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)

The clinical syndrome of heart failure occurs as a consequence of the limitation of compensatory mechanisms, such as cardiac hypertrophy. To clarify transcriptional changes in specific genes in failing hearts, we examined the expression of cardiac Ca(2+)+Mg(2+)-dependent ATPase in the sarcoplasmic reticulum and transforming growth factor beta genes in the ventricles of rat hypertrophied heart, and the expression of guanine nucleotide-binding protein and "fetal" contractile protein genes in the ventricles of cardiomyopathic Syrian hamsters of Bio14.6. Northern blot analysis of total cellular RNA revealed that the mRNA levels of Ca(2+)+Mg(2+)-dependent ATPase were decreased by pressure overload and became 32% of sham in 1 month, and were correlated with corresponding protein levels. Transforming growth factor beta mRNA, a potent activator of collagen synthesis, was increased by pressure overload. The expression levels of the Gs alpha mRNA, which stimulated the adenylate cyclase, in Bio14.6 ventricles were lower than the levels in ventricles of the F1B hamster strain, and decreased as the stage of cardiomyopathy progressed. Moreover, re-expression of fetal mRNA was observed in the ventricle of cardiomyopathic Syrian hamsters of the Bio14.6 strain. These results indicate that reprogramming of cardiac gene expression both of myofibrillar and nonmyofibrillar components might occur in the failing heart.
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PMID:Molecular mechanism of hypertrophied failing heart--abnormalities of the diastolic properties and contractility. 138 37

Heterotrimeric Gi-proteins play an important role in the regulation of cardiac adenylate cyclase. Besides a downregulation of beta-adrenoceptors with an accompanying reduction of the positive inotropic effects of cAMP-dependent positive inotropic agents, an increase of pertussis toxin substrates (Gi alpha-proteins) has been observed. The increase of Gi alpha has been reported to be associated with a reduced adenylate cyclase activity in dilated cardiomyopathy from hearts with heart failure class NYHA IV. Since the quantification of Gi alpha-proteins with the pertussis toxin labeling method is hampered by a number of biological and technical factors, Gi alpha-proteins were quantified radioimmunologically using the iodinated C-terminus 125I-KENLKDCGLF as tracer, purified retinal transducin alpha as standard, and an antiserum (DS 4) raised against the same peptide. With this technique Gi alpha-proteins were increased by 118% in dilated cardiomyopathy and 48% in ischemic cardiomyopathy, although pertussis toxin substrates were only increased by 40% in dilated cardiomyopathy and no change was observed in ischemic cardiomyopathy. In cardiomyopathic tissue, an inverse relationship was observed between the increase of Gi alpha and the positive inotropic effects of isoprenaline or milrinone. These data provide evidence for a functional role of Gi alpha in the reduced positive inotropic effects of cAMP-dependent positive inotropic agents. In addition, results obtained with pertussis toxin labeling for quantification of Gi alpha-proteins do not necessarily reflect the expression of Gi alpha-proteins in the human myocardium.
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PMID:Quantification of Gi alpha-proteins in the failing and nonfailing human myocardium. 149 77

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

In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
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PMID:Receptor function in heart failure. 164 66

Changes in the beta-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing. The contractile response occurring after exposure to the beta-adrenergic agonist dobutamine, measured as peak left ventricular + dP/dt, was decreased after 3 weeks of pacing. To further characterize the diminished functional responsiveness to beta-adrenergic receptor stimulation, beta-adrenergic receptor-adenylate cyclase coupling was investigated using membranes prepared from both control and paced animals. The density of beta-adrenergic receptors was decreased by 40% with a selective downregulation of the beta 1-subtype. The affinity of the receptor for the antagonist radioligand [125I]iodocyanopindolol remained unchanged. A defect in coupling was suggested by a decreased ability of isoproterenol, fluoride, and forskolin to stimulate adenylate cyclase in membranes prepared from failing hearts. Determination of the levels of Gi alpha (the alpha-subunit of Gi) by immunoblotting and pertussis toxin labeling revealed modest increases of approximately 30%. Furthermore, Mn2+ and purified Gs failed to stimulate adenylate cyclase in membranes prepared from failing hearts, indicating an impairment in the catalytic moiety of adenylate cyclase itself or in the ability of adenylate cyclase to couple to Gs. In contrast, complementation assay did not reveal differences in the functional activity of Gs alpha (the alpha-subunit of Gs). Taken together, these data demonstrate a selective decrease in the beta 1-subtype of adrenergic receptors and an increase in a 40-kd G1-like protein in the failing heart. Similar changes have been described in human idiopathic dilated cardiomyopathy. In addition to these changes, we identified a possible defect at the level of the catalytic subunit of adenylate cyclase.
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PMID:Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. 165 3

Beta-adrenoceptor density and affinity, studied by H3-CGP 12177 binding, and adenylate cyclase activity were measured in 12 left ventricles of rabbits with heart failure and compared to 13 left ventricles of control (C) rabbits. Heart failure (HF) was induced by a double volume (aortic insufficiency) plus pressure (aortic stenosis 14 days later) overload. Left ventricular mass was increased in HF by 67% above C. Saturation curves with CGP 12177 showed a 36% decrease in beta-adrenoceptor density (C = 61.5 +/- 5.4 fmol/mg prot., P less than 0.05) but competition curves with isoproterenol were not different in HF and C. Basal and Gpp(NH)p stimulated adenylate cyclase activity were decreased by 36% and 22% respectively in rabbits with heart failure as compared with control animals and cAMP production was significantly smaller in failing left ventricles than in control left ventricles both after NaF stimulation (C: 161.3 +/- 24.9 pmols/mg/min; HF: 98.8 +/- 7.0 pmols/mg/min; P less than 0.05) and even more after forskolin stimulation (C: 159.1 +/- 23.9 and HF: 60.8 +/- 7.3 pmols/mg/min; P less than 0.01). Although isoproterenol stimulated ACA was smaller in HF than in C, EC50 was similar in both groups (1.6 x 10(-7) M). We conclude that in the early stage of heart failure in the rabbit, although adrenoceptor density is decreased, there are no changes of affinity of beta-adrenoceptors for isoproterenol and the major alteration of cAMP production appears to lie down-stream the receptor level with a markedly impaired stimulation of adenylate cyclase activity by forskolin.
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PMID:Beta-adrenoceptors and adenylate cyclase activity in hypertrophied and failing rabbit left ventricle. 167 57

Dopamine receptors of DA-1 and DA-2 subtypes are localized in various regions within the kidney including the renal vasculature (DA-1) as well as sympathetic nerve terminals innervating the renal blood vessels (DA-2). More recent studies using receptor-ligand binding and receptor autoradiography have shown that DA-1 receptors are localized at both the luminal and basolateral membranes at the level of the proximal tubules. Activation of these DA-1 receptors by dopamine and by selective DA-1 receptor agonists results in natriuresis and diuresis. The cellular signaling mechanisms responsible for this response appear to be DA-1 receptor-induced activation of adenylate cyclase and phospholipase C, which via the generation of various intracellular messenger systems cause inhibition of Na(+)-H+ antiport (luminal) and Na+, K(+)-ATPase (basolateral), respectively. Both of these events consequently inhibit sodium reabsorption leading to natriuresis and diuresis. It is also known that dopamine can be synthesized within proximal tubular cells from L-dopa, which is taken up from the tubular lumen, and this locally produced dopamine plays an important role in the regulation of sodium excretion particularly during increases in sodium intake. Furthermore, a defect in the renal dopaminergic mechanism may be one of the pathogenic factors in certain forms of hypertension. Finally, whereas DA-1 receptor agonists are shown to be of therapeutic benefit in the treatment of hypertension, heart failure, and acute renal failure, some selective DA-2 receptor agonists are effective antihypertensive agents.
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PMID:Anatomical distribution and function of dopamine receptors in the kidney. 168 44

Forskolin, a diterpene derivative of the Indian plant Coleus forskhohlii, proved to be a marked positive inotropic and vasodilatory compound in animal experiments with a mechanism of action distinct from catecholamines, cardiac glycosides, and phosphodiesterase-inhibiting compounds. The cardiovascular effects of forskolin seem to be mediated by a direct stimulatory action at the catalytic unit of sarcolemmal adenylate cyclase. The aim of the present study was to clarify the cardiovascular profile of this compound in 12 patients with stage III (NYHA) congestive cardiomyopathy. The effects of forskolin were investigated by invasive techniques using the thermodilution catheter method and compared to the beta 1-receptor agonist dobutamine and the vasodilator sodium nitroprusside in an intraindividual comparison. Forskolin dose-dependently reduced cardiac pre- and afterload values, and led to a reduction in systolic, diastolic, and mean pulmonary artery pressure as well as pulmonary wedge pressure by greater than 50% concomitant with an increase in cardiac output. There was a slight increase in heart rate. Cardiac stroke volume and stroke volume index was increased by approximately 70%. The cardiovascular effects of dobutamine and nitroprusside were less pronounced; however, it seemed that a similar hemodynamic profile could be achieved by the combination of both dobutamine and sodium nitroprusside. In view of the rapid development of tolerance toward beta 1-receptor stimulation, forskolin, with its receptor-independent mechanism of action, may be advantageous for the treatment of severe heart failure, especially in patients with catecholamine-insensitive heart failure.
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PMID:Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy--a comparative study with dobutamine and sodium nitroprusside. 169 72

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

The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 +/- 10.7% of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the beta-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.
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PMID:Effects of isomazole on force of contraction and phosphodiesterase isoenzymes I-IV in nonfailing and failing human hearts. 172 Aug 39


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