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

The isolated perfused working rat heart preparation has been used to study the effects of respiratory acidosis on myocardial metabolism and contractilly. Hearts were perfused with 5 mM glucose and 10(-2) U/ml of insulin in order to enhance metabolsim of glucose relative to that of fatty acids. After perfusion with Krebs bicarbonate medium at pH 6.6, hearts rapidly ceased performing external work and peak left ventricular pressure fell by 75% after 5 minutes. Oxygen consumption, rate of ATP generation and overall glycolytic flux also declined rapidly. After about 2 minutes of perfusion, the fall of glycolytic flux showed a partial reversal, which was largely accounted for by increased lactate production, so that glucose oxidation decreased further. The reversal of glycoltic flux could be accounted for by partial release of H+ inhibition of phospho-fructokinase by increased tissue levels of adenosine 5'-diphosphate (ADP), adenosine monophosphate (AMP) and P1 and decreased levels of adenosine triphosphate (ATP) and creatine phosphate. The increased proportion of glucose uptake converted to lactate together with an increase of the tissue lactate/pyruvate ratio could be accounted for by inhibition of the malate-aspartate cycle combined with tissue hypoxia. Lactate accumulated in the tissue as a result of a decreased permeability of the plasma membrane to lactate. Decreased oxygen delivery to the myocardium was caused by secondary constriction of the coronary vessels. In further experiments, the coronary flow was regulated by an external pump which delivered fluid at a controlled rate into the aortic cannula above the coronary arteries, and the degree of tissue hypoxia was monitored by measuring changes of pyridine nucleotide reduction state by surface fluorescence techniques. The effects of acidosis uncomplicated by possible hypoxia were compared directly with those produced by ischemic hypoxia. The effects of acidosis under these conditions were similar to those described above, and to those produced by ischemia. From these and other data it is concluded that the effects of ischemia are caused by a lowering of the intracellular pH, which decreases the rate of energy production relative to the rate of energy demand. However, it is suggested that the primary cause of the decreased peak systolic pressure with either acidosis or ischemia is not a result of a defect of energy metabolism, but is due to alteration of the calcium cycle of the heart. Possible causes of irreversible heart failure after prolonged ischemia are discussed.
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PMID:Contribution of tissue acidosis to ischemic injury in the perfused rat heart. 0 93

To evaluate the effects of a new phosphodiesterase inhibitor, E-1020 (1, 2-dihydro-6-methyl-2-oxo-5-(imidazo [1, 2-a] pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate), on cardiovascular hemodynamics in acute heart failure, we compared its effects with those of dopamine on experimentally produced acute mitral regurgitation in dogs. After the production of mitral regurgitation by transmyocardial chordal sectioning and obtaining a stable state, dopamine (5 micrograms/kg/min) was infused until the peak positive dP/dt (peak (+) dP/dt) increased to about 50% of the predopamine value. After complete recovery, E-1020 (30 micrograms/kg) was infused over 5 min and the data were obtained 10 min later. Both drugs equally increased peak (+) dP/dt, decreased systemic vascular resistance, and increased cardiac output. Left ventricular (LV) end-diastolic pressure, LV end-diastolic segment length (EDL), and mean left atrial (LA) pressure decreased with both drugs. The changes in EDL and mean LA pressure were larger with E-1020 than with dopamine (p less than .01 and p less than .05). Although mean inferior vena caval blood flow volume (mIVCF) increased and mean inferior vena caval pressure decreased with both drugs, the increment of mIVCF was smaller with E-1020 (p less than .001). Thus, E-1020 had not only a positive inotropic effect but also a vasodilatory action both on resistance vessels and on capacitance vessels.
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PMID:Hemodynamic efficacy of E-1020 in comparison with dopamine on acute mitral regurgitation in anesthetized dogs. 174 68

1. In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.
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PMID:Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure. 267 15

The cardiovascular effects of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new nonglycoside, noncatechol cardiotonic agent, were investigated in dogs. In anesthetized dogs, E-1020 (10-100 micrograms/kg i.v.) dose-relatedly increased cardiac contractility (LV dP/dtmax), enhanced cardiac index and decreased systemic vascular resistance accompanying relatively small reduction in mean aortic pressure and a mild increase in heart rate. Coronary and femoral arterial blood flow were increased by either systemic intravenous or topical administration of E-1020. The degree of increase in myocardial oxygen consumption was only slight (10% at 30 micrograms/kg i.v.). The inotropic effect of E-1020 was not markedly affected by pretreatment with beta-adrenoceptor blockade, reserpine or other cardiotonic agents such as dobutamine or ouabain. In two experimental heart failure models induced by an excessive dose of propranolol or by coronary occlusion following volume-loading, E-1020 (30 micrograms/kg i.v.) rapidly reversed the cardiac depression. In chronically instrumented conscious dogs, E-1020 (30-100 micrograms/kg i.v. or 0.3-10 mg/kg p.o.) produced dose-dependent increases in LV dP/dtmax with minor increases in heart rate. E-1020 did not exacerbate arrhythmias of several experimental models in anesthetized dogs even at high dose of 100 micrograms/kg i.v. These results indicate that E-1020 is an intravenously and orally effective cardiotonic agent with vasodilating property, and that it may be beneficial in the treatment of acute and chronic congestive heart failure.
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PMID:Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 2nd communication: studies in dogs. 271 42

AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%; p less than 0.02) and heart rate (+29 beats/min; p less than 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%; p less than 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p less than 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%; p less than 0.01), and LV end-diastolic pressure (-9.1 mm Hg; p less than 0.01) all dropped significantly, while cardiac output increased slightly; PRA did not rise significantly. After beta-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure; this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.
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PMID:Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure. 617 37

AR-L 115 BS is a new active noncatecholamine, non glycoside phenyl-imidazo-pyridine derivative inotropic agent. It has a strong inotropic effect in experimental animals. Its effectiveness and associated adverse effects were tested in 23 patients with severe heart failure (NYHA class III to IV). Intravenous administration of AR-L 115 BS at 1.4 mg/min for 6 hours in 11 patients increased cardiac index from 2.07 +/- 0.13 to 2.99 +/- 0.203 l/min/m2 (p less than 0.005) while pulmonary wedge pressure decreased from 23 +/- 2 to 13 +/- 2 mm Hg (p less than 0.005). Systemic vascular resistance fell from 1759 +/- 137 to 1263 +/- 71 dynes.sec. cm-5 (p less than 0.005). Heart rate and blood pressure remained unchanged. Following oral administration (450 mg) in 12 other patients, cardiac performance was similarly improved. Hemodynamic changes were apparent as early as 60 min after administration, and the duration of action ranged from 5 to 7 hours. No serious arrhythmias or side effects occurred. It could therefore be useful in the management of congestive heart failure.
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PMID:Acute clinical benefits of a new inotropic agent AR-L 115 BS after i.v. and oral administration. 651 93

By means of right heart catheterisation and thermodilution the hemodynamic response to two different doses of 2-[2-methoxy-4-(methylsulfinyl) phenyl]-1H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS, Vardax) (1.5 mg or 0.7 mg/min) was determined in 10 hospitalized patients with congestive cardiac insufficiency. It was found that sulmazole has a marked positive inotropic effect, increasing the cardiac output and stroke work index and decreasing the peripheral systemic and pulmonary vascular resistance, almost without altering the blood pressure values; furthermore, it reduces the right atrial pressure, the pulmonary capillary pressure and the pulmonary arterial pressure. Tolerance of sulmazole was excellent; no tachyphylaxis nor rebound reactions were observed during the 36-h period of medication.
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PMID:Hemodynamic activity of different doses of sulmazole by infusion. 668 55

The imidazol-pyridine ARL-115 BS (sulmazol) has both positive inotropic and vasodilatory effects. Its hemodynamic effects were studied in 13 patients with shock after myocardial infarction. All patients required dobutamine or dopamine, while nine were treated with intra-aortic balloon counterpulsation. After a loading dose of 50 mg, sulmazol was administered at 50 mg/h followed by 100 mg/h during 30 or 60 minutes. At the highest dose of sulmazol, cardiac output increased from 4.3 +/- 1.1 to 4.9 +/- 1.5 1/min; systemic vascular resistance decreased from 1405 +/- 473 to 1228 +/- 439 dynes . s . cm-5, while pulmonary capillary wedge pressure decreased from 22 +/- 6 to 17 +/- 7 mm Hg. No changes occurred in heart rate or mean arterial pressure. The effect of sulmazol was greater than the effect of an increased dosage of dobutamine in five patients in whom this was studied. Episodes of supraventricular tachycardia occurred in two patients. No other side effects were observed. The hemodynamic changes caused by sulmazol favour its use in the treatment of acute cardiac failure, and cardiogenic shock.
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PMID:Hemodynamic effects of sulmazol (ARL-115 BS), a new vasodilator and positive inotropic agent, in patients with cardiogenic shock. 683 91

The hemodynamic effect of 2-[(2-methoxy-4-methylsulfinyl)phenyl]- 1H-imidazo[4,5-b]pyridine (AR-L 115 BS), a new positive-inotropic substance, was studied in 10 Patients with chronic congestive heart failure after i.v. infusion of increasing does of 1.8 mg/min, 2.7 mg/min and 3.6 mg/min over a period of 40 min each. Prior to each infusion an i.v. bolus of 16 mg was given. The hemodynamic changes were measured by means of a Swan Ganz balloon tipped catheter and by echocardiography. The heart rate remained unchanged whereas systolic, diastolic and mean arterial pressures fell slightly by about 5%. The mean and diastolic pulmonary pressures decreased by 30% with a concomitant increase in cardiac output of 15%. The total peripheral and pulmonary resistance was reduced by 20% and 40%, respectively. The echocardiographically measured fraction of systolic fiber shortening of the left ventricle was increased by 15%. In parallel the ratio of PEP/LVET decreased by 10%. While the increase of the infusion dose from 1.8 mg/min to 2.7 mg/min was followed by an increase in the hemodynamic changes, no further alterations were observed after the dose was increased from 2.7 mg/min to 3.6 mg/min despite a marked increase in the blood level of AR-L 115 BS. The effect was still present 75 min after the infusion had been stopped. The blood level at that time had returned to the level achieved with the dose of 2.7 mg/min. The results are consistent with findings in animals which have shown that AR-L 115 BS exerts not only a positive-inotropic action on the heart, but also exhibits a vasodilating effect, predominantly in the capacitance vessels. As the substance can also be administered orally it could prove to be a useful agent in the management of severe cases of heart failure.
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PMID:The acute effect of a new positive inotropic agent (AR-L 115 BS) on cardiac hemodynamics and contractility in patients with severe chronic congestive heart failure. 719 35

Invasive cardiac measurements were performed at rest and during exercise after i.v. infection of 0.7 mg/kg 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) in 10 patients with heart failure in NYHA class II and III of various origins. At rest AR-L 115 BS increased the cardiac index by 0.74 l/min/m2 (p less than 0.01) and the heart rate by 10 beats/min (p less than 0.01). Mean arterial pressure and pressures in the pulmonary artery and in the pulmonary capillary bed were not changed significantly. Stroke work index remained unchanged. At the highest comparable workload AR-L 115 BS reduced the pulmonary capillary wedge pressure by 7 mm Hg (p less than 0.001) and the mean pulmonary arterial pressure by 8 mm Hg (p less than 0.001). The other parameters measured did not change significantly. In most of the patients there was a reduction in the pulmonary capillary pressure in parallel with a slight increase in the stroke work index, indicating an improvement in left ventricular pump function. Four patients reported bright vision immediately after injection which lasted for several hours in 1 patient and for about 5 min in the others. One patient developed muscle tremor which lasted for several hours. The results suggest that AR-L 115 BS exerts a vasodilating action on the capacitance vessels and a positive-inotropic effect on the heart.
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PMID:Study of the acute effect of AR-L 115 BS, a new positive-inotropic agent in patients with exercise-induced heart failure. 719 37


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