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PubMed1986

Does amrinone inhibition of stimulated bone resorption involve Na+-Ca++ exchange?

Amrinone, a new cardiotonic agent, inhibits stimulated bone resorption in vitro. Pretreatment of neonatal mouse calvaria or fetal rat limb bones in culture with 2 X 10(-4)M amrinone for 6 hr reduces the response to a stimulatory agent added after washing out amrinone. This irreversible inhibition by amrinone could be blocked if the stimulatory agent was present together with amrinone during the pretreatment. To determine whether the early interaction of amrinone with this system involved an effect on a Na+-Ca++ exchange that may be required for stimulated calcium release from bone, the pretreatment effect of amrinone was examined under conditions of altered medium calcium or sodium concentration. If the calcium concentration was lowered during the 6 hr pretreatment, the inhibitory effect of amrinone was partially overcome; conversely increasing the calcium concentration during the pretreatment potentiated the effect of a submaximal concentration of amrinone. Although these results were consistent with amrinone blocking the Na+-Ca++ exchange mechanism, the effects of altering the medium sodium concentration during the 6 hr pretreatment were inconclusive. Therefore sodium-independent effects of amrinone on calcium transport cannot be ruled out. Amrinone also inhibited macromolecular synthesis in bone but this effect does not account for its ability to inhibit stimulated resorption.

Aminopyridines↗
PubMed1993

Effects of amrinone on shortening velocity and force development in skinned skeletal muscle fibres.

The effects of amrinone were studied on single skinned fibres isolated from rat hindlimb muscles. In each fibre a force-velocity relation was determined during maximal calcium activation (pCa = 4.45) in control conditions and in the presence of amrinone. The MgATP concentration was 3.93 mM, close to the physiological value. After the experiment the fibre was classified as fast or slow on the basis of its reactivity with anti-myosin monoclonal antibodies. In fast fibres amrinone (3 mM) potentiated isometric tension (Po) by 13.8 +/- 2.9% (n = 13), reduced maximum shortening velocity (Vmax) by 32.6 +/- 3.2% and the curvature of the force-velocity relation (a/Po) was increased by 98.9 +/- 46.0%. All these effects were less pronounced in slow fibres, where Vmax was reduced only by 11.4 +/- 3.6 (n = 16). The effects of amrinone (0.3-6 mM) on the ATPase activity of myofibrils and myosin prepared from fast (tibialis anterior) and slow (soleus) rat skeletal muscles were studied. Amrinone was found to depress Ca-Mg dependent ATPase activity of myofibrillar preparations of the tibialis anterior (up to 16.6 +/- 2%) and, to a lesser extent, of the soleus (up to 7.2 +/- 1.2%). On the contrary, Ca-stimulated myosin ATPase activity was significantly increased by amrinone in myosin preparations from the tibialis anterior. Experiments were carried out to test whether amrinone (3 mM) might affect the sensitivity of the contractile system to MgATP concentration ([MgATP]). The results obtained showed that (1) the [MgATP] value at which isometric tension reached its maximum was shifted by amrinone from 0.1 mM to 0.3 mM, (2) the slope of the negative relation between [MgATP] and a/Po was made more steep by amrinone, and (3) the Km of the hyperbolic relation between [MgATP] and Vmax was increased from 0.39 to 1.71 mM by amrinone, thus indicating a reduced affinity of myosin for MgATP. These results are in accordance with the hypothesis that amrinone exerts a direct effect on the contractile mechanism.

Amrinone↗
PubMed2000

Pharmacokinetics of amrinone in neonates and infants.

OBJECTIVE: To evaluate the pharmacokinetics of amrinone and its metabolites in neonates and infants after reconstructive surgery for congenital heart disease. DESIGN: Prospective study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Fifteen neonates aged less than 1 month with transposition of the great arteries and 14 infants aged 2 to 6 months with complete atrioventricular septal defect. INTERVENTIONS: Amrinone, loading dose of 2 mg/kg, was administered before weaning from cardiopulmonary bypass, followed by a maintenance infusion of 7.5 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood samples to determine plasma concentrations of amrinone, N-acetylamrinone, and N-glycolylamrinone were drawn before amrinone administration, frequently after the loading dose, every 6 hours during the maintenance infusion, and until 48 hours after the end of the infusion. Amrinone clearance was 2.4 +/- 0.9 mL/kg/min in neonates and 3.2 +/- 1.2 mL/kg/min in infants (p < 0.05). The volume of distribution at steady-state was smaller (p < 0.05) in neonates than in infants. The elimination half-life of amrinone was 10.7 +/- 6.7 hours in neonates and 6.1 +/- 1.4 hours in infants (p < 0.05). There was a linear correlation between the clearance of amrinone and the body surface area (r = 0.67; p < 0.05). The ratio of the plasma concentration of N-acetylamrinone to that of amrinone did not differ between neonates and infants. CONCLUSIONS: Amrinone is eliminated at a slower rate in neonates than in infants. The rate of acetylation of amrinone appears to be similar; the differences in the elimination capacity of amrinone are mainly due to the immature renal function in neonates.

Amrinone↗
PubMed1993

Amrinone enhances myocardial contractility and improves left ventricular diastolic function in conscious and anesthetized chronically instrumented dogs.

BACKGROUND: Volatile anesthetics depress left ventricular mechanical performance in vivo by altering intracellular calcium regulation. Although amrinone has been shown to reverse the negative inotropic effects of volatile anesthetics, the actions of amrinone on anesthetic-induced diastolic dysfunction are unknown. This investigation examined and compared the direct effects of amrinone on left ventricular systolic and diastolic function in conscious and anesthetized dogs. METHODS: Experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system, because autonomic activity may influence the hemodynamic actions of volatile anesthetics and amrinone in vivo. Three groups, comprising a total of 27 experiments, were conducted using 9 dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dt, subendocardial segment length, diastolic coronary blood flow velocity, and cardiac output. Myocardial contractility was evaluated using the preload recruitable stroke work relationship slope (Mw). Diastolic function was characterized by a time constant of isovolumic relaxation (tau), a regional chamber stiffness constant (KT), and maximum segment lengthening velocity during rapid ventricular filling (dL/dtmax). On three separate days, an amrinone bolus of 1 mg/kg, followed by an infusion at 10, 20, 40, or 80 micrograms.kg-1.min-1, was administered. Hemodynamics and ventricular pressure-segment length loops and waveforms were recorded after a 15-min equilibration at each dose in the conscious state or during isoflurane or halothane anesthesia (1.25 MAC). RESULTS: In conscious dogs, amrinone significantly increased myocardial contractility in a dose-dependent manner (Mw of 65 +/- 8 to 108 +/- 10 mmHg at the high dose). Amrinone also shortened isovolumic relaxation (tau of 32.7 +/- 2.1 to 24.8 +/- 0.9 ms at the high dose) and enhanced rapid ventricular filling (dL/dtmax of 34.8 +/- 1.2 to 45.1 +/- 2.3 mm/s at the high dose) in a dose-related fashion. In addition, amrinone reduced regional chamber stiffness (Kp of 0.49 +/- 0.09 to 0.31 +/- 0.08 mm/s at the high dose) in conscious dogs. Amrinone also enhanced left ventricular systolic (increase in Mw) and diastolic function (decreases in tau and Kp and increases in dL/dtmax) when this drug was administered to dogs anesthetized with isoflurane or halothane. CONCLUSIONS: Amrinone produced positive inotropic and lusitropic effects in both conscious and anesthetized dogs with autonomic nervous system blockade. These results indicate that amrinone-induced improvement of left ventricular performance are related to actions in diastole, as well as systole.

Amrinone↗
PubMed1982

Interaction between amrinone and parathyroid hormone on bone in culture.

The cardiotonic agent amrinone has been postulated to directly affect Na-Ca exchange. Because stimulated bone resorption has been proposed to require Na-Ca exchange, we examined the effects of amrinone on bone. Amrinone inhibited release of Ca from neonatal mouse calvaria in organ culture stimulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin d3, or prostaglandin E2. Inhibition was dose dependent and maximal at 2 X 10(-4) M. The effect of amrinone differed from the inhibitory effects of calcitonin, ouabain, or nigericin in that 1) 6-h exposure to amrinone alone prevented the effect of subsequently added PTH; 2) amrinone was only partially effective if added after resorption was initiated by 24-h treatment with PTH; 3) coincubation with amrinone and PTH during the first 48 h of culture allowed for a response to PTH after amrinone was removed; no such protection by a stimulator occurred with ouabain or nigericin. Also submaximal concentrations of amrinone plus calcitonin, ouabain, or nigericin gave greater than additive inhibition of Ca release. Amrinone had no effect on basal bone cAMP or on the acute stimulation of cAMP by PTH. The results suggest that amrinone could have a more direct interaction with the pathway involved in stimulated bone resorption than the other inhibitors.

Aminopyridines↗
PubMed1991

Effects of amrinone on thrombin-induced platelet-derived growth factor-like protein secretion from endothelial cells.

Endothelial cells (EC) secrete platelet-derived growth factor (PDGF)-like protein, which is a potent mitogen to smooth muscle and connective tissue cells. The purpose of this study was to determine if amrinone, a phosphodiesterase inhibitor, could inhibit PDGF-like protein secretion on the basis of its ability to increase cAMP. Human umbilical artery endothelial cells (HUAEC) (n = 7) were preincubated for 4 h with amrinone (10 micrograms/mL) before coincubation with thrombin (10 IU/mL) and amrinone (10 micrograms/mL) for 18 h. The supernatant was then assayed for the presence of both PDGF-like protein by using a competitive 125I-PDGF radioreceptor inhibition assay, and cAMP by using an RIA. Thrombin-induced PDGF-like protein secretion from HUAEC was significantly inhibited by amrinone (7.8 +/- 1.6 fmol/10(6) EC) when compared with thrombin alone (12.1 +/- 2.4 fmol/10(6) EC) (p less than 0.05). Amrinone alone had no effect on baseline PDGF-like protein secretion. Amrinone inhibition of thrombin-induced PDGF-like protein secretion was comparable whether amrinone was added to HUAEC 4 or 0 h before thrombin, and it was dose dependent with a maximal inhibition of 82.7% by amrinone (160 micrograms/mL). In contrast, IL-1 alpha (10 micrograms/mL) and tumor necrosis factor (100 ng/mL) induced less secretion of PDGF-like protein from HUAEC, and this secretion was not inhibited by amrinone. Amrinone (10 micrograms/mL) significantly increased secretion of cAMP from HUAEC from a baseline value of 6.4 +/- 0.4 pmol/10(6) EC to 10.6 +/- 0.1 pmol/10(6) EC (p less than 0.01). We conclude that amrinone inhibits thrombin-induced PDGF-like protein secretion from HUAEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone↗
PubMed1987

Pharmacokinetics and hemodynamics of amrinone in patients with chronic cardiac failure of diverse etiology.

The pharmacokinetics of amrinone and its relationship to ventricular function were assessed in 15 patients with chronic cardiac failure following the administration of a single 100 mg oral dose. Patients examined had Class II (1 patient), Class III (13 patients) and Class IV (1 patient) heart failure as characterized by the New York Heart Association classification. Blood samples were obtained following amrinone administration at selected times for 8 hours following the dose. Cardiac output was assessed serially for 5 hours following amrinone dosing. Mean (SD) peak plasma concentrations of amrinone (2.1 (1.1) mcg/ml) were obtained 0.5 to 2 hours after drug administration. The mean (SD) apparent oral clearance, apparent volume of distribution at steady state and half-life of amrinone were 0.23 (0.13) L/hr/kg, 1.2 (0.4) L/kg, and 4.8 (3.0) hr. Peak increases in cardiac index averaged 50% of baseline values and improvement was maintained at least 5 hours following amrinone dosing when compared to baseline cardiac index (p less than 0.05). Examination of the relationship between cardiac index corrected for baseline and amrinone plasma concentrations within individuals yielded strong and highly significant relationships (r greater than 0.90; p less than 0.025) in five patients, while in the remaining patients, either no relationship existed or insufficient data was available for analysis. When the data from all patients were pooled, a modest though significant relationship (r = 0.67; p less than 0.01) existed between cardiac index corrected for baseline and the post-absorptive, post-distributive amrinone plasma concentration. No difference in response to amrinone as a function of failure etiology or functional aerobic capacity was evident. Evaluation of the relationships between the mean improvement in cardiac index versus amrinone plasma concentration, as well as the time courses of these parameters indicate that the site of action of amrinone may be pharmacokinetically distinguishable from plasma and the tissues in instantaneous equilibrium with plasma.

Acetylation↗
PubMed1986

Dose-related cardiovascular effects of amrinone during enflurane anesthesia in the dog.

The dose-related cardiovascular effects of amrinone, a synthetic cardiotonic and vasodilating drug, were investigated in dogs anesthetized with enflurane (2.2-2.4% end-tidal concentration). Twelve mongrel dogs were divided into two groups of six animals: an enflurane group (E) that received only enflurane, and an amrinone group (A). In the latter group each dog received the following sequential boluses and 30-min infusions: 1) the amrinone solvent alone; 2) amrinone, 1 mg/kg + 5 micrograms X kg-1 X min-1; 3) amrinone, 2 mg/kg + 10 micrograms X kg-1 X min-1; 4) amrinone, 4 mg/kg + 20 micrograms X kg-1 X min-1. Over the course of the experiment, 2.2-2.4% end-tidal enflurane alone resulted in a gradual decrease in cardiac index (CI), stroke volume index (SVI), and the maximum left ventricular dP/dt (LV dP/dtmax), without changes in heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), or pulmonary capillary wedge pressure (PCWP) in group E. Significant differences from group E after 30 min of the lowest dose of amrinone included higher CI and SVI with lower systemic vascular resistance (SVR). The medium dose of amrinone, in addition to the effects already observed with the lowest dose of amrinone, decreased MAP and pulmonary vascular resistance (PVR), and increased LV dP/dtmax, when compared to group E only. Furthermore, the highest dose of amrinone caused lower pulmonary artery mean pressure (PAM), PCWP, and higher HR with shortened PR interval. The differences in MAP, CI, LV dP/dtmax, PCWP, PAM, PR interval, SVR, and PVR compared to E were still significant 30 min after the cessation of the highest dose. This study shows that the myocardial depressant effects of enflurane in an unstimulated canine model with a previously healthy heart can be overcome in a dose-related manner by amrinone. In contrast to other vasodilators, no reflex increase in plasma catecholamines was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyridines↗
PubMed2000

The role of cyclic nucleotides and calcium in the relaxation produced by amrinone in rat aorta.

(1) The vasorelaxation produced by the phosphodiesterase 3 (PDE3) inhibitor, amrinone was investigated in isolated rat aorta denuded of endothelium. In the presence of extracellular Ca(2+), amrinone, milrinone and 3-isobutyl-1-methylxanthine (IBMX), relaxed endothelium-denuded rat aortic rings constricted with phenylephrine. While the actions of milrinone and IBMX were inhibited by the protein kinase G (PKG) inhibitor, Rp-8-Bromo guanosine-3',5' monophosphothioate (Rp-8-Br-cGMPS; 0.5 mM), that of amrinone was only slightly affected; whereas the protein kinase A (PKA) inhibitor, Rp-adenosine-3',5' cyclic monophosphothioate (Rp-cAMPS; 0.5 mM) had no effect on any agent. (2) Amrinone (100 microM) inhibited (45)Ca(2+) influx through receptor- or store-operated Ca(2+) channels following stimulation with phenylephrine (1 microM) or thapsigargin (1 microM). In contrast, amrinone had no effect on KCl (120 mM)-stimulated Ca(2+) influx. (3) In the absence of extracellular Ca(2+), amrinone (30 microM) inhibited the constriction produced by phenylephrine, 5-hydroxytryptamine (5HT) and U46619, and this effect was not affected by Rp-cAMPS or Rp-8-Br-cGMPS. (4) The intracellular mechanism of action of amrinone may involve the phospholipase C (PLC)-inositol 1,4,5 trisphosphate (IP(3))-intracellular Ca(2+) signal transduction pathway. However, amrinone (100 microM) had no effect on either basal- or noradrenaline (100 microM)-stimulated PLC activity. Similarly, IP(3) stimulated a concentration-dependent release of Ca(2+) from rat brain microsomes that was not affected by amrinone (30 and 100 microM). (5) In conclusion, the vasorelaxant action of amrinone does not involve adenosine 3',5' cyclic monophosphate (cAMP) or involve guanosine 3',5' cyclic monophosphate (cGMP) but may include an inhibition of Ca(2+) influx through receptor- or store-operated Ca(2+) channels, although it does not directly affect intracellular Ca(2+) release.

Amrinone↗
PubMed1984

Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double-blind and placebo-controlled withdrawal study.

A placebo-controlled study was employed to evaluate the effects of oral amrinone in patients with congestive heart failure. After a baseline period of at least 4 weeks of standard treatment for refractory congestive heart failure, oral amrinone was added to the treatment regimen of 173 patients. Patients were predominantly male (89%), aged 24 to 76 years (mean 54), with ischemic (52%) or idiopathic (37%) dilated cardiomyopathy, in New York Heart Association functional class II (40%), III (59%) and IV (1%) and having a mean (+/- standard deviation) left ventricular ejection fraction of 25 +/- 15%. Phase 1: After the addition of amrinone (113 +/- 33 mg three times daily), 52 patients (30%) showed a maximal increase in treadmill exercise time exceeding 2 minutes (Naughton protocol), 72 (42%) had a lesser increase, 24 (14%) developed limiting adverse reactions, 20 (12%) died and 5 dropped out of the study. Fifty-two "responders" (30%) who were free of limiting side effects and had a greater than 2 minute increase in exercise time were randomized in double-blind fashion to continued amrinone or switched to placebo (each plus standard treatment) for an additional 12 weeks. Phase 2: Comparison of 31 of these 52 responders who continued to receive amrinone with the remaining 21 randomized to placebo revealed no significant differences in vital signs, indexes of left ventricular size and function, systolic time intervals or maximal exercise time. Continued follow-up study of patients receiving either amrinone or placebo revealed decreases in exercise times of 7 and 10%, respectively (both p less than 0.05 compared with before randomization). Episodes of worsened congestive heart failure severe enough to mandate termination of double-blind treatment were as frequent in patients taking placebo (4[18%] of 21) as in those taking amrinone (4[13%] of 31; p = NS). The average symptom score and functional class of each treatment group remained comparable. Adverse effects such as gastrointestinal and central nervous system complaints were more common with amrinone treatment as were elevations of serum liver enzymes and reduced platelet counts. This large multicenter, randomized double-blind withdrawal study revealed no change in estimates of cardiac performance after the discontinuation of amrinone. These findings suggest that amrinone, in the dosages tested, does not importantly improve cardiac function beyond that provided by standard treatment with digoxin, diuretic drugs and vasodilators.

Adult↗
PubMed1981

Relationship between amrinone plasma concentration and cardiac index.

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high-performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p less than 0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 micrograms/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 micrograms/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p less than 0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first-order terminal elimination t 1/2. The t 1/2 as estimated by log-linear regression ranged from about 3 to 15 hr; mean +/- SEM value was 8.3 (+/- 1.1) hr.

Aminopyridines↗
PubMed1993

Amrinone and the pulmonary vascular pressure-flow relationship in conscious control dogs and following left lung autotransplantation.

BACKGROUND: Amrinone, a bipyridine compound, is known to improve left ventricular function via its positive inotropic and afterload-reducing effects. The goal of this study was to assess the efficacy of amrinone as a pulmonary vasodilator, an effect that could be beneficial in the setting of right heart failure associated with pulmonary hypertension. METHODS: Investigated were the effects of intravenous amrinone (750 micrograms/kg loading dose plus 1-20 micrograms.kg-1.min-1 maintenance dose) on the left pulmonary vascular pressure-flow (LPQ) relationship in chronically instrumented, conscious dogs. The effects of amrinone on the LPQ relationship were assessed in a series of conscious control dogs with (n = 10) and without (n = 9) acute preconstriction with the thromboxane analog U46619 and in a series of conscious dogs 2-4 weeks after left lung autotransplantation (LLA) with (n = 8) and without (n = 8) acute U46619 preconstriction. Left pulmonary vascular pressure-flow plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure/left atrial pressure [PAP/LAP]) and left pulmonary blood flow during gradual (approximately 1 min) inflation of a hydraulic occluder implanted around the right pulmonary artery. RESULTS: Amrinone had no effect on the baseline LPQ relationship in control dogs. U46619 caused acute pulmonary vasoconstriction. For example, PAP/LAP at left pulmonary blood flow of 70 ml.min-1.kg-1 was increased (P < 0.01) from 16 +/- 2 to 37 +/- 2 mmHg during U46619 administration. In this setting of acute preconstriction, amrinone caused pulmonary vasodilation, i.e., PAP/LAP was decreased (P < 0.05) from 37 +/- 2 to 32 +/- 2 mmHg. Left lung autotransplantation was associated with a marked shift in the LPQ relationship, indicating a chronic increase in pulmonary vascular resistance, i.e., PAP/LAP was increased (P < 0.01) from 15 +/- 2 to 32 +/- 3 mmHg. Despite the chronic increase in pulmonary vascular resistance after LLA, amrinone had no effect on the baseline LPQ relationship. However, after acute preconstriction with U46619 after LLA, amrinone caused pulmonary vasodilation, i.e., PAP/LAP was decreased (P < 0.05) from 45 +/- 4 to 39 +/- 4 mmHg. CONCLUSIONS: These results indicate that amrinone exerts a significant, although relatively modest pulmonary vasodilator influence in the setting of acute pulmonary vasoconstriction in conscious control dogs and in conscious dogs after LLA. However, amrinone did not reverse the chronic increase in pulmonary vascular resistance associated with LLA.

Amrinone↗
PubMed2000

Impaired vasodilatation response to amrinone in the forearm of patients with congestive heart failure: role of endothelium-derived nitric oxide.

Recent in vitro experiments have shown that amrinone enhances the release of nitric oxide (NO) from the endothelium and induces NO mediated vasodilatation. This in vivo study examined whether amrinone causes vasodilatation mediated by endothelium-derived NO, and whether this effect is attenuated in patients with endothelial dysfunction. Eight patients with congestive heart failure and 10 age- and sex-matched healthy volunteers were studied. Forearm blood flow (FBF) was measured before and during infusion of drugs of acetylcholine, amrinone, and nitroglycerin in incremental doses. After the completion of these measurements, 100 micromol of N(G)-monomethyl-L-arginine (L-NMMA) was infused intraarterially. Thereafter, FBF measurement in response to incremental doses of amrinone was repeated. Infusion of incremental doses of amrinone caused a comparable increase in amrinone plasma concentration in both groups. Baseline FBF was 3.2+/-0.79 ml/min/100 ml in controls vs. 2.91+/-0.79 ml/min/100 ml in patients (p = 0.43). In both groups, FBF increased in response to acetylcholine, amrinone, and nitroglycerin. During infusion of the highest dose of nitroglycerin, FBF was not different between the two groups (p = 0.51); however, FBF during infusion of the highest doses of acetylcholine and amrinone was significantly less in patients than in controls: 9.75+/-2.69 vs. 24.87+/-8.65 ml/min/100 ml (p < 0.001) and 3.79+/-1.21 vs. 7.15+/-2.06 ml/min/100 ml (p < 0.001), respectively. L-NMMA significantly depressed the increase in FBF in response to amrinone in controls, but not in patients. In conclusion, the selective PDE III inhibitor, amrinone, has endothelium-derived NO-mediated vasodilating effects in addition to direct effects. This property may be impaired in patients with endothelial dysfunction.

Acetylcholine↗
PubMed1995

Beneficial effect of amrinone on murine cardiac allograft survival.

Amrinone is a non-glycoside positive inotropic agent with an inhibitory effect on a cyclic adenosine monophosphate (AMP) phosphodiesterase isoenzyme. In the present study, we examined the immunosuppressive action of amrinone, since several other cyclic AMP-elevating agents have been shown to suppress T lymphocyte activation. First, the in vivo effects of amrinone were investigated. Oral amrinone treatment, at 40 mg/kg per day, significantly prolonged median cardiac allograft survival compared with non-treated controls (22.0 days versus 10.5 days, P < 0.01) when DBA/2 mouse hearts (H-2d) were heterotopically transplanted into C57B1/6 mice (H-2b). Histopathological examination showed that there was less prominent cellular infiltration in the amrinone-treated than in the non-treated allografts. Plasma amrinone concentrations of mice after a single oral dose of 40 mg/kg were within the range of clinical relevance. To clarify the mechanism of action, in vitro studies were done. The generation of specific cytotoxic T lymphocytes after mixed lymphocyte culture was significantly suppressed by addition of amrinone to the culture medium at 5 micrograms/ml. The production of IL-2 and the interferon-gamma during mixed lymphocyte culture was also suppressed by amrinone at 5 micrograms/ml. However, the level of intracellular cyclic AMP in mouse splenic lymphocytes was not affected significantly by the same dose of amrinone. In conclusion, amrinone has immunosuppressive actions at the therapeutic doses, and it may be a beneficial agent for therapy against acute cardiac allograft rejection.

Amrinone↗
PubMed1997

Amrinone improves lung compliance in patients receiving mechanical ventilation for cardiogenic pulmonary edema.

BACKGROUND: Decrease in lung compliance is one of the major causes of respiratory failure. We investigated whether amrinone could improve lung compliance. METHODS: We selected 20 consecutive patients with respiratory failure due to severe cardiogenic pulmonary edema to receive mechanical ventilation. Patients were administered a bolus injection (1 mg.kg-1) over 10 min followed by continuous intravenous infusion (10 micrograms.kg-1.min-1) of amrinone. Lung compliance, blood gas values, hemodynamic parameters, and sample plasma amrinone levels were assessed over a 120-min period after the onset of the continuous infusion of amrinone. RESULTS: Ten min following amrinone infusion, dynamic compliance (Cdyn) and static compliance (Cst) increased from 30 +/- 11 to 36 +/- 12 ml/cm H2O and from 37 +/- 12 to 42 +/- 13 ml/cm H2O, respectively (P < 0.01). Plasma amrinone levels reached a therapeutic level as vasodilator and positive inotropic effects at 10 min after amrinone infusion. The significant change in mean pulmonary artery pressure and pulmonary artery wedge pressure occurred later than the change in compliance of respiratory system. However, there were significant correlations between the mean pulmonary artery pressure and Cdyn (r = 0.36, P < 0.01) and Cst (r = 0.44, P < 0.01), as well as between plasma amrinone levels and Cdyn (r = 0.30, P < 0.05) and Cst (r = 0.41, P < 0.01). CONCLUSIONS: Amrinone-induced improvement in lung compliance was considered mainly to be due to an increase in the number of functioning lung units by improvement of the hemodynamics and a direct positive effect of amrinone on respiratory muscle contraction.

Aged↗
PubMed1998

Dose-related cardiovascular effects of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression.

BACKGROUND: To ascertain the efficacy of amrinone and epinephrine in reversing bupivacaine-induced cardiovascular depression, we investigated the time course of recovery of cardiac function with 3 doses of both agents after bupivacaine administration. METHODS: In sevoflurane-anaesthetized dogs, bupivacaine was infused intravenously at 1 mg.kg-1.min-1 until mean arterial pressure fell to 60 mmHg or less. The 3 doses of amrinone (1, 2, and 4 mg.kg-1) or the 3 doses of epinephrine (2, 5, and 10 micrograms.kg-1) were administered as a bolus in randomized order in each dog. RESULTS: Amrinone improved maximum left ventricular dP/dt, a time constant of left ventricular isovolemic relaxation and cardiac index persistently and dose-relatedly. Amrinone increased heart rate and decreased left ventricular end-diastolic pressure and systemic vascular resistance index. Amrinone at 1 and 2 mg.kg-1 significantly increased mean arterial pressure, but amrinone at 4 mg.kg-1 did not. Epinephrine increased mean arterial pressure, maximum left ventricular dP/dt, and systemic vascular resistance dose-relatedly. The duration of action of epinephrine, peaking at 1 min and subsequently decreasing by 10 min after administration, did not differ among the groups. Epinephrine at all doses failed to improve a time constant of left ventricular isovolemic relaxation and cardiac index. ECG evidence of serious ventricular dysrhythmias was seen in 1 out of 6 dogs after administrating each dose of amrinone and in 3, 3 and 5 out of 6 dogs after administrating 2, 5 and 10 micrograms.kg-1 of epinephrine, respectively. CONCLUSION: Bolus amrinone may have a certain efficacy in reversing bupivacaine-induced cardiovascular depression, and improving cardiac contractility and relaxation dose-relatedly. In contrast to amrinone, bolus epinephrine remains indispensable for resuscitation, causing a rapid, massive, transient and dose-related rise in blood pressure. However, the use of amrinone may be limited predominantly by a decrease in systemic vascular resistance, while the use of epinephrine may be limited predominantly by the generation of serious ventricular dysrhythmias and lack of effectiveness on cardiac index and on cardiac relaxation.

Amrinone↗
PubMed1986

Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure.

The effects of amrinone, dobutamine, and a combination of the two drugs on peak positive left ventricular dP/dt and left ventricular performance were evaluated in 11 patients with chronic congestive heart failure. When administered alone, both dobutamine (10.9 micrograms/kg/min) and intravenous amrinone (1.9 mg/kg/min) significantly increased left ventricular dP/dt and performance. When compared with dobutamine alone, the addition of amrinone resulted in further increases in left ventricular dP/dt and cardiac index (to 1319 +/- 419 from 1202 +/- 376 mm Hg/sec, p less than .002, and to 3.56 +/- 0.78 from 3.04 +/- 0.67 liters/min/m2, p less than .01, respectively). The combination also induced a further reduction in left ventricular end-diastolic pressure (to 15.3 +/- 11.3 from 18.2 +/- 10.3 mm Hg, p less than .05) when compared with amrinone alone. The combination of dobutamine and amrinone increased heart rate slightly when compared with either drug alone, but did not further reduce systemic arterial pressure when compared with amrinone alone. The dose-response curve of left ventricular dP/dt and performance during titration of dobutamine with and without the addition of intravenous amrinone was evaluated in seven patients. The addition of amrinone to any dose of dobutamine produced higher cardiac index and lower systemic vascular resistance than dobutamine or amrinone alone. Thus, when compared with dobutamine alone in patients with chronic congestive heart failure, the addition of intravenous amrinone to dobutamine results in an additive improvement in left ventricular performance throughout the dose range.

Adult↗
PubMed1999

[Endothelial-derived nitric oxide mediates the peripheral vasodilatory effects of amrinone in humans].

Amrinone, which is used for the treatment of acute congestive heart failure, has vasodilatory and positive inotropic effects through the increment of intracellular cyclic adenosine monophosphate. Recent in vitro investigations have shown that amrinone has an endothelium-dependent vasodilatory effect. The present study examined whether amrinone shows this endothelium-dependent vasodilatory effect in human peripheral vessels. Forearm blood flow during intra-arterial infusion of graded doses (12.5, 25, 50, 100, 200 micrograms/min) of amrinone was measured using plethysmography in 10 healthy subjects without organic vascular disease before and after nitric oxide synthase blocking with NG-monomethyl-L-arginine (L-NMMA, 400 mumol). The graded dose of amrinone produced progressive increases in amrinone plasma concentrations, and a dose over 100 micrograms/min caused amrinone plasma concentrations of more than 1.0 microgram/ml. The increase in forearm blood flow in response to amrinone was significantly depressed after L-NMMA doses of less than 100 micrograms/min, but the increase in forearm blood flow during infusion of higher doses (100, 200 micrograms/min) was not affected by L-NMMA. These results suggest that endothelial-derived nitric oxide may partially contribute to amrinone-induced vasodilation in humans. Thus, the vasodilatory effect of amrinone might be impaired in patients with endothelial dysfunction.

Adult↗