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PubMed1991

Milrinone inhibits sympathetic-mediated tachycardia by a postjunctional action independent of cyclic AMP.

In pithed rats with stimulated sympathetic outflow, the phosphodiesterase inhibitor milrinone (0.3 mg/kg, i.v.) decreased the peak tachycardiac response produced by both sympathetic nerve stimulation (15 s at 0.5-3 Hz) and norepinephrine administration (0.3-5 micrograms/kg, i.v.). However, another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 0.5 mg/kg, i.v.) had no effect on the peak tachycardic response to sympathetic stimulation. Similarly, in isolated rat atria, milrinone (9 mumol/L) inhibited the tachycardia produced by norepinephrine, whereas IBMX (1 mumol/L) had no effect. The inhibitory effect of milrinone on sympathetic responses was not due to changes in norepinephrine release since milrinone (9 mumol/L) increased norepinephrine release in isolated rat atria incubated with [3H]norepinephrine. When the duration of the tachycardia (rather than the peak tachycardic response) produced by sympathetic nerve stimulation was measured, it was found to be prolonged by both milrinone and IBMX, suggesting that in this case cyclic AMP was involved. Furthermore, in contrast to its inhibitory effects on norepinephrine-induced tachycardia in rat atria, milrinone enhanced the tachycardia produced by the adenylate cyclase activator forskolin. These results suggest that milrinone has complex actions on sympathetic control of heart rate and that beta-adrenoceptor tachycardia occurs by mechanisms dependent on and independent of cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Relationship between myocardial milrinone content and its acute hemodynamic and electrophysiologic effects.

One of the major determinants of the short-term effects of many cardioactive drugs is the concentration of the drug specifically within the myocardium. However, no information regarding the disposition of the phosphodiesterase inhibitor milrinone in the heart is available. We therefore determined the time course of short-term myocardial milrinone uptake from paired transcoronary sampling and simultaneous coronary sinus blood flow after a 1-mg intravenous bolus in patients undergoing diagnostic cardiac catheterization. In accordance with this intention, a sensitive, reproducible method for the determination of milrinone in human whole-blood samples was developed. The reverse-phase high-performance liquid chromatographic method described used a C18 column with UV-absorbance detection at 326 nm, with a limit of detection of 0.6 ng/ml, and was highly reproducible. The short-term hemodynamic and electrophysiologic effects of the drug also were determined. Significant increases in spontaneous heart rate and LV+dP/dtmax (at constant heart rate) were observed, accompanied by reductions in mean arterial pressure, systemic vascular resistance, and PR interval, without significant changes in atrioventricular nodal or ventricular effective refractory periods. Peak content (1.89 +/- 0.30% of injected dose) was rapidly attained, 0.56 +/- 0.06 min after milrinone injection. Time of peak effects was significantly delayed (7-10 min after injection) relative to time of peak myocardial milrinone content. Residual myocardial milrinone content was 69.1 +/- 5.7% of maximum 12.5 min after injection. It is concluded that both myocardial uptake and the onset of positive inotropic effects after intravenous injection of milrinone were very rapid. However, there was significant hysteresis between peak myocardial content and subsequent hemodynamic effects.

Adult↗
PubMed2004

Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart.

Levosimendan is a novel calcium sensitizer that increases contraction force without change in intracellular calcium ([Ca2+]i); milrinone is a phosphodiesterase inhibitor that exerts a positive inotropic effect by increasing [Ca2+]i. The effects of levosimendan and milrinone on oxygen consumption in the isolated guinea-pig heart were studied. Isolated guinea-pig hearts were paced (280 beats/min) and perfused according to the Langendorff technique. Levosimendan (0.01-1 microM) or milrinone (0.1-10 microM) were added cumulatively and changes from baseline for diastolic and systolic pressure (LVEDP and LVSP), contractility and relaxation (+dP/dt and -dP/dt), and coronary flow and oxygen consumption (CF and VO2) were calculated. Levosimendan was found to be 10 to 30 times more potent than milrinone as an inotropic agent. The effect on VO2 was markedly lower in levosimendan-perfused hearts than in milrinone-perfused hearts (P = 0.031 between the concentration-dependent effects of the two drugs). The maximum increase in VO2 was 10 +/- 4% in the levosimendan group and 38 +/- 15% in the milrinone group. The economy of the contraction was more advantageous in levosimendan-perfused hearts (P </= 0.005 vs. milrinone group on both VO2/+dP/dt and VO2/LVSP). It was concluded that levosimendan exerts a positive inotropic effect without disturbing the energy balance of the heart.

Animals↗
PubMedDate not supplied

Predictors of clinical outcome in advanced heart failure patients on continuous intravenous milrinone therapy.

Home-based milrinone therapy (HMT) is used as a bridge to cardiac transplant (CT). The safety, efficacy, and predictors of success of HMT were assessed. Forty-five patients with heart failure, referred for CT, were prospectively studied. After initial assessment, low-dose milrinone was titrated based on clinical response. Hemodynamic status was then reevaluated. Thirty-nine patients were discharged on HMT. Patients needing a left ventricular assist device (LVAD) despite milrinone (group I) and those not requiring LVAD (group II) were compared. Six of the 45 patients were ineligible for CT; 16 of 39 required LVAD as a bridge to CT despite milrinone (group I); 23 were stable on milrinone and did not require LVAD (group II). Group I was younger than group II (mean age 38.4 +/- 14.5 years vs. 57.3 +/- 5.9 years, p < 0.001). Initial acute response to intravenous milrinone [e.g., fall in the PCWP (-10.7 +/- 9.5 vs. -2.7 +/- 10.4, p = 0.02), rise in pulmonary artery oxygen saturations (16.5 +/- 8.7 vs. 7.3 +/- 10.9, p = 0.05)] was significantly better in group II than in group I. Acute hemodynamic response to milrinone predicts success of HMT as a bridge to CT.

Adult↗
PubMed1985

The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret.

The effects of milrinone and piroximone were compared to those of isoprenaline, dibutyryl adenosine 3':5'-cyclic monophosphate (dibutyryl cyclic AMP), forskolin, isobutylmethylxanthine, increased extracellular calcium [( Ca2+]o) and caffeine in ferret right ventricular papillary muscles that were loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium. The positive inotropic action of each drug, except caffeine, was associated with an increase in the peak amplitude of the aequorin light signal (i.e. intracellular Ca2+ transient) reflecting an increased amount of calcium available for excitation-contraction coupling; the positive inotropic effect of caffeine appears to occur by other mechanisms. The time courses of the aequorin light signal and corresponding tension response were shortened by isoprenaline, forskolin, isobutylmethylxanthine, dibutyryl cyclic AMP, milrinone and piroximone; unchanged by increased [Ca2+]o and prolonged by caffeine, suggesting that the rates of Ca2+ release and uptake by the sarcoplasmic reticulum were respectively increased, unchanged or decreased by these groups of drugs. Relative to changes in [Ca2+]o, the ratio of the peak of the aequorin light signal to the peak of the tension response was increased by isoprenaline, milrinone and piroximone, and decreased by caffeine, indicating that the Ca2+-sensitivity of the myofilaments was respectively decreased, and increased by these drugs. The effects of milrinone and piroximone on the amplitude and time course of the aequorin light signal, as they relate to changes in uptake and release of calcium from the sarcoplasmic reticulum and to changes in the sensitivity of the myofilaments to Ca2+, are consistent with the findings that positive inotropic doses of these agents act by increasing intracellular concentrations of cyclic AMP. Higher doses of milrinone and piroximone produced negative inotropic effects that were characterized by diminution of developed tension but no change or an increase in the amplitude of the aequorin light signal, suggesting a decrease in the sensitivity of the contractile elements to Ca2+. Toxic doses of milrinone, piroximone and isoprenaline were associated with development of a Ca2+-overload state characterized by the presence of after-glimmers, after-contractions and dysrhythmias, and by decreased amplitude of both the aequorin light signal and tension response. The negative inotropic and toxic effects of milrinone and piroximone can be explained only in part by increased intracellular concentrations of cyclic AMP; we suggest that these drugs may have other cardiac actions.

Aequorin↗
PubMed1994

A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts.

1. The functional and anti-ischaemic effects of the phosphodiesterase (PDE)-inhibitors, amrinone, milrinone and levosimendan, a new agent combining PDE-inhibitory with calcium-sensitizing properties, were investigated in rabbit isolated hearts (Langendorff, constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol l-1, 37 degrees C). Anti-ischaemic effects were studied in electrically-driven hearts (200 beats min-1). Acute regional ischaemia was induced by ligature of a branch of the circumflex coronary artery and quantified from epicardial NADH-fluorescence photography. 2. Cumulative concentration-response curves in spontaneously beating hearts in the presence of isoprenaline (10(-10) M), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 x 10(-7) M) compared to milrinone (EC50: 7.7 x 10(-6) M) or amrinone (EC50: 2 x 10(-5) M). Although the maximal coronary dilator activity was similar for the three agents, the maximal inotropic and chronotropic effects were lower for levosimendan than for amrinone or milrinone (P < 0.05). 3. In regionally ischaemic hearts, milrinone (10(-5) M) or levosimendan (5 x 10(-6) M) similarly enhanced the left ventricular pressure (+15-20%) (P < 0.05) and the global coronary flow (+40-50%) (P < 0.05). The epicardial NADH-fluorescence area was significantly diminished by milrinone or levosimendan (-20-30%) (P < 0.05) and there was no significant difference between the anti-ischaemic effects of either agent (P > 0.05). 4. It is concluded that amrinone and milrinone possess similar functional profiles in rabbit isolated hearts and a higher inotropic and chronotropic efficacy than levosimendan. At functionally equieffective concentrations, milrinone and levosimendan show similar anti-ischaemic effects, related to an improvement of myocardial perfusion. The calcium-sensitizing properties seem not to be relevant for cardioprotection by levosimendan at the concentration used.

Amrinone↗
PubMed1994

Mechanical and electrophysiological effects of milrinone on the force-frequency relationship in mammalian myocardium.

Isometric force, action potential and current-voltage relation were studied in guinea-pig and ferret papillary muscles. Milrinone (1 microM) increased peak twitch force by 40 +/- 4%, reduced time to peak tension (TPT) by 12.1 +/- 3% (n = 6, P < 0.01) and reduced time to half relaxation by 17.3 +/- 4.1% (n = 6, P < 0.01). The effect of milrinone was potentiated by rolipram, a RI-PDE inhibitor which in itself had no inotropic effect. After the addition of rolipram peak isometric force was increased by 104 +/- 8% (n = 6, P < 0.001), TPT was further reduced whereas time to half relaxation was slightly increased after the addition of rolipram. Action potential duration at 75% repolarization was decreased by 11 +/- 5 ms (n = 6, P < 0.05). Milrinone also potentiated the second inward current (Isi) by 21 +/- 3.2% (n = 6, P < 0.01). Peak twitch force in response to a test stimulus after an interval, i.e. mechanical restitution was increased at all intervals. The onset of restitution was faster and time to full restitution also shortened. Maximum postextrasystolic potentiation was greater in the presence of milrinone, whereas relative potentiation was smaller in presence of milrinone (46 +/- 7%) than in control (74 +/- 7%). The recirculation fraction of activator calcium was enhanced by milrinone from 0.35 +/- 0.04 to 0.48 +/- 0.07. The results support the view that the positive inotropic effect of milrinone is due to a greater inflow of calcium during the action potential and a more efficient intracellular calcium handling.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1995

The haemodynamic effects of milrinone HCl in halothane anaesthetised horses.

The haemodynamic effects of milrinone hydrochloride were determined in halothane-anaesthetised horses. Six healthy adult horses were anaesthetised with guaifenesin and thiamylal and maintained with halothane in oxygen (end-tidal halothane concentration of 1.15%). Baseline haemodynamic data were recorded after a 45 min stabilisation period. All 6 horses received a single loading dose of milrinone HCl, 0.2 microgram/kg i.v., followed by progressively increasing infusions of 2.5, 5, 10 and 20 micrograms/kg bwt/min. Each infusion lasted for 15 min and produced dose related increases in heart rate, mean arterial blood pressure, cardiac output, maximum rate of increase and decrease of left ventricular pressure (+/- dP/dtmax) and ejection fraction in halothane anesthetised horses. Median artery blood flow increased following milrinone administration. Right atrial and pulmonary artery pressures, systemic vascular resistance and left ventricular end-diastolic and end-systolic volumes decreased. Most haemodynamic changes were sustained throughout the infusion period and for 30 min following the termination of milrinone infusion. Systemic vascular resistance was increased above baseline values at 30 min following the termination of milrinone infusion. No adverse side effects were observed during this study although a milrinone infusion rate of 20 micrograms/kg bwt/min increased heart rate to values greater than 50 beats/min. The results of this study suggest that milrinone produces beneficial haemodynamic effects in halothane anaesthetised horses and is potentially useful in the treatment of patients with a reduced cardiac output.

Anesthetics, Inhalation↗
PubMed1998

Milrinone inhibits contractility in skinned skeletal muscle fibers.

Direct action of the cardiotonic bipyridine milrinone on the cross bridges of single fibers of skinned rabbit skeletal muscle was investigated. At 10 degrees C and pH 7.0, milrinone reduced isometric tension in a logarithmically concentration-dependent manner, with a 55% reduction in force at 0.6 mM. Milrinone also reduced Ca2+ sensitivity of skinned fibers in terms of force production; the shift in the force-pCa curve indicated a change in the pCa value at 50% maximal force from 6.10 to 5.94. The unloaded velocity of shortening was reduced by 18% in the presence of 0.6 mM milrinone. Parts of the transient tension response to step change in length were altered by milrinone, so that the test and control transients could not be superimposed. The results indicate that milrinone interferes with the cross-bridge cycle and possibly detains cross bridges in low-force states. The results also suggest that the positive inotropic effect of milrinone on cardiac muscle is probably not due to the drug's direct action on the muscle cross bridges. The specific and reversible action of the bipyridine on muscle cross bridges makes it a potentially useful tool for probing the chemomechanical cross-bridge cycle.

Animals↗
PubMed1999

Effect of milrinone on small mesenteric artery vasoconstriction: role of K(+) channels.

We examined whether milrinone-mediated attenuation of small mesenteric artery vasoconstriction results predominantly from the activation of vascular smooth muscle K(+) channels. Resistance arteries (approximately 150 micrometers) were dissected from rat mesentery and were mounted on a wire myograph. Isometric force development in response to increasing concentrations of norepinephrine (NE) was monitored before and after treatment with the type 3 phosphodiesterase inhibitor milrinone. Milrinone significantly reduced NE-induced vasoconstriction, attenuating both NE sensitivity and maximal tension generation. Inhibition of ATP-sensitive K(+) channels or voltage-gated K(+) channels did not prevent the milrinone-induced attenuation of NE responses. Blockade of inwardly rectifying K(+) channels or Ca(2+)-sensitive K(+) channels prevented the milrinone-mediated reduction in NE sensitivity, but this effect was apparently due to direct enhancement of vasoconstrictor responsiveness rather than interference with the mechanism of milrinone action. In addition, milrinone elicited substantial relaxation in vessels preconstricted with 100 mM KCl. This effect was mimicked by the adenylyl cyclase activator forskolin and was reversed by the Rp diastereomer of cAMP, which is a cAMP-dependent protein kinase (PKA) inhibitor. Our results indicate that cAMP/PKA-mediated impairment of vasoconstriction may occur without the contribution of K(+) channel regulation.

Animals↗
PubMed1999

Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure.

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/dt), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 micrograms . kg-1. min-1 iv) increased LV dP/dt by 1,854 +/- 157 from 2,701 +/- 105 mmHg/s (P < 0.05) before HF. After HF the increase in LV dP/dt in response to milrinone was attenuated significantly (P < 0.05); it increased by 615 +/- 67 from 1,550 +/- 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/dt (+445 +/- 65 mmHg/s) in response to milrinone were markedly less (P < 0.01), and milrinone increased LV dP/dt even less in HF (+240 +/- 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly (P < 0.05) in LV endocardium (-26%) but not significantly in LV epicardium (-14%). PDE activity was also decreased significantly (P < 0.05) in LV endocardium (-18%) but not in LV epicardium (-4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

Animals↗
PubMed1992

Preload-dependent hemodynamic effects of milrinone in moderate heart failure.

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 micrograms/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38% with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7% fall in mean arterial pressure and a 13% rise in heart rate (all p less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16% (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p less than 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures greater than 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.

Administration, Oral↗
PubMed1994

Comparison of positive inotropic effects of milrinone, dobutamine and ouabain.

This study compared the positive inotropic actions of milrinone in isolated rabbit myocardium with that of the conventional positive inotropic drug, dobutamine, and a cardiac glycoside, ouabain. Maximal increase in developed tension (g/mm2) was significantly (p < 0.05) greater with ouabain (from 2.0 to 4.4; 132 +/- 11%) than with dobutamine (from 3.9 to 6.0; 77.8 +/- 22.4%) or milrinone (from 2.4 to 3.6; 54.0 +/- 12.0%). Maximal augmentation of the rate of tension development (g/s/mm2), however, was similar with ouabain (from 14.3 to 39.7; 187 +/- 20%) and dobutamine (from 25.9 to 64.4; 174 +/- 35%), and both were significantly (p < 0.05) greater than with milrinone (from 18.2 to 30; 73.1 +/- 14.7%). In combination with dobutamine, however, the dose-response curve of milrinone was shifted to the left, and its ED10 was significantly (p < 0.001) reduced by 100-fold to 1.6 x 10(-7) M. Thus, milrinone is significantly less potent than dobutamine or ouabain in vitro and is without contractile effect at clinically relevant concentrations. However, data from the combined application of a catecholamine and milrinone in isolated myocardium suggest that milrinone may induce a direct positive inotropic effect at clinical concentrations in the presence of augmented sympathetic neurohumoral stimulation.

Animals↗
PubMed1986

Identification of the direct vasodilator effect of milrinone with an isolated limb preparation in patients with chronic congestive heart failure.

We developed an isolated limb preparation to evaluate the direct vasoactive properties of cardioactive drugs on the forearm vasculature in patients with congestive heart failure. Using this model, we infused milrinone in subsystemic doses (1, 10, and 20 micrograms/min per 100 ml forearm volume [FAV] ) into the brachial artery of 13 patients with moderate-to-severe congestive heart failure. We monitored forearm hemodynamics, systemic hemodynamics, and milrinone plasma concentration from both the forearm venous effluent and pulmonary artery. This preparation enabled us to assess the direct forearm vascular response to milrinone. Compared with baseline forearm blood flow (2.46 +/- 1.37 ml/min/100 ml FAV), the three doses of milrinone resulted in increases in forearm blood flow to 2.66 +/- 1.43, 4.21 +/- 1.79, and 6.73 +/- 3.69 ml/min/100 ml FAV. This was associated with a reduction of forearm vascular resistance from the baseline value of 52 +/- 38 U to 47 +/- 36, 25 +/- 13, and 17 +/- 10 U. The p value for the difference in response of flow and resistance after the 10 and 20 micrograms doses vs that at baseline was .05. This forearm vasodilatation occurred without change in systemic hemodynamics or therapeutic milrinone plasma concentrations in the pulmonary artery. In five patients, we compared the response to intra-arterial milrinone with that of nitroprusside. At a dose of 10 micrograms/min/100 ml FAV, the response to nitroprusside (7.20 +/- 3.24 ml/min/100 ml FAV) was greater than that to milrinone (4.65 +/- 2.18 ml/min/100 ml FAV) (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Role of milrinone in the management of congestive heart failure.

Milrinone is a bipyridine derivative with positive inotropic and vasodilating properties. The intravenous form of the drug has been approved by the Food and Drug Administration (FDA) for short-term management of congestive heart failure (CHF). The FDA has requested additional mortality data prior to approval of the oral form. Milrinone produces positive inotropic and vasodilating effects through unknown mechanisms, and causes a dose-dependent increase in cardiac index and a decrease in systemic vascular resistance and pulmonary capillary wedge pressure. It is extensively absorbed following oral administration with an elimination half-life of approximately 1.5-2 hours and a corresponding duration of action of 3-6 hours. Its major route of elimination is renal (83 percent). The intravenous dose is 50 micrograms/kg given over ten minutes, followed by a maintenance infusion of 0.375-0.75 micrograms/kg/min titrated to the desired hemodynamic response. The average effective oral dosage is 7.5-10 mg four to six times daily. Milrinone is most effective in the short-term management of CHF where the majority (60-80 percent) of patients have symptomatic and hemodynamic improvement as well as increases in exercise duration. However, many patients do not derive long-term benefit from milrinone therapy. Available evidence suggests that milrinone does not arrest the natural progression of CHF, and some investigators feel it may actually worsen CHF and shorten patients' length of survival. Milrinone has been generally well tolerated with a low risk of major organ toxicity. The most common adverse reactions with intravenous milrinone include ventricular arrhythmias (12 percent) and supraventricular arrhythmias (4 percent).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotonic Agents↗
PubMed1994

Cardiovascular effects of dibutyryl cyclic AMP and milrinone under right heart bypass in anesthetized dogs.

To compare the cardiovascular effects of dibutyryl cyclic AMP (DBcAMP) and milrinone, we used the right heart bypass method in intact anesthetized dogs. The preload of the left ventricle was maintained constant throughout the experiment. Therefore, the effects of DBcAMP and milrinone on cardiac contractility and afterload of the left ventricle were investigated respectively without preload influence. DBcAMP and milrinone exhibited marked positive chronotropic-, positive inotropic-, vasodilative- and diuretic-activity. DBcAMP expressed these effects gradually and continuously, whereas milrinone expressed its pharmacological actions rapidly, but for a short duration of time. Both the afterload-reducing and the cardiac contractile force-enhancing activities of DBcAMP were longer lasting than those of milrinone. Mean arterial pressure was not altered by DBcAMP infusion, whereas it was increased significantly (p < 0.05) by milrinone infusion. The results of this study suggested that DBcAMP appeared to be indicated when there is a need to increase cardiac output by reducing afterload and increasing cardiac contractile force gradually and continuously. On the other hand, milrinone would seem to be indicated when the goal is to raise blood pressure rapidly and to increase cardiac output simultaneously.

Animals↗
PubMed1994

Milrinone versus glucagon: comparative hemodynamic effects in canine propranolol poisoning.

Glucagon has been reported to be one of the most effective treatments for severe beta-blocker poisoning. Recently, amrinone was suggested as an alternative therapeutic choice for beta-blocker poisoning. Milrinone, a derivative of amrinone, acts independently of beta-adrenoceptors and increases cyclic AMP. Therefore milrinone may also be effective in the treatment of beta-blocker poisoning. In the present study, we compared the effect of glucagon and milrinone in treating severe beta-blocker poisoning. Following the administration of 10 mg/kg propranolol i.v. over 10 min, heart rate, cardiac output, mean arterial pressure, stroke volume, and end tidal CO2 were depressed, while central venous pressure, and pulmonary capillary wedge pressure increased significantly (p < 0.05). Following the administration of saline (Group S, N = 3), glucagon 20 micrograms/kg (Group G, N = 5), and milrinone 300 micrograms/kg (Group M, N = 5), hemodynamic parameters were observed for 30 min. In group M, mean arterial pressure, cardiac output and stroke volume recovered to their baseline values, while central venous pressure and pulmonary capillary wedge pressure decreased. Although there were no significant differences between groups G and M, the heart rate, central venous pressure and pulmonary capillary wedge pressure, mean arterial pressure and stroke volume did not return to baseline values in group G. Milrinone administration produced a significant hemodynamic improvement without increasing the heart rate in the canine model of severe heart failure caused by propranolol. In the glucagon treatment group, central venous pressure and pulmonary capillary wedge pressure improved less than the milrinone group. Although more data are needed before a clinical recommendation, milrinone might be an effective drug to treat beta-blocker poisoning.

Animals↗
PubMed2000

Effect of milrinone on postbypass pulmonary hypertension in children after tetralogy of Fallot repair.

BACKGROUND: Postbypass pulmonary hypertension in surgical correction of tetralogy of Fallot (TOF) is a risk for right ventricular failure. Effective management remains a major challenge. Milrinone is a new drug with a unique mechanism of "inodilation", which offers both inotropic and vasodilatory effects. We attempted to determine if application of milrinone could improve cardiopulmonary dysfunction in children after TOF repair. METHODS: We studied 10 children with postbypass pulmonary hypertension after TOF repair within six months. Heart rate, systolic pulmonary arterial pressure (PAP), systolic arterial blood pressure (SBP), pulmonary capillary wedge pressure and PAP/SBP ratio were recorded. Standard cardiopulmonary bypass (CPB) was performed. After CPB, if PAP/SBP was more than 0.5, pulmonary hypertension was suspected and milrinone was administered with a loading dose of 20 micrograms/kg followed by continuous infusion of 0.2 microgram/kg/minute. Hemodynamics were compared before and after administration of milrinone to evaluate its effect. RESULTS: significant reduction in PAP/SBP ratio within 15 minutes was found after administration of milrinone. The effect persisted for 24 hours during continuous infusion of milrinone. No remarkable adverse effect was noted in the study. CONCLUSIONS: We conclude that milrinone is effective in the management of pulmonary hypertension following CPB in children who underwent TOF repair.

Adolescent↗