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PubMed1992

Perioperative experience with amrinone.

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.

Amrinone↗
PubMed1991

Stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures.

The stability of amrinone and digoxin, procainamide hydrochloride, propranolol hydrochloride, sodium bicarbonate, potassium chloride, or verapamil hydrochloride in intravenous admixtures was studied. Admixtures of amrinone and digoxin were studied at one concentration. Amrinone admixtures with propranolol hydrochloride, sodium bicarbonate, potassium chloride, and verapamil hydrochloride were studied at two concentrations. In general, 0.45% sodium chloride injection was used as the diluent; 5% dextrose injection was also used for the procainamide hydrochloride experiments. Duplicate solutions of each test admixture and single-drug control admixture were prepared and stored for four hours at 22-23 degrees C under fluorescent light. Samples were analyzed by visual inspection, tested for pH, and assayed by high-performance liquid chromatography. Admixtures containing amrinone 1.25 or 2.5 mg/mL (as the lactate salt) and sodium bicarbonate 37.5 mg/mL precipitated immediately or within 10 minutes. No changes in pH or visual appearance were noted for amrinone admixtures with procainamide hydrochloride, digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Appreciable degradation of both amrinone and procainamide was observed after four hours when the two were mixed in 5% dextrose. No degradation of amrinone or procainamide was seen when the 5% dextrose was replaced by 0.45% sodium chloride. Amrinone and sodium bicarbonate were incompatible in intravenous admixtures. Amrinone was compatible with digoxin, propranolol hydrochloride, potassium chloride, and verapamil hydrochloride. Amrinone and procainamide were compatible in 0.45% sodium chloride injection but not in 5% dextrose injection.

Amrinone↗
PubMedDate not supplied

In vitro electrophysiologic properties of amrinone in mammalian cardiac tissue.

We studied the actions of amrinone on transmembrane electrical activity in isolated normal and physiologically compromised mammalian cardiac Purkinje and ventricular tissues. No arrhythmogenic effects of amrinone were identified in canine Purkinje tissue superfused with concentrations of 18.7 and 187 micrograms/ml (10(-4) and 10(-3) M) or in feline papillary tissue at concentrations of 18.7 and 56.1 micrograms/ml (10(-4) and 3 X 10(-4)M). In K+-depolarized canine Purkinje tissue, amrinone at 100 micrograms/ml (5.3 X 10(-4) M) failed to restore excitability; however, in norepinephrine-activated, K+-depolarized Purkinje tissue, amrinone significantly increased slow potential upstroke velocity and action potential amplitude and duration at doses ranging from 10 to 300 micrograms/ml. In K+-depolarized canine trabecula carneae, amrinone initiated slow potentials in the absence of norepinephrine and produced dose-dependent increases in slow potential upstroke velocity and in action potential amplitude and duration over a dose range of 30-300 micrograms/ml. Amrinone at 100 micrograms/ml did not influence transmembrane electrical activity of Purkinje tissue with tetracaine-depressed Na+-channel function. Amrinone did not produce oscillatory afterpotentials, influence ouabain-induced afterpotentials, or alter overdrive-induced depolarization. Amrinone caused no distinctly arrhythmia-producing effects in a heterogeneous population of depolarized canine Purkinje tissues removed from canine myocardial infarction, although small changes were observed in some tissues exhibiting slow channel action potentials. These experiments show that amrinone did not influence either Na+-dependent inward currents or Na+-K+ exchange mechanisms. Instead, amrinone facilitated slow channel action potentials in cardiac tissue and thereby could alter cardiac contractility, as well as conduction within reentry circuits in hearts which possess appropriate pathophysiologic substrates.

Action Potentials↗
PubMed1993

The effects of amrinone versus dobutamine on myocardial mechanics and energetics after hypothermic global ischemia.

The effects on the postischemic myocardium of amrinone and dobutamine were studied in canine hearts that underwent 90 minutes of hypothermic (10 degrees C) arrested ischemia. In an isolated heart preparation cross-circulated by a support dog, left ventricular pressure-volume loops were collected under a constant afterload based on a mock circulatory system and a range of preload conditions controlled by a computerized servo volume pump. Dobutamine (0, 5, 10, 15 micrograms/kg per minute) and amrinone (0, 0.75, 1.5, 3.0 mg/kg) were tested in this order based on the weights of the support dogs in eight experiments. Changes in intrinsic myocardial contractility were analyzed as percent increases in the preload recruitable stroke work area from baselines. Dobutamine exhibited significant dose-related increases in the preload recruitable stroke work area. Amrinone did not produce significant increases in preload recruitable stroke work area at 0.75 mg/kg; amrinone's inotropic effect was equivalent to dobutamine, 5 micrograms/kg per minute at 1.5 mg/kg, and at the maximum dose (3.0 mg/kg) it was equivalent to dobutamine, 10 micrograms/kg per minute. The myocardial energetic efficiency was determined from the analysis of the myocardial oxygen consumption-pressure volume area relationship. The y intercept represents the basal metabolic oxygen requirement of the unloaded beating heart, and the slope is inversely proportional to the rate of energy conversion for increasing loading conditions. Dobutamine significantly increased the y intercepts, but it had no effects on the slopes. These changes demonstrate reduced myocardial efficiencies that are consistent with previous reports. Amrinone (0.75 and 1.50 mg/kg) did not result in change of the y intercepts and the slopes of myocardial oxygen consumption-pressure-volume area relationship from baseline conditions. The y intercept was increased with amrinone (3.0 mg/kg), although still not significantly higher than baseline and not to the extents of the dobutamine group. Dobutamine did not have any primary effect on coronary resistance, while amrinone significantly reduced coronary resistance in all loading conditions at 1.5 and 3.0 mg/kg. This study demonstrates that the inotropic effects of amrinone tested under this constant afterload preparation were lower than those of dobutamine. Amrinone has a superior profile of myocardial efficiency on the postischemic myocardium since it does not produce the oxygen-wasting effects of the traditional inotropic agents such as the beta agonists. This benefit, together with amrinone's coronary dilating effects, critically improves the supply/demand ratio that may be of importance in certain clinical situations.

Amrinone↗
PubMed1997

Comparative effects of dobutamine and amrinone on coronary blood flow in patients with idiopathic dilated cardiomyopathy.

Although amrinone has favorable hemodynamic effects in patients with congestive heart failure, little is known about its effects on coronary blood flow (CBF). We compared the effects of intravenous low-dose dobutamine and amrinone on CBF in 10 patients with dilated cardiomyopathy using a Doppler guidewire. We infused dobutamine at a dose of 5 and 10 microg/kg/min for 5 min. After the end of each stage, coronary flow velocity (CFV) and coronary arterial diameter (CAD) in the proximal left anterior descending coronary artery, and hemodynamic variables were obtained. After the CFV and hemodynamics returned to baseline, we infused 1 mg/kg of amrinone over 5 min, and obtained these variables at 5 and 10 min after the cessation of the infusion. CAD did not increase with dobutamine, but significantly increased after amrinone (% increase: 10 +/- 7%; P < 0.001 vs. baseline). CFV progressively increased with dobutamine (5 microg/kg/min: 21 +/- 26%; P < 0.05 vs. baseline; 10 microg/kg/min: 53 +/- 42%; P < 0.005 vs. baseline and 5 microg/kg/min), but slightly decreased after amrinone (-4 +/- 17%; P = not significant vs. baseline). CBF increased during dobutamine (5 microg/kg/min: 25 +/- 29%; P < 0.05; 10 microg/kg/min: 66 +/- 55%; P < 0.005) and after amrinone (19 +/- 22%; P < 0.05) compared to that at baseline. Although there was a significant correlation between the percent increase in CFV and that in dP/dt during dobutamine infusion (r = 0.82, P < 0.001), this correlation was not observed after amrinone (r = 0.23). In conclusion, although both agents significantly increased CBF in patients with dilated cardiomyopathy, they do so by different mechanisms. Amrinone mainly increases CBF by causing dilatation of epicardial coronary arteries. These results suggest that amrinone has beneficial effects on coronary flow dynamics in dilated cardiomyopathy.

Adult↗
PubMed1986

Relative contribution of inotropic and vasodilator effects to amrinone-induced hemodynamic improvement in congestive heart failure.

The relative contribution of inotropic and vasodilator effect to amrinone-induced hemodynamic improvement in congestive heart failure (CHF) is unknown. In 9 patients with CHF, the effects of amrinone and nitroprusside on hemodynamic and radionuclide measurements were compared to determine whether reduced afterload accounts for the amrinone-induced decrease in left ventricular end-systolic volume. In each patient, the end-systolic pressure-volume relation was derived using nitroprusside. After terminating nitroprusside treatment, intravenous amrinone (3 mg/kg) caused end-systolic volume to decrease from 148 +/- 32 ml/m2 (mean +/- standard deviation) to 133 +/- 32 ml/m2 (p less than 0.05), causing an increase in cardiac index from 1.9 +/- 0.8 to 2.7 +/- 0.8 liters/min/m2 (p less than 0.001). Arterial end-systolic pressure decreased in all patients during amrinone administration, from 96 +/- 22 to 84 +/- 19 mm Hg (p less than 0.005), as did systemic vascular resistance. Nitroprusside doses needed to match the decrease in LV end-systolic volume induced by amrinone caused significantly greater decreases in arterial end-systolic pressure than did amrinone (p less than 0.01). The amrinone-induced decrease in end-systolic volume exceeded that predicted for a pure vasodilator based on arterial end-systolic pressure and the nitroprusside-derived pressure-volume relation in 6 patients. In 3 patients, the decrease in end-systolic volume did not exceed that expected for a pure vasodilator. In conclusion, after amrinone treatment, afterload reduction occurs in all patients with severe CHF and is the sole effect in some.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparison of intravenous amrinone and dobutamine in congestive heart failure due to idiopathic dilated cardiomyopathy.

A prospective randomized study was performed in 46 consecutive patients with refractory congestive heart failure (CHF) due to idiopathic dilated cardiomyopathy to compare the hemodynamic responses to 48-hour infusions of amrinone and dobutamine. Both drugs substantially reduced pulmonary arterial wedge pressure, right atrial pressure and systemic vascular resistance and increased cardiac index. Amrinone caused a greater decrease in right atrial pressure than dobutamine (p less than 0.02) and had a positive chronotropic effect not observed with dobutamine (p less than 0.01). The increase in heart rate produced by amrinone correlated inversely with the changes in right atrial and pulmonary arterial wedge pressures, suggesting a baroreceptor response to reduced preload. Dobutamine produced a larger increase in stroke volume index than amrinone (p less than 0.01). Ninety-one percent of patients receiving amrinone and only 65% receiving dobutamine had reduction of greater than or equal to 30% in pulmonary arterial wedge pressure (p less than 0.05). Cardiac index increased greater than or equal to 30% in similar numbers of patients given amrinone (74%) and dobutamine (65%). Negative fluid balance was recorded in all patients receiving amrinone and in 78% of patients receiving dobutamine (p less than 0.05). Target hemodynamic criteria were achieved in 83% of patients receiving 10 micrograms/kg/min of amrinone. The effective maintenance dose of dobutamine was extremely variable. No clinically important adverse effects were observed with either drug regimen. Both amrinone and dobutamine are effective and safe agents for short-term parenteral therapy of patients with dilated cardiomyopathy in severe CHF that is unresponsive to oral medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1980

Differential effects of amrinone on contractility and taurine influx in rat and guinea pig hearts.

Amrinone (5-amino-3,4'-bipyridin-6(IH)-one) is a non-glycoside, non-catecholamine, positive inotropic agent with an unknown mechanism of action. In the Langendorff-perfused isolated guinea pig heart, we found that amrinone produced a maximum increase in contractile force of 33% at a concentration of 10 micrograms/ml (10.7 x 10(-5) M), without change in heart rate. Maximum response occurred within 2 min of initiating perfusion, and increased contractility persisted for several minutes of drug-free washout. Amrinone neither alleviated nor aggravated spontaneous arrhythmias. At the time of maximum inotropic response, amrinone produced no change in cyclic AMP levels. In contrast to the guinea pig, the Langendorff-perfused isolated rat heart responded with a decreased contractility when perfused with amrinone. Furthermore, whereas amrinone stimulated the influx of taurine in guinea pig hearts, taurine influx remained unaltered in rat hearts. This is the first case of stimulated taurine influx not being associated with an increase in cAMP concentrations. In the guinea pig heart, amrinone increased markedly the half life of exchange of intracellular calcium. It has been suggested that amrinone is positively inotropic because of a direct action on the contractile proteins. On the basis of our observations, we think it more likely to be due to the alterations in calcium flux caused by amrinone.

Aminopyridines↗
PubMed1992

Amrinone and dobutamine as primary treatment of low cardiac output syndrome following coronary artery surgery: a comparison of their effects on hemodynamics and outcome.

This study was undertaken in order to compare the effectiveness of amrinone and dobutamine as primary treatment of a low cardiac output (CO) after coronary artery bypass graft (CABG) surgery. Thirty patients with preoperative left ventricular dysfunction participated in this open-label randomized study. Patients were included if they failed to separate from cardiopulmonary bypass (CPB) without inotropic support or if they had a cardiac index (CI) less than 2.4 L/min/m2 after CPB regardless of the blood pressure, in the presence of adequate filling pressures. The treatment objectives were to separate from CPB and achieve a CI > or = 2.4 L/min/m2 and a mean arterial pressure > or = 70 mmHg. Patients treated with amrinone received 0.75 mg/kg followed by 10 micrograms/kg/min; when the objectives were not achieved within five minutes, another 0.75 mg/kg was given. Patients treated with dobutamine received an initial infusion of 5 micrograms/kg/min increased stepwise to 15 micrograms/kg/min if necessary. Eleven of 15 amrinone versus 6 of 15 dobutamine patients achieved the predefined treatment objectives with the test drug alone (P = NS). Comparisons of hemodynamics in patients treated solely with amrinone (n = 7) or dobutamine (n = 6) after CPB showed no significant differences between the treatment groups. The incidence of myocardial ischemia as detected by Holter monitor was 36% with amrinone and 33% with dobutamine. Two patients suffered ventricular fibrillation and two had significant supraventricular tachyarrhythmias (heart rate > 130/min) during treatment with dobutamine alone, whereas no significant arrhythmias occurred in the amrinone group (P = NS). Six dobutamine patients (40%) had postoperative myocardial infarction (MI) as opposed to none among the amrinone patients (P = 0.017). These results indicate that amrinone compares favorably with dobutamine as a primary treatment of low CO after CABG. Further study in a larger number of patients will be required in order to determine if the lower incidence of MI in the amrinone group was due to the treatment drug.

Amrinone↗
PubMed2002

Effects of amrinone on hepatic ischemia-reperfusion injury in rats.

BACKGROUND/AIMS: The present study was designed to investigate the effect of amrinone, a phosphodiesterase III inhibitor, on hepatic ischemia-reperfusion injury in rats. METHODS: Amrinone was infused at a rate of 20 or 100 microg/kg/min, and 60-min partial ischemia was induced. The effects of amrinone on hemodynamic status, hepatic tissue cyclic adenosine 5'-monophosphate (cAMP), hepatic tissue blood flow, platelet aggregation and plasma levels of transaminase were examined. The expression of intercellular adhesion molecule-1 (ICAM-1) and myeloperoxidase activity were analyzed and histological examination was performed in the injured liver. The cumulative survival rates for 14 days were also examined. RESULTS: Hemodynamic status was not affected by amrinone. The levels of cAMP during reperfusion were significantly higher in rats with amrinone. Hepatic tissue blood flow during reperfusion was increased and platelet aggregation was inhibited by amrinone. The expression of ICAM-1 mRNA and protein in the injured liver was suppressed in rats with amrinone. The levels of transaminase, necrotic changes and myeloperoxidase activity were suppressed after reperfusion and higher survival was achieved in the rats treated with amrinone. CONCLUSIONS: Amrinone protected against ischemia-reperfusion injury of the liver in the present model.

Alanine Transaminase↗
PubMed1996

Amrinone stimulation test: ability to predict improvement in left ventricular ejection fraction after coronary bypass surgery in patients with poor baseline left ventricular function.

OBJECTIVES: This study sought to determine whether the response to amrinone in patients with severe baseline left ventricular dysfunction can predict improvement in left ventricular ejection fraction after coronary artery bypass graft surgery. BACKGROUND: Previous studies have suggested that the inotropic response to dobutamine can identify viable myocardium in the setting of chronic coronary disease and left ventricular dysfunction. However, increased oxygen demand stimulated by dobutamine can lead to superimposition of ischemia on the hibernating state, potentially confounding interpretation of results. Amrinone is an inotropic agent that does not critically augment myocardial oxygen demand and may be useful for identification of hibernating myocardium in the chronically ischemic state. METHODS: Forty-four consecutive patients with coronary artery disease and left ventricular ejection fraction < 40% referred for coronary artery bypass graft surgery underwent amrinone stimulation (1 mg/kg body weight). Left ventricular ejection fraction was determined before amrinone stimulation, 20 min after infusion and 21 days after bypass surgery. RESULTS: Baseline ejection fraction was 28 +/- 7% (mean +/- SD). Ejection fraction increased to 35 +/- 5% after amrinone stimulation (p < 0.0001) and to 33 +/- 6% after bypass surgery (p < 0.0001). Postbypass ejection fraction was significantly correlated with postamrinone ejection fraction (r = 0.65, p < 0.0001). Furthermore, the change in ejection fraction from baseline to after bypass surgery was highly correlated with the change in ejection fraction after amrinone stimulation (r = 0.75, p < 0.0001). Of 13 patients with an increase in ejection fraction > or = 10% after amrinone, all 13 had an increase of at least 8% and 11 (85%) of 13 had an increase > or = 10% after bypass surgery. In contrast, of 31 patients with an increase in ejection fraction < 10% after amrinone, only 2 (6%) had an increase > or = 10% (p < 0.0001) and 28 (90%) of 31 had an increase < 5% after bypass surgery. CONCLUSIONS: Augmentation of myocardial contraction by amrinone in patients with chronic coronary artery disease and severe baseline left ventricular dysfunction predicts improvement in left ventricular ejection fraction after coronary artery bypass graft surgery.

Aged↗
PubMed1996

Endothelium-dependent relaxation of rat thoracic aorta by amrinone-induced nitric oxide release.

To determine whether amrinone and its induced increase of cyclic AMP releases nitric oxide and enhances endothelium-dependent vascular relaxation, we studied nitric oxide production and vascular relaxation of rat thoracic aorta on treatment with amrinone and forskolin, an activator of adenylate cyclase. When 20 microM amrinone was applied to ring segments of aorta previously contracted with phenylephrine, relaxation was greater in segments with endothelium than in those without (% relaxation 94 +/- 4 vs 37 +/- 7%, P < 0.01). However, a higher concentration of amrinone (> 50 microM) induced the same degree of relaxation in ring segments with or without endothelium, probably due to its direct effect on vascular smooth muscle. The maximal relaxant concentration (100 microM) of amrinone induced an increase (2.5 fold) in cyclic GMP in ring segments. Forskolin also induced concentration-dependent relaxation, but removal of the endothelium attenuated the relaxation induced by forskolin about seven-fold. NG-nitro L-arginine reversed the relaxation induced by amrinone or forskolin in ring segments with, but not without, endothelium. Nitric oxide production in ring segments of aorta, following application of amrinone or forskolin, was detected by nitric oxide-selective electrode and electron paramagnetic resonance spin trapping methods. Pre-treatment with NG-nitro L-arginine or removal of the endothelium suppressed nitric oxide production by amrinone or forskolin. These data showed that amrinone enhances the release of nitric oxide from rat aortic endothelial cells, and induces endothelium-derived relaxing factor/nitric oxide-mediated vasodilation.

Amrinone↗
PubMed1991

Pharmacokinetics of amrinone during cardiac surgery.

Amrinone is a nonglycosidic noncatecholamine with both vasodilator and positive inotropic effects that may be administered to patients undergoing cardiac surgery. As an initial step toward elucidating the optimal dosage of amrinone for cardiac surgical patients we studied the pharmacokinetics of amrinone during and after cardiac surgery requiring cardiopulmonary bypass. The study population comprised 35 adult patients, each receiving a single dose of amrinone (0.75, 1.5, 2.0, or 2.5 mg/kg) administered into the venous reservoir near the end of cardiopulmonary bypass. Additionally, 15 of the 35 patients also received intravenous infusions of either 5 or 10 micrograms.kg-1.min-1. Arterial blood was sampled over the next 22 h, and plasma concentrations of amrinone were determined by high-performance liquid chromatography. Protein binding of amrinone, assayed by equilibrium dialysis, was 21.6 +/- 2.5%. The decay of amrinone concentrations in plasma over time was fit to a biexponential equation by nonlinear least-squares regression. The manufacturer's recommended dose of 0.75 mg/kg followed by an infusion of 10 micrograms.kg-1.min-1 was inadequate to maintain the plasma concentration within the therapeutic range based on the pharmacodynamics of amrinone in patients with chronic congestive heart failure. This was due to significant redistribution of amrinone in the body after the loading dose. To maintain a therapeutic plasma concentration of 1.5-2.0 micrograms/ml, a larger loading dose or a supplemental loading dose as well as a continuous infusion is required.

Amrinone↗
PubMedDate not supplied

Positive inotropic action of amrinone: effect of elevated external Ca2+.

To investigate the positive inotropic effect of amrinone under conditions of maximal contractile stimulation, we compared cumulative amrinone one-half log dose-response curves (dose range, 3.1 X 10(-5)-3.1 X 10(-3) M amrinone) of isolated cat right ventricular papillary muscle in normal (2.5 mM) and high (7.5 mM) calcium Krebs solution. In 2.5 mM calcium, amrinone induced significant (p less than 0.01) dose-dependent increases in peak developed tension (T), maximum dT/dt, and maximum relaxation rate (-dT/dt), which were accompanied by small but significant decreases in time-to-peak tension (TTP). At 10(-3) M, changes in T, dT/dt, and TTP were 61.9 (2.7 g/mm2), 98.1 (33.2 g/s/mm2), and -13.1% (-26 ms), respectively. In 7.5 mM calcium, the increases in T, dT/dt, and -dT/dt, and the reduction of TTP, were markedly less at each concentration. At 10(-3) M amrinone, T and dT/dt increased significantly by 16.7 (1.3 g/mm2) and 23.5% (17.4 g/s/mm2), respectively, with no change in TTP. The amrinone-induced reductions in one-half relaxation time and twitch duration persisted in high calcium and were similar in magnitude to those in 2.5 mM calcium. The substantial reduction of amrinone's positive inotropic effect in high Ca2+ suggests that a major part of the drug's action involves an augmentation of contractile Ca2+. An amrinone-induced effect on rate of Ca2+ delivery to the contractile apparatus or on myofilament Ca2+ sensitivity would be consistent with a persistent inotropic action in high Ca2+. Contractile changes induced by amrinone are discussed in relation to a possible effect on intracellular cyclic AMP levels.

Aminopyridines↗
PubMed1987

The cardiotonic agent amrinone does not increase anatomic infarct size.

The effect of the positive inotropic agent amrinone on anatomic infarct size induced by coronary artery occlusion and reperfusion in dogs is unknown, although previous studies have shown that amrinone increases indices of myocardial ischemia during very brief coronary artery occlusions. Thus, this study was performed to determine if amrinone changes anatomic infarct size and improves hemodynamics induced by 3 h of coronary occlusion and 3 h of reperfusion in anesthetized, open-chest dogs. Amrinone (1-mg/kg bolus followed by 6 mg/kg/h) or an equivalent volume of saline was administered intravenously for 3 h beginning 30 min postocclusion. The area at risk was 19.7 +/- 2.6% in the control group (n = 9) and 20.2 +/- 1.8% in the amrinone-treated group (n = 9; p = NS). The amount of the area at risk that developed infarction was 60.6 +/- 6.1% in the control group and 54.6 +/- 5.6% in the amrinone-treated group (p = NS). Pretreatment left ventricular end-diastolic pressure increased from 11.4 +/- 1.8 to 20.1 +/- 3.0 mm Hg (p less than 0.05) in the control group and from 10.8 +/- 1.3 to 17.3 +/- 1.3 mm Hg (p less than 0.05) in the amrinone-treated group following coronary artery occlusion. During coronary occlusion, amrinone administration significantly increased left ventricular maximum +dP/dt [+483 +/- 85 vs. -11 +/- 53 mm Hg/s (p less than 0.01) in amrinone vs. control group, respectively] and heart rate (+27 +/- 6 vs. -4 +/- 2 beats/min; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone↗
PubMed1988

Inotropic interactions of dichloroacetate with amrinone and ouabain in isolated hearts from endotoxin-shocked rats.

The inotropic effects of ouabain and amrinone singly and in combination with dichloroacetate (DCA) were assessed using isolated working perfused hearts from endotoxin-shocked (LD50/6 h) rats, with glucose and free fatty acids as substrates. Amrinone (2.7 X 10(-4) M) and ouabain (10(-5) M) alone improved myocardial mechanical performance from 25 to 75%, depending on the preload. Amrinone was more effective than ouabain at all left atrial filling pressures tested. DCA enhanced the inotropic effect of both compounds, improving myocardial work greater than 65% in combination with ouabain (at low filling pressures) to 125% with amrinone (at high filling pressures). Glucose oxidation rose two- to threefold when DCA was present with either drug. Ouabain was without effect on pyruvate dehydrogenase (PDH) activity; however, when present with DCA, PDH activity increased fourfold. Amrinone alone augmented PDH activity 2.5 times as compared with controls, and 4.5 times when combined with DCA. All three compounds individually elevated myocardial ATP levels, but in contrast to the inotropic effects, when used in combination caused no further increase in ATP. Myocardial cyclic AMP (cyclic AMP) levels were augmented five times control values in the presence of amrinone. The simultaneous presence of DCA and amrinone did not further augment the myocardial concentration of cAMP. DCA alone enhanced the myocardial oxidation of glucose in isolated myocardial cells from endotoxin-shocked animals. In contrast, ouabain and amrinone did not affect cellular glucose oxidation. These data indicate that the provision of DCA can enhance the inotropic effect of amrinone and ouabain on the isolated working heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1987

Possible role of adenosine in the relaxant effect of amrinone on guinea-pig ileum.

In isolated segments of guinea-pig ileum, amrinone (0.3 mM-0.3 M) caused a transient contraction followed by a concentration-dependent relaxation. Theophylline (0.1-0.5 mM) mimicked the effects of amrinone but apparently inhibited relaxation induced by the latter. However the total decrease of muscle tension measured in preparations exposed to amrinone before and after theophylline treatment was quantitatively comparable. Dipyridamole (0.1 microM) potentiated the relaxing effect of amrinone. The stimulatory response of the ileum to high concentrations of adenosine (10-50 mM) was abolished by amrinone. In preparations treated with adenosine deaminase (10 U/ml) the basal tone was decreased and both amrinone and theophylline were ineffective. In rat ileum, amrinone exerted a marked relaxing effect that was abolished by adenosine deaminase. Thus amrinone appears to cause relaxation of intestinal smooth muscle from different species by hindering the stimulatory effect of endogenous adenosine. The possible intracellular localization of the amrinone-adenosine interaction site is discussed.

Acetylcholine↗
PubMed1989

Chronotropic and inotropic actions of amrinone, carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition.

1. The chronotropic and inotropic effects of amrinone, carbazeran and 3-isobutyl-1-methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined. 2. Amrinone (2.4 x 10(-4)M-2 x 10(-3) M), carbazeran (9.1 x 10(-6) M-1.2 x 10(-3) M), and IBMX (1.8 x 10(-5) M-4.5 x 10(-4) M) produced concentration-dependent positive inotropic responses of papillary muscle preparations, the rank order of potency being carbazeran = IBMX greater than amrinone. Sub-threshold positive inotropic concentrations of all three compounds potentiated the positive inotropic effects of isoprenaline; leftward shifts in the concentration-effect curves were 5 fold (IBMX), 11 fold (amrinone) and 46 fold (carbazeran). 3. Amrinone and IBMX produced concentration-dependent positive chronotropic responses in isolated right atria and showed a similar rate selectivity to isoprenaline, but carbazeran elicited a decrease in beating frequency. None of these drugs potentiated the positive chronotropic effects of isoprenaline. 4. Concentrations of amrinone, carbazeran and IBMX that produced similar positive inotropic responses were associated with different increases in papillary muscle cyclic AMP and cyclic GMP concentrations. 5. All three compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition. 6. The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX. In contrast, carbazeran exerts both positive inotropic and negative chronotropic effects. Phosphodiesterase inhibition and elevation of intracellular cyclic AMP concentration may be involved, at least in part, in the cardiac effects of these drugs.

1-Methyl-3-isobutylxanthine↗