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 cardiovascular properties of MS-857 [4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ], a novel cardiotonic agent, were investigated in anesthetized and conscious dogs. MS-857 (1-100 micrograms/kg i.v.) produced a significant and dose-dependent increase in cardiac contractility with relatively small changes in heart rate and blood pressure. This indicates a sizable separation between positive inotropic and other effects of MS-857. Oral administration of MS-857 to conscious dogs (0.1-1 mg/kg) also produced a sustained increase in cardiac contractility in a dose-dependent manner. The total duration of action was longer than 7 h at a dose of 1 mg/kg p.o. There occurred no arrhythmias and no changes in animal behavior. After chronic oral administration, MS-857 completely retained its activities, indicating the lack of tachyphylaxis. In the acute heart failure models induced by either propranolol or pentobarbital, MS-857 reversed the cardiac depressant effects of these drugs. Moreover, MS-857 also significantly improved the pentobarbital-induced heart failure in the heart-lung preparation. MS-857 did not inhibit the Na+, K+-ATPase, but inhibited the phosphodiesterase (PDE) III selectively, both of which were prepared from the dog ventricular muscle. Thus, MS-857 can be characterized as a potent nonsympathomimetic, nonglycoside cardiotonic drug with a selective inhibitory activity on PDE III. The cardiovascular properties revealed by this study strongly suggest that MS-857 will exert a beneficial effect in the treatment of congestive heart failure.
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PMID:Cardiovascular properties of MS-857, a new and potent cardiotonic agent, on normal and failing hearts. 246 58

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28-29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70-80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as "chronotropic incompetence") found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiac adaptations to endurance training in rats with a chronic myocardial infarction. 252 73

Rats treated with the alkaloid monocrotaline developed right ventricular hypertrophy with a left:right ventricle weight ratio of 1.35 +/- 0.10 (mean +/- s.e.m., n = 25) compared with 3.83 +/- 0.40 (n = 14) in diet-matched controls (P less than 0.001). Urine volume and sodium content were reduced and body water increased consistent with heart failure. In 10 out of 26 treated rats pleural, pericardial or peritoneal effusions were present. Urine norepinephrine content was significantly raised (P less than 0.02) but epinephrine was unchanged. Plasma norepinephrine levels were raised though not significantly. Myocytes isolated from the right ventricle had a reduced myosin Ca2+-activated ATPase (P less than 0.05) activity and a shift towards slower V2 and V3 myosin isoforms. There was no decrease in maximum contraction amplitude with calcium or isoproterenol in either left or right ventricular cells of treated rats. Right ventricular cells from treated rats showed a reduced rate of contraction in maximum isoproterenol (P less than 0.05) and a significant rightward shift in PD2 (P less than 0.05) representing a two-fold increase in EC50 for isoproterenol compared with right ventricular cells from control animals. There was no shift in EC50 for isoproterenol in left ventricle cells. In parallel experiments, myocytes isolated from both ventricles of rats treated with isoproterenol for one week showed a rightward shift of more than 50-fold in the isoproterenol concentration-response curve and a depressed response to maximum isoproterenol. In the rat monocrotaline model of right-sided cardiac hypertrophy and failure, changes in sensitivity to beta-adrenoceptor agonists are slight, and present only in the right ventricle. The lack of change in the left ventricle seems to suggest that this functional desensitisation is not a consequence of raised circulating catecholamines.
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PMID:Isoproterenol sensitivity of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and heart failure. 255 26

Certain forms of cardiac failure appear to be associated with a decrease in the Ca++ sensitivity of the contractile structures, possibly due to troponin I phosphorylation. Interference of cardiotonic drugs with myofibrillar Ca++ activation instead of enhancement of Ca++ influx may therefore provide a more causal therapeutic concept in the treatment of cardiac insufficiency. APP 201-533 (3-Amino-6-methyl-5-phenyl-2(1H)-pyridinone) (the structure of which is shown below) is a novel cardiotonic agent acting neither via beta adrenoceptor stimulation nor inhibition of Na+/K+ ATPase. In the 100 microM concentration range, it increases the Ca++ sensitivity and the Ca++ affinity of functionally isolated cardiac contractile structures. This coincides with an inhibitory effect on the cAMP-dependent protein kinase from rat liver. A possible relation with the regulation of troponin I phosphorylation is discussed.
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PMID:Myofibrillar Ca++ activation and heart failure--Ca++ sensitization by the cardiotonic agent APP 201-533. 281 53

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.
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PMID:Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents. 283 2

New method for measuring plasma and urinary Na-K-ATPase inhibitor (ATPI) was developed. Plasma and urine were extracted with reversed phase cartridge column and sample was reconstituted by assay buffer. Na-K-ATPase inhibitory activity of sample was monitored by continuously recording the absorbance of NADH at 340 nm, which coupled to the dephosphorylation of ATP. Ouabain was used for standards of Na-K-ATPase inhibition and this standard showed good linearity ranged 5-100 nmol/ml. Using this new method, P-ATPI and U-ATPI were quantitatively evaluated and paradoxical Na-K-ATPase stimulating phenomenon which observed in conventional method (Hamlyn et al) was diminished. Adopting of this new method for measuring plasma(P-) and urinary(U-)ATPI, and radioimmunoassay for P- and U-digitalis-like substance(DLS)--using crossreactivity to anti digoxin antibody--, these substances were estimated in patients with essential hypertension (EHT), chronic heart failure(CHF), primary and idiopathic hyperaldosteronism(HA), hyperthyroidism(BA) and chronic renal failure(CRF). In EHT, U-DLS, P-DLS, U-ATPI, P-ATPI were significantly higher than those of control(C). In CHF and BA, U-DLS and -ATPI were also significantly higher than those of C. In HA, U-ATPI, DLS distributed in wide range, and a few patients showed high levels of U-DLS and -ATPI. In CRF, P-DLS and -ATPI levels were significantly higher than those of C in prehemodialytic state but P-ATPI was significantly decreased after hemodialysis. From these results it is suggested that 1) DLS and ATPI might contribute to the etiology of hypertension. 2) Volume expansion stimulates the secretion of DLS and ATPI. 3) Stimulatory effect of volume expansion and inhibitory effect of mineralocorticoid may be responsible for wide distribution of these factors in HA. 4) DLS and ATPI are not the same substances.
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PMID:[Endogenous digitalis-like substance and Na-K-ATPase inhibitor in cardiovascular and renal disease]. 283 14

To elucidate further the possible role of atrial natriuretic peptide (ANP) and hypothetical natriuretic hormone (NH) in volume and BP regulation in chronic renal failure (CRF) we measured plasma ANP, digitalis-like substances (DLS) and Na+-K+-ATPase activity (using 86Rb influx into RBC) in 9 patients with CRF before and after hemodialysis. Volume expansion between consecutive dialyses led in all patients to the elevation of plasma ANP (83.4 +/- 14.2 pmol/l) reaching in some overhydrated subjects and/or patients with concomitant cardiac insufficiency concentration greater than 150 pmol/l. Reduced 86Rb influx into RBC before hemodialysis (37.7 +/- 4.9% of controls) was accompanied by higher DLS concentrations (201 +/- 32 pmol/l). Ultrafiltration during hemodialysis with ECFV reduction lowered both ANP and DLS concentrations to 28.1 +/- 9.4 pmol/l and to 151 +/- 23 pmol/l, respectively, and abolished partly the inhibition of Na+-K+-ATPase activity (64.9 +/- 7.6% of controls). These changes corresponded to the degree of ECFV alteration. Our results suggest that both natriuretic principles are activated during ECFV expansion in CRF, probably as a corrective mechanism, with a tendency to normalize when ECFV is reduced during hemodialysis.
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PMID:Atrial natriuretic peptide concentration and natriuretic hormone activity in plasma of patients with chronic renal failure. 285 Sep 86

The epidemiology and etiology, pathophysiology, diagnosis, and treatment of congestive heart failure (CHF) are reviewed. CHF affects as many as 4 million Americans and is one of the most prevalent causes of death in hospitalized patients. Major risk factors for developing CHF include advanced age, male sex, hypertension, coronary artery disease, smoking, hypercholesterolemia, diabetes mellitus, and rheumatic heart disease. Heart failure results from decreased intrinsic myocardial contractility caused by one or more of three changes: (1) altered adrenergic nervous system function, (2) impaired delivery of calcium to contractile elements in the heart, and (3) reduced myosin-ATPase activity in the myocardium. The disease is progressive, and no intervention has yet been found to stop it effectively. CHF is diagnosed based on subjective signs and symptoms and objective assessment using auscultation, ECG, chest roentgenogram, laboratory tests, and noninvasive and invasive tests. Treatment of CHF begins with restriction of physical activity and sodium intake. Pharmacologic interventions start with either digitalis glycosides or thiazide diuretics; both may be used concomitantly as the disease progresses. Current studies are focusing on the use of angiotensin-converting enzyme inhibitors as first-line agents for CHF. When CHF worsens, loop diuretics are substituted for or added to the thiazide diuretics, and vasodilators are added to reduce the workload on the heart. Other inotropic agents, including the new bipyridine derivatives, may also be used. In patients not responding to these and other aggressive therapeutic interventions, cardiac transplantation is the only option. Despite advances in management of CHF, little improvement in overall survival has been demonstrated, and no intervention has stopped or reversed the progression of CHF.
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PMID:Current concepts in clinical therapeutics: congestive heart failure. 287 92

The oxidative phosphorylation as well as calcium transporting properties of heart mitochondria and calcium transport activities of the fragments of the sarcoplasmic reticulum (microsomes) were studied during the life span of cardiomyopathic hamsters (UM-X7.1). Control healthy hamsters of the same age group were used for comparison. No changes in the oxidative phosphorylation ability of cardiomyopathic mitochondria were seen at early and moderate stages of heart failure; however, at severe stages, mitochondrial respiratory functions, but not the ADP:0 ratio, were impaired. Both creatine phosphate and ATP contents were decreased without any significant changes in the ATPase activities of myofibrils from the failing hearts. Heart mitochondria from cardiomyopathic animals at severe stages of failure exhibited less calcium binding and uptake activities in comparison with the control values whereas no changes in the mitochondrial calcium binding and uptake were seen in cardiomyopathic hamsters which showed no clinical signs of heart failure. Although mitochondrial calcium binding in cardiomyopathic hearts at early and moderate stages of failure was decreased, mitochondrial calcium uptake was not significantly different from the control. Microsomal calcium binding activity, unlike calcium uptake activity, was decreased in the hearts of cardiomyopathic hamsters without any signs of heart failure. Both calcium binding and calcium uptake activities of microsomes from animals with early, moderate and severe heart failure were less in comparison with the control values but were not associated with any changes in the Ca2+-stimulated ATPase activity. These results suggest that changes in the process of mitochondrial energy production and mitochondrial Ca2+-transport may be secondary to other factors whereas alterations in the sarcoplasmic reticular Ca2+-transport may lead to the development of heart failure in the cardiomyopathic hamsters.
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PMID:Impairment of mitochondrial and sarcoplasmic reticular functions during the development of heart failure in cardiomyopathic (UM-X7.1) hamsters. 294 28

The activity of the azide-insensitive Ca2+-dependent ATPase (highly enriched in myofibrillar ATPase activity) was studied in specimens of both right and left atria which were taken from patients with ischemic and/or valvular heart disease during coronary by pass and/or valvular substitution. A significantly lower enzymatic activity was found in atrial specimens from patients with left ventricular heart failure in comparison to the atrial fragments obtained from the patients with normal heart function. Such an inhibition reflected a significant increase in the Km of the enzyme for ATP and was associated with a concomitant reduction in Vmax, both more evident in the left atrial fragments. Moreover, tissue homogenates of atrial specimens from failing hearts exhibited a lower protein SH group content when compared to the atrial homogenates from the heart with normal left ventricular heart function.
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PMID:Analysis of azide-insensitive Ca2+-dependent ATPase activity in atrial specimens from patients with coronary or valvular heart disease. 295 56


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