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At least 19 recordsLinked to original sources
PubMed1991

Studies on cardiotonic agents. VII. Potent cardiotonic agent KF15232 with myofibrillar Ca2+ sensitizing effect.

A series of novel 4,5-dihydro-5-methyl-6-(2 or 4-substituted 7-quinazolinyl)-3(2H)-pyridazinones was synthesized and examined for cardiotonic activity in anesthetized dogs. The 4-substituted aminoquinazolines generally showed potent and long-lasting inotropic activity. Fall in the activity was observed on the introduction of substituent at the 2-position of the quinazoline ring. The 3-substituted 4 (3H)-quinazolinimines generally exhibited weak activity. Ca2+ sensitizing effect of the 4-substituted amino derivatives was also examined in chemically skinned fiber from papillary muscle of guinea pig. The alkylamino derivatives exhibited small sensitizing effect, while the benzylamino derivatives exhibited large effect. Among them, KF15232 (Ix) was found to have the most potent cardiotonic and Ca2+ sensitizing activities.

Animals↗
PubMed1988

[First-line treatment of cardiac insufficiency: digitalis glycosides, diuretics, vasodilator agents or new cardiotonic agents?].

The advent of vasodilator therapy and new cardiotonic agents has modified the medical treatment of heart failure. First-line treatment is no longer standard; its choice must take into account a number of individual factors such as patient's age, causative cardiopathy, severity of the disease, response to treatment, contra-indications and side-effects of drugs. The aim is to obtain an improvement not only in the patient's comfort but also in long-term prognosis. The prescription of digitalis compounds to heart failure patients with sinus rhythm has been questioned. Alternatives to the conventional therapeutic approach based on cardiac glycosides and diuretics are now available. They include the use at an early stage of vasodilator therapy, and notably angiotensin-converting enzyme inhibitors, in the hope of avoiding gradual reduction of cardiac performance.

Cardiotonic Agents↗
PubMed1989

[Value and limitations of new cardiotonic agents].

New cardiotonic agents are an original approach in the treatment of severe heart failure. They can be classified into two groups: --beta-adrenergic agonists which stimulate beta-adrenergic receptors and, therefore, increase cyclic AMP production and intracellular calcium concentration; --phosphodiesterase inhibitors which block the cyclic AMP intracellular degradation pathway. Rapid tachyphylaxis may occur with beta-adrenergic agonists through a down-regulation phenomenon and, therefore, limits the value of this group to short-term treatment. Several different biochemical compounds are under evaluation in the second group. Short-term effects appear beneficial but cardiac side-effects may occur. The value and indications of these drugs in long-term treatment of chronic congestive heart failure remain to be determined.

Cardiotonic Agents↗
PubMed1985

A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid A new class of A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid pumiliotoxin B (8-hydroxy-8-methyl-6-alkylidene-1-azabicyclo[4.3.0]nonanes).

Pumiliotoxin B (PTX-B, 6-(6',7'-dihydroxy-2',5'-dimethyl-(E)-4'-octenylidene)-8-hydroxy-8 -methyl-1- azabicyclo-[4.3.0] nonane) increases the force of contractures of spontaneously beating guinea pig atrial strips by 3- to 5-fold with half-maximal effects at about 3 microM and increases rates of atrial contractions by 2- to 3-fold with half-maximal effects at about 6 microM. The presence of an axial 7-hydroxy substituent (PTX 339A) decreases the efficacy but not the potency of PTX-B as a positive inotropic agent while having only slight effects on activity as a positive chronotropic agent. The presence of an equatorial 7-hydroxy substituent (PTX 339B) greatly decreases efficacy and potency of PTX-B as a positive chronotropic and inotropic agent. Pumiliotoxin A which lacks the side-chain 7'-hydroxy group of PTX-B causes only a 2-fold increase in force of contracture at 54 microM while having minimal effects on rate. The presence of an axial 7-hydroxy substituent (PTX 323B' and 323B", epimeric at the 6'-hydroxy) markedly enhances positive inotropic and chronotropic effects of PTX-A. Another congener, PTX 251D with a 6-(2'-methylhexylidene) side chain, and a synthetic analogue with a 6-(6'-heptenylidene) side chain are cardiac depressants. Both lack hydroxyl groups in the side chain. The presence of an omega-1 hydroxy group in the side chain of PTX 251D yields an alkaloid (267C) with weak positive inotropic effects and minimal chronotropic effects. The presence of an axial 7-hydroxy group in the indolizidine ring of PTX 251D results in a compound (PTX 267A) with very weak positive inotropic effects while retaining the negative chronotropic effects of PTX 251D. A synthetic analogue with a 6-(7'-hydroxyheptylidene) side chain is a cardiac depressant even though it contains a side-chain hydroxyl corresponding in position to the 7'-hydroxyl of the side chain of PTX-B. The positive chronotropic and inotropic effects of pumiliotoxin B are reversed only by relatively high concentrations of the calcium channel blockers nifedipine and verapamil, suggesting that pumiliotoxin B may owe its cardiotonic activities to effects on internal mobilization of calcium.

Alkaloids↗
PubMed2002

Mechanisms of action of novel cardiotonic agents.

Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca2+ mobilization (upstream mechanism), an increase in Ca2+ binding affinity to troponin C (central mechanism), or facilitation of the process subsequent to Ca2+ binding to troponin C (downstream mechanism). cAMP mediates the regulation induced by Ca2+ mobilizers such as beta-adrenoceptor agonists and selective phosphodiesterase III inhibitors acting through the upstream mechanism. These agents act likewise on the central mechanism to decrease Ca2+ sensitivity of troponin C in association with the cAMP-mediated phosphorylation of troponin I. In addition to such a well-known action of cAMP, recent experimental findings have revealed that Ca2+ sensitizers, such as levosimendan, OR-1896, and UD-CG 212 Cl, require the cAMP-mediated signaling for induction of Ca2+ sensitizing effect. These agents shift the [Ca2+] -force relationship to the left, but their positive inotropic effect (PIE) is inhibited by carbachol, which suppresses selectively the cAMP-mediated PIE. These findings imply that cAMP may play a crucial role in increasing the myofilament Ca2+ sensitivity by cross-talk with the action of individual cardiotonic agents. No clinically available cardiotonic agents act primarily via Ca2+ sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in myofilament Ca2+ sensitivity. Evidence is accumulating that cardiotonic agents with Ca2+ sensitizing action are more effective than agents that act purely via the upstream mechanism in clinical settings. Further clinical trials are required to establish the effectiveness of Ca2+ sensitizers in long-term therapy for congestive heart failure patients.

Animals↗
PubMed1993

A novel class of cardiotonic agents: synthesis and biological evaluation of pyridazino[4,5-b]indoles with cyclic AMP phosphodiesterases inhibiting properties.

Some fused pyridazino[4,5-b]indoles (7) were synthesized. These new compounds present a planar topography and some resemblance to carbazeram, imadozan, and other pyridazino agents with cardiotonic activity. These compounds also possess a complementary effect as inhibitors of platelet aggregation. 6-(3,5-Dimethylpyrazolyl)-1,2,4-triazolo[4,3-b]pyridazino[4, 5-b]indole (7a) has a good profile as an inodilatador with antiaggregate activity due to the inhibition of phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Quantitative structure-activity relationships of cardiotonic agents.

Quantitative structure-activity relationships (QSARs) of different cardiotonic agents are presented. A critical analysis of all QSARs provides a very vivid picture of the mechanisms of varying cardiotonic agents. The cardiotonics can be broadly put into 2 categories: cardiac glycosides and nonglycoside cardiotonics, which include phosphodiesterase of type III (PDE III) inhibitors, sympathomimetic (adrenergic) stimulants, A1-selective adenosine antagonists, Ca2+ channel activators and vasopressin antagonists. For cardiac glycosides, QSARs reveal that the position of carbonyl oxygen in their lactone moiety and shifting of the lactone ring from its original position or its replacement by another group would be crucial for their activity. The carbonyl group or its isostere like CN is indicated to be the sole binding entity and the hydrogen bonding through this group is considered to be the most likely binding force. For nonglycoside cardiotonics that include PDE III inhibitors and A1-selective antagonists, a five-point model has been established for their activity, the salient features of which are: (1) the presence of a strong dipole, (2) an adjacent acidic proton, (3) a methyl-sized lipophilic space, (4) a relatively flat overall topography and (5) a basic or hydrogen-bond acceptor site opposite to the dipole. For Ca2+ channel activators, the importance of steric, electrostatic, lipophilic and hydrogen-bonding properties of molecules is indicated, while for vasopressin antagonists the lipophilic and electronic properties are suggested to be the most important.

Animals↗
PubMed1985

Analysis of the efficacy of the new cardiotonic agent TA-064.

TA-064 is a new cardiotonic agent which is also effective orally, according to investigations conducted in Japan. We analyzed computer-assisted alterations of pressure-volume relationships serially and of indirect myocardial oxygen consumption (MVO2) estimations on line during TA-064 influence in 16 patients with congestive cardiomyopathy: left ventricular function was moderately decreased in seven patients (group A) and drastically decreased in nine (group B). Results showed that TA-064, 8 micrograms/kg/min intravenously, exerted positive inotropic effects in both groups and induced mean maximal delta percentage changes at about 5 minutes of infusion as follows: left ventricular stroke work index +65% and +47%; dP/dtmax +61% and 59%; left ventricular efficiency +62% and 53%; MVO2 +31% and +11% (p less than 0.05). TA-064, 20 mg by mouth induced serum levels (group A = 23.8 +/- 12ng/ml and group B = 26.4 +/- 20 ng/ml) corresponding to the effects with dosages of 1 to 2 ng/kg/min intravenously (p greater than 0.05), thus implying that significant changes in left ventricular function require higher oral dosages. We conclude that TA-064 improves left ventricular function, primarily via a contractility increase, also in group B patients without toxic side effects. On-line indirect MVO2 assessment and analysis of serial pressure-volume relationships helped to provide a more complex definition of the mechanism and efficiency of the cardiotonic agent under study.

Administration, Oral↗
PubMed1985

Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent.

CI-914 is a novel positive inotropic agent whose cardiotonic activity is not due to inhibition of Na+, K+-ATPase or to stimulation of cardiac beta-receptors. CI-914 also has no direct effect on sarcoplasmic reticulum, mitochondria or adenylate cyclase activity. CI-914 does, however, exert a potent inhibitory effect on cardiac phosphodiesterase activity. In evaluating the effect of this agent on the different molecular forms of phosphodiesterase present in cardiac muscle, CI-914 was found to selectively inhibit PDE III, which is a low Km, cAMP-specific form of the enzyme (IC50 = 6.1 microM). This inhibitory effect was found to be competitive with respect to the substrate. Papaverine and theophylline on the other hand were found to inhibit all three forms of phosphodiesterase present in cardiac muscle. The role of phosphodiesterase inhibition in mediating the positive inotropic response to CI-914 is supported by the finding that this agent: (i) significantly elevates cyclic AMP levels in ventricular tissue; (ii) shifts the normal concentration-response to the beta-receptor stimulant isoproterenol to the left: and (iii) restores contractility to K+-depolarized papillary muscles.

Adenosine Triphosphate↗
PubMedDate not supplied

Cardiovascular properties of a new cardiotonic agent, MDL 19205.

The cardiovascular properties of a new cardiotonic agent, MDL 19205, were investigated in anesthetized and conscious dogs and in a dog heart-lung preparation. MDL 19205 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced a dose-related increase in cardiac contractile force lasting up to 1 h. It also produced a relatively minor increase in heart rate and a brief decrease in blood pressure. These effects did not involve beta-adrenergic receptor stimulation, as they were observed in dogs after a myocardial-depressant dose of propranolol. Given orally to conscious dogs, MDL 19205 (1 and 3 mg/kg) produced a dose-related increase in dP/dt without producing a significant alteration in heart rate or blood pressure. When administered to anesthetized dogs by constant intravenous infusion, MDL 19205 (0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and decreases in blood pressure and left atrial pressure, but did not produce a significant change in cardiac output or stroke volume, indicating an enhancement of cardiac pump function. Intravenous MDL 19205 reversed the hemodynamic characteristics of heart failure produced by propranolol in anesthetized dogs. In addition, it reversed the depressant effect of pentobarbital on cardiac function in a dog heart-lung preparation. These studies show that MDL 19205 is a potent, direct-acting cardiotonic agent in animals.

Animals↗
PubMed1987

Cardiotonic agent milrinone stimulates resorption in rodent bone organ culture.

The cardiotonic agent amrinone inhibits bone resorption in vitro. Milrinone, an amrinone analog, is a more potent cardiotonic agent with lower toxicity. In contrast to amrinone, milrinone stimulated resorption in cultures of neonatal mouse calvaria and fetal rat limb bones. Threshold doses were 0.1 microM in calvaria and 0.1 mM in limb bones; maximal stimulation occurred in calvaria at 0.1 mM. Maximal responses to milrinone and parathyroid hormone were comparable. Milrinone concentrations below 0.1 mM did not affect calvarial cyclic AMP. 0.5 microM indomethacin inhibited milrinone effects in calvaria but usually not in limb bones. 3 nM calcitonin inhibited milrinone-stimulated resorption and there was no escape from this inhibition. Structural homology between milrinone and thyroxine has been reported. We find similarities between milrinone and thyroxine actions on bone, because prostaglandin production was crucial for the effects of both agents in calvaria but not in limb bones, and neither agent exhibited escape from calcitonin inhibition.

Animals↗
PubMed2003

Synthesis and pharmacological characterization of functionalized 2-pyridones structurally related to the cardiotonic agent milrinone.

A new class of cardiotonic agents characterized by a 2-pyridone structure was synthesized. Appropriate sym-2-dimethylaminomethylene-1,3-diones reacted with methylcyanoacetate to afford the desired compounds. These derivatives were evaluated for their ability in inducing cardiotonic response on guinea pig isolated myocardial preparations. Compound 8b increased atrial contractility to an extent which is significantly higher than that of milrinone, the parent drug used as a reference compound. The pharmacological characterization and the docking studies performed on 8b highlighted its selective mechanism of action via type 3 PDE (PDE3) inhibition.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat.

Effects of the new cardiotonic and selective beta 1-adrenergic agonist TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, on circulating concentrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg (ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective beta-adrenergic antagonist) and practolol (a selective beta 1-adrenergic antagonist). The non-selective beta-adrenergic agonist isoproterenol and the selective beta 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective beta 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.

Adrenergic beta-Agonists↗
PubMed1982

A small animal model for monitoring inotropic responses to cardiotonic agents.

A method for evaluating potential cardiotonic agents in vivo has been developed in a small laboratory animal. In this study, right ventricular inotropic responses are measured in an anesthetized, closed-chested guinea pig using a pressure-sensitive transducer inserted into the right ventricle of the heart via the right jugular vein. dp/dt is used as an index of ventricular contractility. Agents known to have positive inotropic effects in other models were found to have similar effects using this new method. Some advantages of using such a model include: relatively rapid surgical preparation; use of less costly small animals; and the need for less compound for experimentation.

Animals↗
PubMed1988

The new cardiotonic agent sulmazole is an A1 adenosine receptor antagonist and functionally blocks the inhibitory regulator, Gi.

Although many of the new cardiotonic agents are known to increase cAMP and to inhibit with variable potency a low Km cAMP phosphodiesterase, there is still debate as to the mechanism(s) by which these agents act. In a rat adipocyte membrane model we demonstrate that only approximately 50% of the effect of the new cardiotonic agent sulmazole on cAMP accumulation can be attributed to phosphodiesterase inhibition and that the remaining production of cAMP involves stimulation of adenylate cyclase activity. Two distinct pathways for stimulation of adenylate cyclase are herein reported. Sulmazole, UD-CG 212 CL, enoximone, piroximone, amrinone, and milrinone are all shown to be competitive antagonists of inhibitory A1 adenosine receptors, with EC50 values of 11-909 microM. Elimination of the effects of endogenous adenosine with adenosine deaminase reveals a third distinct mechanism for activation of adenylate cyclase. This mechanism appears to involve Gi, the inhibitory guanine nucleotide-regulatory protein, in that sulmazole attenuates the capacity of GTP to inhibit adenylate cyclase activity, and covalent modification of Gi by pertussis toxin treatment abolishes the capacity of sulmazole to mediate stimulation. Thus, functional blockade of Gi activity is the likely mode of action. Restoration of sulmazole's stimulatory effect on adenylate cyclase activity in pertussis toxin-treated membranes can be accomplished by reconstituting purified preparations of either Gi or mixtures of Gi/Go into treated adipocyte membranes. Of note, this stimulatory effect is completely reversed by inhibitory receptor agonists. Thus, the new cardiotonic agent sulmazole mediates increases in cAMP accumulation by mechanisms other than phosphodiesterase inhibition, including A1 adenosine receptor antagonism and inhibition of Gi function.

Adenylate Cyclase Toxin↗
PubMedDate not supplied

Reduction of adriamycin cardiotoxicity by a new cardiotonic agent.

Recently several non catecholamine, non glycoside cardiotonic drugs have been described. New compounds include amrinone, sulmazole, milrinone and pimobendan. In an attempt to alleviate anthracycline toxicity, we have previously reported that these compounds reduced the negative inotropic effect of adriamycin, 4-epiadriamycin and esorubicin in isolated guinea pig atria. The present study reports the effects of a new cardiotonic agent synthesized and studied by us: 2,3-Dihydro-6- (2,5-dimethoxyphenyl) imidazo [2,1-b]thiazole (VA-5), the most active of a series of 32 compounds with imidazo [2,1-b] thiazole and thiazoline moiety. Exposure for 60 to adriamycin (100 micrograms/ml) of electrically driven isolated guinea pig left atrium, in normodynamic or hypodynamic conditions, caused a depression of contractile force and of maximal rate of contractile force (df/dt). The negative effects of adriamycin are antagonized by VA-5 (100 micrograms/ml).

Animals↗
PubMed1981

Ergometric and hemodynamic studies on a new cardiotonic agent AR-L 115 BS.

The cardiotonic agent, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazol[4,5-b]pyridine (AR-L 115BS), increases cardiac contractility and lowers cardiac pre- and afterload. These properties were shown to favourably influence hemodynamics at rest and under exercise in patients with coronary heart disease and angina pectoris. Although it reduces pre- and afterload, unlike isosorbide dinitrate it does not improve exercise tolerance in symptom limited ergometry. There was, however, no worsening of exercise tolerance. It appears that the decrease in oxygen consumption due to a decreased pre- and afterload is compensated for by an increase in oxygen requirement during contractility.

Angina Pectoris↗
PubMed1991

Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent.

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.

Adenosine Triphosphate↗