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)

Anthopleurin-A (AP-A), a polypeptide with MW ca. 5500 (53 amino acids), isolated from the sea anemone, Anthopleura xanthogrammica (Brandt), elicited a potent positive inotropic effect but without an accompanying chronotropic effect on the isolated cardiac muscles of rat, rabbit, guinea pig and cat. Similarly in dogs and cats in situ, i.p. injections of AP-A increased the contractile force without effect on heart rate or blood pressure. The cardiotonic potency for AP-A was equivalent to that of isoproterenol but much greater than that for ouabain or glucagon on the isolated cardiac muscle. AP-A increased the contractile force (cardiac output) and decreased atrial pressure in dog heart during pentobarbital-induced failure. This inotropic effect was not inhibited by propranolol pretreatment. The Ca++ requirement to restore the contractile force was less in AP-A-treated than in ouabain or isoproterenol-treated tissues. After AP-A treatment, the cardiac contractility was more resistant to hypoxia and to low or high temperature stress than ouabain-treated or control preparations. AP-A at 5 10(-9) M increased the duration of the action potential, its mean rate of rise and conduction in the guinea-pig atria and ventricles. At the maximum effective concentration, AP-A did not inhibit Na+, K+-activated adenosine triphosphatase, phosphodiesterase (high Km and low Km) and cyclic 3',5'-adenosine monophosphate content of guinea-pig heart. AP-A (5 X 10(-8) to 5 X 10(-7) M) neither contracted nor relaxed the isolated vascular smooth muscle. The results suggest that AP-A may be useful in the clinical management of cardiac failure and as an experimental tool to study the pharmacology and physiology of cardiac muscle.
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PMID:A polypeptide (AP-A) from sea anemone (Anthopleura xanthogrammica) with potent positive inotropic action. 1 Apr 26

Mitochondrial calcium uptake, but not binding, like microsomal calcium uptake in failing human hearts, was less than the control values for dog, rabbit, and hamster hearts. Decrease in mitochondrial calcium binding and uptake was observed in genetically myopathic hamsters (BIO 14.6) at early, moderate, and late stages of congestive heart failure. Inhibitors of mitochondrial calcium transport, Dicumarol, dinitrophenol, and sodium azide, were found to produce a rapid fall in contractility of the isolated rat heart. Inability of rat hearts to generate contractile force on perfusion with Na+- or K+-free medium was associated with an increase in mitochondrial calcium uptake. A dramatic increase in mitochondrial calcium uptake was observed on perfusing rat hearts with control medium after CA++-free medium. No change in mitochondrial calcium uptake was noted in acute ischemic dog myocardium or hypoxic rat heart in which contractile force was severely depressed. Both mitochondrial calcium transport and contractility were decreased on perfusing rat hearts with substrate-free medium; however, the change in calcium uptake was secondary to the fall in contractile force. Decrease in pH, ATP:ADP ratio, ATP6AMP ratio, and K+:Na+ ratio were found to reduce the dog heart mitochondrial calcium uptake. It is likely that various factors such as pH, ATP:ADP ration, ATP:AMP ratio, and K+ :Na+ ration, in addition to damage in mitochondrial structure, play an important role in inhibiting mitochondrial calcium transport in failing hearts. The results also suggest that alterations in mitochondrial calcium transport are dependent upon the degree and type of heart failure.
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PMID:Role of mitochondrial calcium transport in failing heart. 5 79

Sarcolemmal Ca++-ATPase, Mg++-ATPase, and (Na+-K+)-ATPase activities were increased in late stages of heart failure in myopathic hamsters (BIO 14.6) without any changes in the adenylate cyclase activity. On the other hand, these hamsters at early and moderate stages of heart failure showed depressions in mitochondrial calcium binding and uptake and microsomal calcium binding. Sarcolemmal (Na+-K+)-ATPase was decreased in failing hearts because of substrate lack, oxygen lack, and perfusion with Ca++-free, Na+-free, or K+-free medium. Both Mg++-ATPase and Ca++-ATPase activities of sarcolemma did not change on perfusing the hearts with substrate-free, hypoxic, Na+-free, or K+-free medium. Adenylate cyclase activity decreased on substrate-free or Ca++-free perfusion. Intracellular calcium overload produced by perfusing the hearts with medium containing calcium after Ca++-free perfusion was associated with decrease in all the sarcolemmal-bound enzyme activities. All types of failing hearts employed in this study showed a dramatic shift in the electrolyte composition. Failure of the cardiac muscle to generate contractile force on treatment with trypsin was associated with defects in the functions of sarcolemma, mitochondria, and sarcoplasmic reticulum, whereas such an effect on treatment with phospholipase C was limited to alterations in the activities of sarcolemma. The data suggest that abnormality at the level of sarcolemma plays an important role in the pathogenesis of heart dysfunction; however, the degree and direction of alterations in the sarcolemmal functions seem to be dependent upon the type of heart failure.
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PMID:Role of sarcolemmal changes in cardiac pathophysiology. 13 Jun 63

The isolated isovolumic rat heart was used as a model of cardiac hypoxia. Force of cardiac contraction and cardiac cyclic nucleotide levels (cyclic GMP and cyclic AMP) were monitored in hearts subjected to hypoxia for 5 min and allowed to recover by reoxygenation. Hearts were obtained from both control animals and animals pretreated with methylprednisolone at 18 hr and 1 hr prior to sacrifice. Myocardial levels of cyclic GMP which were significantly (p less than 0.05) elevated above control during all periods of hypoxia were found to be lower when hearts were pretreated with methylprednisolone prior to hypoxic exposure. Hearts of animals pretreated with methylprednisolone also demonstrated better recovery during reoxygenation than did control hearts. These studies suggest that methylprednisolone may be beneficial in the prevention of myocardial failure following hypoxia via a modulation in myocardial cyclid GMP content.
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PMID:Possible role of cyclic nucleotides in the mechanism of the protective effect of methylprednisolone on the hypoxic rat heart. 21 63

Each of 12 types of glycogen storage disease (GSD O-XI) is delineated by clinical, biochemical and histologic features that allow its identification in future patients. GSD II occurs in 2 forms that are not both encountered in the same family. GSD IIa is the infantile fatal form with cardiomegaly, increased cardiac glycogen concentration and cardiac failure; GSD IIb is the adult form with clinically normal heart and normal cardiac glycogen concentration. Nonetheless, the heart muscle of both forms is equally deficient in acid alpha-glucosidase activity, and this raises questions as to the latter's role in the pathophysiology of GSD II. The appearance of hepatocytes in GSD IIa becomes normal after the administration of alpha-glucosidase. Using electron microscopy of uncultured amniotic fluid cells, the prenatal diagnosis of GSD IIa is feasible within one day after the amniocentesis. GSD VI and IX are instances of benign hepatomegaly except when GSD IX and III occur in the same child; one such patient died suddenly at home. There are 2 modes of inheritance in GSD IX: one (GSD IXa) is autosomal recessive, the other one (GSD IXb) is X-linked recessive. In either form the Km of the remaining liver phosphorylase kinase is normal. Both forms of GSD IX have the normal blood sugar response to glucagon, whereas GSD VI does not. Equally, the glucagon tolerance curve is flat in GSD XI although in vitro activity of glycolytic enzymes is normal. The in vivo administration of glucagon in GSD XI is followed by the normal increase of both urinary 3'5'-AMP and hepatic phosphorylase activity. GSD V may have increased activity of muscle phosphorylase kinase. Deficiencies of debrancher, liver phosphorylase and liver phosphorylase kinase can occur singly or in combination. Before any novel treatment of GSD is initiated, one should obtain tissue for the biochemical determination of the exact type of GSD. This is so because the clinical signs may not indicate the type with the necessary precision, and because some types are compatible with normal life and thus may not require therapy, especially if the latter is unproved and potentially dangerous.
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PMID:Glycogen storage diseases. 78 7

Experimental hyperthyroidism was produced in guinea pigs by daily intraperitoneal injection of l-thyroxine (T4) in various doses (0.7, 0.35, 0.175, and 0.07 mg/kg/day) for 7 days. Controls received solvent only. The following metabolites were determined in heart muscle (freeze-stop technique, enzymatic tests): Pi, adenosine tri-, di-, and monophosphates (ATP, ADP, AMP), creatine phosphate (CP), glucose 6-phosphate (G-6-P), fructose diphosphate (FDP), pyruvate, and lactate. Thyroxine induced a dose-related decrease of CP and a corresponding increase of Pi even in the lowest dose used in this study (0.07 mg/kg) and became more pronounced with increased doses. No remarkable changes of adeninenucleotides (ATP, ADP, AMP) were observed. G-6-P and FDP levels were markedly elevated in all dosages. Besides other possible effects (thyroxine-induced activation and induction of enzymes) the dose-related decrease of CP and increase of Pi may be due to the increasing contractility. In the physiological and pathophysiological range of thyroxine doses (T4 less than 20 mug%) high energy phosphates stores are dose-related decreased but not to a critical level. In the toxic range heart failure as a consequence of a deficit of CP may occur.
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PMID:Dose-relation of thyroxine-induced changes in myocardial energy stores. 121 45

The cardiac in vitro effects of R 80122, a novel phosphodiesterase (PDE) inhibitor, were investigated and compared with those of the reference compound milrinone and of the calcium-sensitizer adibendan. In guinea pig left atria, both milrinone and R 80122 increased contractile force; 10 microM milrinone was equieffective to 1 microM R 80122. The rate of spontaneously beating atria was not altered by R 80122 in the concentration range of 0.01-0.3 microM. Higher concentrations (1-10 microM) led to a statistically insignificant increase of 20%. Milrinone's effect on frequency was more pronounced and amounted to 21% at 10 microM and to 40% at 100 microM. Adibendan increased heart rate (HR) by 10% at a concentration of only 0.03 microM. This effect was not enhanced any further by increasing the concentration. In papillary muscle, the positive inotropic effects of both milrinone and R 80122 were inhibited by carbachol, indicating involvement of cyclic AMP. Further indications for a cyclic AMP-dependent action were obtained by induction of slow action potentials and synergism with isoprenaline. In electrophysiologic measurements, milrinone reduced action potential duration (APD) in a high concentration whereas R 80122 had no effect. Action potential changes elicited by a toxic concentration of ouabain were reduced by R 80122. Relaxation of rat aortic rings contracted by KCl and relaxation of guinea pig aortic rings contracted by norepinephrine (NE) was comparable for both milrinone and R 80122. R 80122 also caused relaxation of canine coronary arteries constricted with prostaglandin F2 alpha (PGF2 alpha) both with and without endothelium. NE-induced contractions in canine gastrosplenic arteries were not affected by R 80122. Cardiac contractility that had been impaired to various degrees by pentobarbital or by aging was restored to control values by both milrinone and R 80122. R 80122 enhanced cardiac contractility at lower concentrations than milrinone with no concomitant increase in frequency or shortening of the action potential, which may be advantageous for treatment of heart failure.
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PMID:In vitro pharmacology of R 80122, a novel phosphodiesterase inhibitor. 128 Jul 31

The effects of 5-hydroxytryptamine (5-HT) on left atrial preparations obtained from 5 patients with terminal heart failure who were undergoing heart transplant surgery were investigated. The preparations were paced under isometric conditions. In the presence of (-)-pindolol 1 mumol/l (to block beta-adrenoceptors) and cocaine 6 mumol/l (to block tissue uptake of 5-HT) 5-HT increased contractile force with a pEC50 of 7.0. The maximum effect of 5-HT amounted to 24.5% of that caused by a maximally effective concentration of (-)-isoprenaline (200 mumol/l) and 25% of that caused by 6.75 mmol/l CaCl2. The effects of 5-HT were competitively antagonised by 3 alpha-tropanyl-1H-indole-3-carboxylate (ICS 205-930) with a pKB of 6.8. The effects of 5-HT on cyclic AMP levels and cyclic AMP-dependent protein kinase activity were also studied using left atrial tissues from one of the patients; 5-HT increased the cyclic AMP content and stimulated the kinase. The results are consistent with the existence of a human left atrial 5-HT receptor which is similar to the recently identified human right atrial 5-HT receptor that resembles the 5-HT4 receptor. The left atrial 5-HT4-like receptor is functional in tissues obtained from patients with terminal heart failure.
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PMID:A 5-HT4-like receptor in human left atrium. 132 Feb 6

Abnormal intracellular calcium ([Ca2+]i) handling appears to be a major cause of both systolic and diastolic dysfunction in animals and human beings with hypertrophy and/or heart failure. We utilized the bioluminescent calcium indicator aequorin to examine the cyclical variations in intracellular calcium levels during isometric contractions. Studies of ventricular muscle from patients with end-stage heart failure exhibited three physiologic findings not seen in preparations taken from normal hearts including: 1) abnormalities in calcium handling; 2) deficient production of cyclic AMP; and 3) a reversed force-frequency relationship. These observations have important implications with regard to the pathogenesis and therapeutics of heart failure in man.
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PMID:Pathophysiology of cardiac hypertrophy and failure of human working myocardium: abnormalities in calcium handling. 132 61

1. In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.
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PMID:Differential inotropic effects of flosequinan in ventricular muscle from normal ferrets versus patients with end-stage heart failure. 132 72


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