphosphate stimulation of the stimulatory guanylyl nucleotide binding protein Gs and beta-adrenergic receptor stimulation by isoproterenol were also significantly decreased (42%) in both ventricles of the adriamycin-treated rabbits with no change in Kact. Despite the decrease in receptor-mediated cyclic AMP production, no decrease in beta-adrenergic receptor population was found. Mechanical studies on the isolated right ventricular papillary muscle revealed a decrease in baseline total tension (3.1 +/- 0.4 g/mm2 to 1.8 +/- 0.2 g/mm2) and dT/dt (15.1 +/- 1.6 g/mm2 s to 7.9 +/- 0.8 g/mm2 s) in the adriamycin-treated rabbits. Furthermore, tension generation and dT/dt response to increasing concentrations of forskolin or isoproterenol were both significantly lower in the adriamycin-treated rabbits as compared to normal. We suggest that a decrease in the activity of the adenylyl cyclase component of the beta-adrenergic stimulatory pathway is largely responsible for the decrease in cyclic AMP generation in the adriamycin-treated rabbits. This defect may play an important role in the decrease of contractility in this model of heart failure.
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PMID:Adriamycin-induced changes to the myocardial beta-adrenergic system in the rabbit. 165 46

Severe decompensated chronic heart failure is associated to increased levels of circulating catecholamines and decreased density of myocardial beta-adrenergic receptors. In 14 patients with stable, class II-III heart failure we studied circulating lymphocytes to determine the number of beta adrenergic receptors, the dissociation constant of 3H dihydroalprenolol (kd) and the intracellular content of cyclic AMP (AMPc). Results (mean +/- SEM) were compared to those obtained in 10 healthy controls. The number of beta receptors was significantly decreased (105 +/- 16 vs 185 +/- 24, fmol/mg of membrane protein, p less than 0.01). No differences were found in Kd (1.65 +/- 0.2 vs. 1.36 +/- 0.28 nm) nor the level of AMPc (7.9 +/- 2.1 vs 7.1 +/- 2.9 pmol/mg protein), respectively. The decreased number of beta adrenergic receptors in the circulating lymphocytes may be related to the increased level of circulating catecholamines that have been shown to be present during exercise in these patients.
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PMID:[Beta adrenergic receptors in circulating lymphocytes of patients with chronic heart failure]. 166 48

Catecholamines mediate their effects in the heart through beta 1- and beta 2-receptors. Beta 1-receptors mediate the effects of sympathetic nerve stimulation. Alpha-receptors may have a role but, unlike the beta-receptor mediated responses, act without producing any increase in cyclic AMP. Prolonged receptor stimulation results in a reduction in beta-receptor sensitivity. In contrast blockade with a non-agonist agent is associated with an increase in catecholamine sensitivity which may be responsible for the withdrawal reactions that can occur when beta-blocking drugs are rapidly withdrawn in patients with ischaemic heart disease. Experimentally, prolonged noradrenaline infusions result in ventricular hypertrophy. Catecholamines have been implicated in several pathologies. High and rising catecholamine levels are associated with worsening of prognosis in patients with heart failure. These patients show a decreased beta-receptor number and cellular concentration of catecholamines. On the other hand cardiomyopathy is associated with an increased sensitivity to catecholamines. Catecholamines aggravate cardiac damage in ischaemia. Excessively high catecholamine loads cause myocardial damage in otherwise normal hearts, for example in patients with a phaeochromocytoma and those with various forms of cerebral damage such as subarachnoid haemorrhage, cerebrovascular accidents, and head injury.
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PMID:Heart and catecholamines. 168 38

Recent reports suggested that a complex alteration in beta-receptor function occurs in failing human myocardium. We evaluated beta-receptor-subtype activity in an experimental model of monocrotaline (MCT)-induced cardiomyopathy in the rat. Through pulmonary hypertension, MCT causes right ventricular hypertrophy (RVH), either associated with heart failure or not, beta-Receptor function was evaluated in both failing-hypertrophic and hypertrophic hearts in binding studies with [125I]iodocyanopindolol (ICYP) and by measuring adenylate cyclase (AC) activity. In the right failing ventricle, beta 1- but not beta 2-receptor density was decreased. Lesion-associated modifications in the adenylate cyclase system were also observed: isoproterenol- and guanosine 5' [beta, gamma-imido]triphosphate [Gpp(NH)p]-stimulated cyclic AMP formation was reduced in the right failing ventricle, while the cyclic AMP responses to NaF and forskolin were unchanged. On the other hand, no changes in either beta-receptor density or function were found in hypertrophic ventricles. MCT-induced heart failure in the rat is thus associated with a selective decrease of beta 1-receptor density and function. These results suggest that MCT-induced cardiac failure may be an appropriate model in which to investigate heart insufficiency further.
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PMID:Beta 1- and beta 2-receptors are differentially desensitized in an experimental model of heart failure. 170 9

We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in Gs functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and Gs activity, as determined in the S49 cyc- reconstitution assay, were measured in sarcolemma from normal (NL), left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously, we measured the mRNA level encoding for the Gs alpha subunit. These studies indicate that Gs activity and Gs alpha mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (Gs activity, pmol cyclic AMP/10 min per microgram, NL 4.2 +/- 0.4, LVH 3.0 +/- 0.2, HF 3.2 +/- 0.3; Gs alpha mRNA, pg/10 micrograms RNA, NL 131 +/- 9.0, LVH 104 +/- 7.4, HF 97.4 +/- 9.1; P less than 0.05 as compared with NL for LVH and HF). Accompanying this decrement in Gs activity is a fall in adenylyl cyclase, both basal and stimulated. However, we also identified a further decrease in adenylyl cyclase without any additional change in Gs or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g., NaF-stimulated activity, pmol cyclic AMP/min per mg, NL 420.2 +/- 17.5, LVH 347.1 +/- 29.6, HF 244.2 +/- 27.3; P less than 0.05 compared with NL for LVH and HF, P less than 0.05 compared with LVH for HF). In summary, these studies indicate that both Gs and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase, independent of Gs, in the setting of heart failure.
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PMID:Decreased Gs alpha mRNA levels accompany the fall in Gs and adenylyl cyclase activities in compensated left ventricular hypertrophy. In heart failure, only the impairment in adenylyl cyclase activation progresses. 182 33

Potentially malignant ventricular arrhythmias are common in chronic heart failure. The aggravation of such arrhythmias has many causes in these patients and cannot be predicted. Therefore, proarrhythmia due to PDE-inhibitors which increase cytosolic calcium levels by specific inhibition of the degradation of cyclo-AMP may be difficult to recognize. A retrospective analysis of 24-h Holter ECG was performed in 31 patients (NYHA classes III and IV) under long-term enoximone therapy. At baseline, 68% of the patients had ventricular couplets and nonsustained ventricular tachycardia. After a mean treatment period of 7 months, 10% of the patients showed a significant increase, 16% a significant decrease (greater than 90%) of ventricular couplets and salvos, and an additional 32% of the patients showed a significant decrease (greater than 70%) of single PVCs. The change of the arrhythmia profile was not related to the clinical course in these patients. Furthermore, 24-h Holter recordings were analyzed in a randomized long-term trial with captopril and enoximone that included 20 patients of NYHA class II. Despite comparable baseline findings, a reduction of cardiopulmonary exercise capacity was observed in patients treated with enoximone, but not with captopril. However, the arrhythmia profile was similar in both treatment groups. These findings suggest that, in most patients with advanced chronic heart failure, long-term enoximone therapy is not associated with an important increase of ventricular arrhythmias. According to the 24-h Holter findings of the European Enoximone Data Bank, proarrhythmia can be expected in 12% of all patients. Control of the arrhythmia profile, however, is mandatory, because the incidence of proarrhythmia cannot be predicted in the individual patient.
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PMID:[Enoximone and ventricular arrhythmia in chronic heart failure]. 183 3

A model of heart failure produced by rapid ventricular pacing in the conscious dog instrumented with a conductance catheter to monitor instantaneous left ventricular volume has been developed. This experimental model is capable of analysis of the left ventricular pressure-volume relationship on a beat-to-beat basis, and has been used to assess ventricular function serially in the progress of heart failure and effects of pharmacological intervention. In seven dogs the magnitude of cardiotonic effects were significantly attenuated after development of heart failure. These findings support the concept that in the failing heart there is subsensitivity to beta-adrenergic stimulation in proportion to the severity. The failing heart was characterized by incomplete left ventricular relaxation. Dobutamine improved left ventricular early relaxation but did not affect chamber distensibility. In contrast new phosphodiesterase inhibitor, E-1020, improved ventricular distensibility with less marked changes in active relaxation; improved left ventricular relaxation appeared to be mediated by increased systolic shortening with enhancement of internal restoring forces, and improved distensibility by accelerated function of sarcoplasmic reticulum through increased intracellular cyclic AMP.
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PMID:Mechanics of contraction and relaxation of the ventricle in experimental heart failure produced by rapid ventricular pacing in the conscious dog. 191 38

Catecholamines play an essential role in the activation of the cardiovascular system and in the regulation of energy metabolism in a variety of physiological conditions. Many of these effects are mediated through beta-adrenoceptors located on cell membranes. Binding of catecholamines to beta-adrenoceptor increases the concentration of intracellular cyclic AMP which in turn activates protein kinase A. This enzyme phosphorylates a number of other intracellular enzymes influencing cell metabolism and functions. The primary structures of the receptor and its topography in the cell membrane as well as its binding domains have been partially clarified. In studies of the human beta-adrenergic receptors blood lymphocytes have mostly been used as model cells. These cells carry receptors of mainly the beta 2-subtype. The adequacy of this model system has been demonstrated in several studies. In clinical work receptor assays have had limited use until now. However, studies on the pathophysiology of the adrenergic system in several diseases have revealed that receptor alterations may constitute an important factor in the disease process. Measurements of adrenergic receptors may also have increasing usefulness in determining optimal drug concentrations. Our own studies have primarily focused on physiological adjustments in the beta-adrenergic system during acute or prolonged physical exercise as well as receptor changes in heart failure, muscle diseases and the alcohol withdrawal syndrome. We have also explored receptor dynamics during therapy with beta-blocking agents. These studies, briefly reviewed in this communication, have led to the following conclusions: (1) High aerobic capacity is associated with an increased density and ability of lymphocytic beta-adrenoceptors to respond to catecholamines. (2) Both short-and long-term physical exercise induce a rapid up-regulation and more effective functioning of lymphocytic beta-adrenoceptors. (3) Administration of beta-blocking drugs is associated with a subnormal exercise-induced up-regulation and decreased functioning of the lymphocytic beta-adrenoceptors. (4) The exercise-provoked up-regulation and improved functioning of beta-adrenoceptors is blunted in heart failure patients. (5) Patients with Duchenne-type of muscular dystrophy have a reduced number of lymphocytic beta-adrenoceptors. (6) In chronic alcoholics the lymphocytic beta-adrenoceptor level is subnormal but during abrupt ethanol withdrawal a rapid increase in the number and functioning of the receptors to a normal level takes place. This sequence of events may lead to a condition of relative adrenergic hypersensitivity.
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PMID:The beta-adrenergic system in man: physiological and pathophysiological response. Regulation of receptor density and functioning. 197 55


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