Dog Heart-lung Preparation Research Articles

Improvement of cardiac performance by pimobendan, a new cardiotonic drug, in the experimental failing dog heart.

The cardiotonic effect of pimobendan was studied in 6 dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. Pimobendan in doses of 1-10 mg improved cardiac function in a dose-dependent manner and at 10 mg improved it beyond the control. These doses of pimobendan, however, produced neither a significant increase in heart rate nor arrhythmias. The results indicate that the drug may be of use in the treatment of heart failure.

Improvement of Drug-Induced Cardiac Failure by NKH477, a Novel Forskolin Derivative, in the Dog Heart-Lung Preparation

The efficacy of NKH477, a novel water-soluble forskolin derivative, in improving cardiac failure was assessed in dog heart-lung preparations. Cardiac functions depressed by pentobarbital, propranolol or verapamil so that cardiac output had been reduced by about 40-50% of the respective control were all improved by NKH477 (10-100 μg) in a dose-dependent manner. With 100 /μg NKH477, almost complete restoration of cardiac performance was attained in the respective cardiac failures. In the combination of NKH477 with ouabain (30 μg), 30 μg of NKH477 completely restored the cardiac function depressed by pentobarbital, associated with a slight but not significant increase in heart rate. No arrhythmias were induced by any of the NKH477 doses used in the experiments. These results suggest that NKH477 should be subjected to clinical trials in the treatment of cardiac failure.

Improvement of Drug-Induced Cardiac Failure by NKH477, a Novel Forskolin Derivative, in the Dog Heart-Lung Preparation.

The efficacy of NKH477, a novel water-soluble forskolin derivative, in improving cardiac failure was assessed in dog heart-lung preparations. Cardiac functions depressed by pentobarbital, propranolol or verapamil so that cardiac output had been reduced by about 40-50% of the respective control were all improved by NKH477 (10-100 micrograms) in a dose-dependent manner. With 100 micrograms NKH477, almost complete restoration of cardiac performance was attained in the respective cardiac failures. In the combination of NKH477 with ouabain (30 micrograms), 30 micrograms of NKH477 completely restored the cardiac function depressed by pentobarbital, associated with a slight but not significant increase in heart rate. No arrhythmias were induced by any of the NKH477 doses used in the experiments. These results suggest that NKH477 should be subjected to clinical trials in the treatment of cardiac failure.

Improved heart failure protection by FK664, a novel positive inotropic agent, in dog heart-lung preparations

The effects of FK664, a novel positive inotropic agent, and enoximone on pentobarbital-induced heart failure were compared in dog heart-lung preparations. Both FK664 and enoximone improved the cardiac function curve in a dose-dependent manner and restored it to the control level at drug concentrations of 1μg/ml and 10μg/ml, respectively. Therefore, the cardiotonic potency of FK664 appears to be 10 times that of enoximone. These agents were almost equal in force-rate separation of cardiac effect. Neither of the agents produced arrhythmia at any dose tested. These results suggest that FK664 may be a potent cardiotonic agent for the treatment of heart failure.

2(1H)-Quinolinones with cardiac stimulant activity. 2. Synthesis and biological activities of 6-(N-linked, five-membered heteroaryl) derivatives

A series of 6-(N-linked, five-membered heteroaryl)-2(1H)-quinolinone derivatives was synthesized and evaluated for cardiotonic activity. Most compounds were prepared by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide or by condensation of a 2-amino-5-heteroarylbenzaldehyde or -acetophenone derivative with the ylide derived from triethyl phosphonoacetate. In anesthetized dogs, 6-imidazol-1-yl-8-methyl-2(1H)-quinolinone (3; 25 micrograms/kg) produced a greater increase in cardiac contractility (percentage increase in dP/dt max) than alternative 6-(five-membered heteroaryl)-substituted analogues (4-8). Introduction of 4-methyl (10) or 2,4-dimethyl (13) substituents into the imidazole ring of 3 produced a marked increase in inotropic activity, and these compounds were some 10 and 5 times more potent than milrinone. Most of these quinolinones also displayed positive inotropic effects (decrease in QA interval) in conscious dogs after oral administration (0.0625-1 mg/kg) and in many cases (3, 5-7, 9, 11, 13, 16) there was little difference in activities at both the 1- and 3-h time points. Compound 13 (62.5, 125, 250 micrograms/kg po) demonstrated dose-related cardiac stimulant activity which, in contrast to milrinone, was maintained over the whole 7-h test period. No changes in heart rate were detected at any dose level and compounds 3, 9, 10, and 13 also displayed high selectivity for the stimulation of cardiac contractile force rather than heart rate in the Starling dog heart-lung preparation. Increases in dP/dt max of approximately 50% were accompanied by heart rate changes of less than 10 beats/minute. Physicochemical measurements gave a log P of 1.64 for 13 with pKa values of 7.13 +/- 0.04 and 11.5 +/- 0.2 for the imidazole and quinolinone moieties, respectively. X-ray structural analysis of 13 showed the imidazole and quinolinone rings at 52 degrees to one another in close agreement with the minimum-energy conformation (30 degrees) suggested by PCILO calculations. 6-(2,4-Dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolinone (13, UK-61,260) is currently undergoing phase II clinical evaluation in congestive heart failure patients.

Interaction of BAY K-8644 with effects of digoxin in the dog heart-lung preparation

Concentration-dependent effects of BAY K-8644, a dihydropyridine calcium channel agonist, on heart rate (HR), left atrial pressure (LAP) and maximal rate of left intraventricular pressure rise (+dP/dt max) were compared with those of isoproterenol and digoxin in dog heart-lung preparations during exposure to 0.8 vol% halothane. All there agents reduced LAP to nearly equal levels at maximally effective concentrations. Maximal increases in +dP/dt max induced by BAY k-8644 and digoxin were of similar magnitude (35 and 31%, respectively), and both agents increased HR slightly. Isoproterenol elevated both +dp/dt max and HR more than twice as much as the other agents. At a concentration which produced only small changes by itself, BAY K-8644 markedly increased the effects of digoxin on LAP and +dP/dt max. Furthermore, the same concentration of BAY K-8644 significantly reduced toxic effects of digoxin (arrhythmogenesis, elevation of LAP, reduction in systemic output). These data indicate that in the isolated blood-perfused heart digoxin's positive inotropic action may be enhanced by an appropriate concentration of BAY K-8644, while adverse effects are diminished.

Myocardial recovery from the cardiac depressant effects of enflurane and halothane

Recovery from the cardiac depressant effects of enflurane and halothane was examined in the dog heart-lung preparation (HLP) and in right ventricular muscle solated from guinea pig hearts. In the HLP, recovery was studied under two conditions: (1) After a two-hour exposure to anesthetic concentrations increasing from 0.36 to 1.2 MAC, and (2) after a one-hour exposure to a single concentration that raised the left atrial pressure (LAP) to 9 to 10 mmHg. Under either condition, +dP/dt max was significantly less depressed with enflurane and returned to preanesthetic control levels, while recovery with halothane remained significantly below control. Following the longer exposure, recovery of the LAP and left ventricular function curves (LVFC) was significantly less with halothane; however, this difference was not observed after the shorter exposure period. In electrically paced, isometrically contracting right ventricular strips exposed for one hour to 2.25 vol% enflurane (a concentration that reduced contractility by 45%), force development returned within 60 minutes to values above preanesthetic control values. After an identical depression for one hour with halothane (0.80 vol%), force development recovered to values less than those observed following enflurane. These data indicate that the recovery from anesthetic-induced negative inotropic effects in isolated cardiac preparations is better with enflurane than halothane.

Improvement of Pentobarbital-lnduced Heart Failure by MCI-154, a Novel and Potent Cardiotonic Agent, in the Dog Heart-Lung Preparation

The efficacy of MCI-154, a new pyridazinone cardiotonic agent, in improving heart failure was assessed in dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. MCI-154 in doses of 10–100 μg improved the cardiac function curve and restored it to the control level at 100 μg. At this dose, MCI-1 54 neither produced an increase in heart rate beyond the control value nor induced arrhythmias. The effects of MCI-154 were not affected by atenolol, a cardioselective β1-blocker. These results indicate that MCI-154 would be of potential use in the treatment of heart failure.

Improvement of pentobarbital-induced heart failure by MCI-154, a novel and potent cardiotonic agent, in the dog heart-lung preparation.

The efficacy of MCI-154, a new pyridazinone cardiotonic agent, in improving heart failure was assessed in dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. MCI-154 in doses of 10-100 micrograms improved the cardiac function curve and restored it to the control level at 100 micrograms. At this dose, MCI-154 neither produced an increase in heart rate beyond the control value nor induced arrhythmias. The effects of MCI-154 were not affected by atenolol, a cardioselective beta 1-blocker. These results indicate that MCI-154 would be of potential use in the treatment of heart failure.

Comparison of cardiac effects of enflurane, isoflurane, and halothane in the dog heart-lung preparation

Minimum alveolar concentration (MAC) was determined in intact dogs (N = 10 for each anesthetic) to be 2.12 ± 0.04 vol% for enflurane (ENF), 1.28 ± 0.04 vol% for isoflurane (ISO), and 0.94 ± 0.03 vol% for halothane (HAL). Then, the direct cardiac effects of these three anesthetics were studied at 0.36, 0.6, 1.0, and 1.2 MAC in the dog heart-lung preparation (HLP): an in situ whole heart preparation devoid of major extracardiac influences and reflex control. All three agents produced concentration-dependent decreases in heart rate (HR) that became significantly different from control at 0.6 MAC. HAL and ISO reduced +dP/dt max by the same degree at all MAC levels, becoming statistically significant at 0.6 MAC, while a significant reduction in +dP/dt max for ENF occurred first at 1.0 MAC. Marked increases in left atrial pressure (LAP) were observed at 1.0 MAC for all anesthetics and the first significant depression of systemic output (SO) occurred at 1.0 MAC. Each agent produced significant shifts of the left ventricular function curves (LVFC) to the right with each consecutive MAC fraction. Marked reductions in the slope of the LVFC were first observed at 1.0 MAC, and this change in slope was more pronounced with ENF. At 1.2 MAC, ENF seemed to produce a more severe cardiodepression than HAL or ISO, as suggested by a greater incidence of cardiac failure; however, this was not statistically significant. In general, the data suggest that at MAC fractions up to 0.6, ENF is less cardiodepressant than ISO or HAL, but that ENF has a tendency to be more depressant than HAL or ISO at concentrations higher than 1.0 MAC.

Pharmacology of enoximone

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and hot mediated by stimulation of adrenergic receptors, histaminic receptors, cholinerqic receptors, Ca ++-adenosine triphosphatase, Mg ++-adenosine triphosphatase, adenyl cyclase or inhibition of Na +, K +-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect. Specific inhibition of type IV phosphodiesterase appears to have a role in the inotropic and vasodilator actions of enoximone. These properties suggest a useful role for enoximone in the therapy of patients with congestive heart failure.

Isosorbide dinitrate blocks thromboxane synthesis caused by CO2 in dog heart-lung preparation.

Effects of isosorbide dinitrate (ISDN) on coronary flow and arterial prostaglandin (PG) concentrations were investigated, using dog heart-lung preparations. Two kinds of gases (low and high CO2 gases) were used for the artificial respiration. Low CO2 gas contained 55% O2 and 0.2% CO2, whereas high CO2 gas contained 55% O2 and 8% CO2. Administration of ISDN into a blood reservoir at high CO2 caused an increase in coronary sinus blood flow, which was blocked by indomethacin, but not at low CO2. In the absence of ISDN, the arterial concentration of thromboxane (TX) B2 was larger at high CO2 than at low CO2. ISDN attenuated such an increase in TXB2 concentration caused by CO2. The arterial concentration of 6-keto PGF1 alpha was altered by neither CO2 nor ISDN, but slightly increased with time. Indomethacin lowered the concentrations of 6-keto PGF1 alpha and TXB2. These results suggested that the arterial CO2 tension enhanced the TXA2 synthesis and that ISDN inhibited such a relation between CO2 and TXA2 synthesis. Additionally, the vasodilatory effects of PGI2 was enhanced by elevating the arterial CO2 tension. Thus, the increase in canine coronary flow at high CO2 in the presence of ISDN may be related to the inhibitory effects of ISDN on the TXA2 synthesis enhanced by the high arterial CO2 tension and the facilitatory effects of CO2 on the PGI2-induced vasodilation.

Graphic analysis of serotonin effects in dog heart-lung preparation.

Graphical analysis of the effects of serotonin on cardiac function and pulmonary circulation was performed, using the dog heart-lung preparation. The equilibrium points, at which the cardiac output (CO)-curve and venous return (VR)-curve cross in the right atrial pressure (RAP) or left atrial pressure (LAP)-CO relations, were directly recorded on two X-Y recorders. CO- and VR-curves were directly depicted by changing the blood level in the reservoir, and by inducing ventricular fibrillation and simultaneously occluding pulmonary arterial trunk, respectively. Single injections of serotonin, 300 micrograms, into the right or left atrium, induced a negative inotropic response. Low rate (less than 30 micrograms/min) of infusion of serotonin had no effect on the CO-curve or on the slope-gradient of VR-curve in the LAP-CO relation. At a rate of 60 or 120 micrograms/min, however, the CO-curve was moved downwards to the right, indicating a negative inotropic effect. Pulmonary mean filling pressure increased and the slope-gradient of pulmonary VR-curve decreased, indicating an increased resistance to venous return from the pulmonary circulation. Pulmonary arterial pressure was markedly elevated. In order to obtain the capacitance ratio between the extracorporeal circuit and the pulmonary circulation, a shift of blood volume to the pulmonary circulation was induced by elevating the aortic pressure, which also decreased the slope-gradient. The calculated capacitance ratio became greater during the infusion of serotonin, indicating that the capacitance in the pulmonary circulation was lowered. It is likely that serotonin has contractile effects on the pulmonary arterial and venous vascular beds, elevating the pulmonary filling pressure and resistance to venous return.

Isosorbide Dinitrate Blocks Thromboxane Synthesis Caused by CO2 in Dog Heart-Lung Preparation

Effects of isosorbide dinitrate (ISDN) on coronary flow and arterial prostaglandin (PG) concentrations were investigated, using dog heart-lung preparations. Two kinds of gases (low and high CO2 gases) were used for the artificial respiration. Low CO2 gas contained 55% O2 and 0.2% CO2. whereas high CO2 gas contained 55% O2 and 8% CO2. Administration of ISDN into a blood reservoir at high CO2 caused an increase in coronary sinus blood flow, which was blocked by indomethacin. but not at low CO2. In the absence of ISDN, the arterial concentration of thromboxane (TX) B2 was larger at high CO2 than at low CO2. ISDN attenuated such an increase in TXB2 concentration caused by CO2. The arterial concentration of 6-keto PGF1α was altered by neither CO2 nor ISPN, but slightly increased with time. Indomethacin lowered the concentrations of 6-keto PGF1α and TXB2. These results suggested that the arterial CO2 tension enhanced the TXA2 synthesis and that ISDN inhibited such a relation between CO2 and TXA2 synthesis. Additionally, the vasodilatory effects of PGI2 was enhanced by elevating the arterial CO2 tension. Thus, the increase in canine coronary flow at high CO2 in the presence of ISDN may be related to the inhibitory effects of ISDN on the TXA2 synthesis enhanced by the high arterial CO2 tension and the facilitatory effects of CO2 on the PGI2-induced vasodilation.

The effects of milrinone (Win 47203) on the coronary blood flow and oxygen consumption of the dog heart-lung preparation

Milrinone is a new bipyridine-positive inotropic agent that is closely related to amrinone. In the nonfailing heart, coronary blood flow was increased and coronary bed resistance was decreased by milrinone, most probably by a direct action of milrinone on the coronary vasculature. Oxygen consumption was increased at the lower workloads. In the failing heart milrinone (0.1 to 0.5 mg/L of blood) increased cardiac output and coronary blood flow and reduced coronary vascular resistance. With the 0.1 mg dose oxygen consumption was reduced, especially at the high workloads, and was not significantly changed at the low work levels. With higher doses of milrinone oxygen consumption of the heart was not changed significantly while external work was increased. These data show that milrinone can increase the work of the heart with a decrease or no significant change in oxygen consumption of the isolated failing heart. The use of this drug in heart failure accompanied by restricted blood flow may thus be indicated.

Improvement by denopamine (TA-064) of pentobarbital-induced cardiac failure in the dog heart-lung preparation.

The efficacy of denopamine, an orally active beta 1-adrenoceptor agonist, in improving cardiac failure was assessed in dog heart-lung preparations. Cardiac functions depressed by pentobarbital (118 +/- 28 mg; mean value +/- SD) such that cardiac output and maximum rate of rise of left ventricular pressure (LV dP/dt max) had been reduced by about 35% and 26% of the respective controls were improved by denopamine (10-300 micrograms) in a dose-dependent manner. With 100 micrograms denopamine, almost complete restoration of cardiac performance was attained, associated with a slight increase in heart rate. No arrhythmias were induced by these doses of denopamine. The results warrant clinical trials of denopamine in the treatment of cardiac failure.

Coronary flow in heart-lung preparation affected by cardiopulmonary nerves and arterial PCO2.

Studies on coronary vasodilator drugs utilizing heart-lung preparations (HLP) have been disturbed by a spontaneous gradual increase in coronary blood flow. With the purpose of finding out what would cause the gradual increase, the time course of coronary sinus blood flow (CSBF) was investigated in 20 dog HLPs under four experimental conditions, according to whether cardiopulmonary nerves (CPN) were severed or not and whether CO2 content in the inspiratory gas was high (95% O2-5% CO2) or low (50% O2-50% room air). The gradual increase in CSBF was observed, accompanied by a significant increase in 6-ketoprostaglandin F1 alpha in the arterial blood, only when CPN were intact and, simultaneously, inspiratory CO2 was high. Nevertheless, the hemodynamic parameters, except CSBF, were almost similar under four conditions. These results suggested that CSBF in HLP could be affected via a synthesis and/or a release of prostaglandin I2 by the interaction of CPN and arterial PCO2.

Amelioration of heart failure by MDL 17043 and MDL 19205, novel positive inotropic drugs, in dog heart-lung preparations.

The efficacies of MDL 17043 and MDL 19205 in ameliorating heart failure were assessed in dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. Six preparations were used for each drug. Both drugs in doses of 1-30 mumol similarly improved cardiac function in a dose-dependent manner and at 30 mumol improved it beyond control values. AV conduction impaired by pentobarbital was restored by 30 mumol of the 2 drugs. In these doses, however, neither of the drugs produced a significant increase in heart rate or arrhythmias. These results indicate that the 2 drugs would be of use in the treatment of heart failure.

Enhanced Responsiveness of the Coronary Blood Vessel of the Dog Heart-Lung Preparation to PGI2 after Chronic Chemical Sympathectomy

Chronic chemical denervation of the sympathetic nervous system with 6-OH dopamine resulted in an augmentation of the coronary blood flow (CBF) increase inherent in the canine heart-lung preparation, but not in an augmented accumulation of 6-keto PGF1α in the circulating blood. In denervated HLP, 6-keto PGF1α was lower and the vasodilator response to PGF2 larger at the start of the experiments. It was concluded that exaggerated increase in CBF was due to a potentiation of the vasodilator response to PGI2.

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.