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PubMed2002

Effects of milrinone on hemodynamics and regional blood flow in the hypoxic dog.

Milrinone, a therapeutic agent for acute congestive heart failure, has both inotropic and vasodilatory effects, but investigations of these effects of milrinone were almost all conducted under normoxia, and few reports have investigated how milrinone affects the hemodynamics and redistribution of regional blood flow under severe hypoxia. By using colored microspheres, we investigated how milrinone affects hemodynamics and the redistribution of regional blood flow under severe hypoxia. Twelve healthy mongrel dogs were divided into 2 groups. The milrinone group was infused with milrinone cumulatively at 25, 75 and 250 microg/kg for 5 min each. The intact group was infused with saline instead of milrinone. We measured the hemodynamics and cerebrum, cerebellum and kidney blood flow in both groups. Both groups were inspired with 10% oxygen. Milrinone induced significant decrease in mean pulmonary artery and pulmonary vascular resistance, compared with the intact group. In both groups slight decreases in mean arterial pressure, systemic vascular resistance and double-product were seen. In regional blood flow, milrinone-induced increases in blood flow were seen in the cerebrum, cerebellum, and especially in the kidneys. Milrinone's vasodilatory effects were sufficient even under hypoxia. And milrinone increased regional blood flow slightly in the cerebrum and cerebellum, and significantly in the kidneys. These results suggested that milrinone protects against hypoxia-induced organ damage especially in the kidneys. In addition, milrinone is very potent in improving severe congested hemodynamics which complicates hypoxic pulmonary vasoconstriction.

Animals↗
PubMed2003

Dopamine stabilizes milrinone-induced changes in heart rate and arterial pressure during anaesthesia with isoflurane.

BACKGROUND AND OBJECTIVE: Phosphodiesterase-III inhibitors and dobutamine effectively improve cardiac function in patients with cardiac failure, but they are limited by possible hypotensive effects. We tested the hypothesis that dopamine contributes to stabilizing milrinone-induced haemodynamic changes. METHODS: Nine patients undergoing major surgery were anaesthetized using nitrous oxide and oxygen supplemented with isoflurane 1-2%. After baseline haemodynamics were recorded, milrinone (25 or 50 microg kg(-1)) was administered over 10min, followed by a continuous infusion (0.5 microg kg(-1) min(-1). The second set of haemodynamic values was measured 50 min after beginning the continuous infusion of milrinone. Dopamine (4 microg kg(-1) min(-1)) was then administered with milrinone. RESULTS: Milrinone significantly increased the heart rate from 81 +/- 8 to 102 +/- 16beats min(-1), but it decreased the mean arterial pressure from 83 +/- 10 to 66 +/- 10 mmHg and systemic vascular resistance (P < 0.05 for each). The pulmonary capillary wedge pressure, cardiac index and pulmonary vascular resistance did not change significantly. The addition of dopamine to the milrinone infusion significantly decreased the heart rate (94 +/- 12 beats min(-1)) and increased the mean arterial pressure (82 +/- 11 mmHg). Dopamine and milrinone, but not milrinone alone, significantly increased the cardiac index and the rate-pressure product. CONCLUSIONS: The combination regimen of milrinone and dopamine improved cardiac function, and changes in heart rate and mean arterial pressure induced by milrinone were attenuated by dopamine. The results suggest that a combination regimen of milrinone and dopamine rather than milrinone alone should be used to maintain arterial pressure.

Analysis of Variance↗
PubMed2002

Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart.

We investigated the basis for the difference in the cardiotonic effects of the PDE3 inhibitors cilostazol and milrinone in the rabbit heart. Cilostazol displayed greater selectivity than milrinone for inhibition of cAMP-PDE activity in microsomal vs cytosolic fractions from rabbit heart. This difference was due to the inhibition of significantly less cytosolic cAMP-PDE activity by cilostazol compared to milrinone. A combination of cilostazol (>15 microM) and the PDE4 selective inhibitor, rolipram (5 microM), inhibited levels of cytosolic cAMP-PDE activity similar to those inhibited by milrinone on its own. This suggested that milrinone inhibited PDE4 in addition to PDE3 activity. In isolated rabbit cardiomyocytes, milrinone (>10 microM) caused greater elevations in intracellular cAMP and calcium than cilostazol. In the presence of rolipram, however, the cAMP and calcium elevating effects of cilostazol and milrinone were similar. Therefore, in rabbit heart, partial inhibition of PDE4 by milrinone contributed to greater increases in cardiomyocyte cAMP and calcium levels than cilostazol. PDE4 activity in failing human heart was lower than in rabbit heart and there was no significant difference in the inhibition of human cytosolic cAMP-PDE by cilostazol and milrinone. Our results suggest that in normal rabbit heart inhibition of PDE4 by milrinone may partly contribute to the greater cardiotonic effect of milrinone when compared to cilostazol. However, the lower level of PDE4 activity in failing human heart suggests that factors other than inhibition of PDE4 by milrinone may contribute to differences in cardiotonic action when compared to cilostazol.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.

We randomly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin, milrinone, both, or placebo. The effects of each were compared during a 12-week, double-blind trial. Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo (by 82 and 64 seconds respectively; 95 percent confidence limits, 44 and 123, and 30 and 100). Both treatments reduced the frequency of decompensation from heart failure, from 47 percent with placebo to 34 percent with milrinone (P less than 0.05; 95 percent confidence limits, 22 and 46) and 15 percent with digoxin (P less than 0.01; 95 percent confidence limits, 7 and 26). However, the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun, as compared with only 3 percent of those taking digoxin (P less than 0.05). The left ventricular ejection fraction at rest was not significantly changed by milrinone (+0.2 percent; 95 percent confidence limits, -1.5 and 1.9), but it was increased by digoxin (+1.7 percent; P less than 0.01; 95 percent confidence limits, -0.03 and 3.4) and decreased by placebo (-2.0 percent; 95 percent confidence limits, -3.8 and -0.1). Three-month survival was related inversely to the base-line ejection fraction. Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone (P = 0.064). After adjustment for an excess of patients with lower ejection fractions randomly assigned to receive milrinone, this trend was not significant (P = 0.26). Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not (18 vs. 4 percent; P less than 0.03). We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure. However, in the population of patients studied, milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone. Furthermore, our data suggest that milrinone may aggravate ventricular arrhythmias.

Administration, Oral↗
PubMed1998

A multicenter, randomized, blind comparison of amrinone with milrinone after elective cardiac surgery.

UNLABELLED: Amrinone and milrinone are phosphodiesterase inhibitors with positive inotropic effects useful for the treatment of ventricular dysfunction after cardiac surgery. Forty-four patients undergoing elective cardiac surgery at four centers received either amrinone (n = 22) or milrinone (n = 22) in a randomized, blind fashion. Immediately after separation from cardiopulmonary bypass (CPB), two bolus doses of either amrinone 0.75 mg/kg or milrinone 25 microg/kg were administered over 30 s, separated by 5 min. Hemodynamic measurements were recorded before each dose and at the end of the 10-min study. Both amrinone and milrinone increased the cardiac index (48% vs 52%, P = not significant [NS] for amrinone and milrinone, respectively). There was a small increase in mean arterial pressure (MAP) after amrinone administration (from 68 +/- 3 to 72 +/- 3 mm Hg at 10 min, P < 0.05) with no significant change in MAP after milrinone administration. Central venous pressure was significantly higher in the amrinone group at baseline and 5 min (12 vs 10 mm Hg and 11 vs 10 mm Hg, respectively; P < 0.05). Systemic and pulmonary vascular resistances decreased significantly and to a similar extent after either amrinone or milrinone administration. Phenylephrine was required in 11 of 22 patients receiving amrinone and in 11 of 22 patients receiving milrinone to maintain arterial blood pressure. The proportion of patients requiring an intravascular volume infusion (15 of 22 vs 17 of 22, P = NS) and the total fluid volume infused were similar (402 +/- 57 vs 350 +/- 49 mL, P = NS for amrinone and milrinone, respectively). Amrinone and milrinone seem to have similar hemodynamic effects after CPB, with the exception of blood pressure, although the need for vasopressor support of blood pressure did not differ. Selection between these two drugs may include nonhemodynamic considerations such as cost. IMPLICATIONS: Amrinone and milrinone are drugs that improve cardiac contraction. Their effects have never been directly compared in patients. We found that amrinone and milrinone produced similar hemodynamic effects in adult patients undergoing cardiac surgery. Choice between the two drugs can be based on nonhemodynamic considerations such as cost.

Adult↗
PubMed1993

Effect of milrinone on thromboxane A2 synthesis, cAMP phosphodiesterase and 45Ca2+ uptake by human platelets.

The phosphodiesterase inhibitors milrinone and isobutylmethylxanthine (IBMX) inhibited the conversion of [3H]cAMP to [3H]AMP by washed human platelets in concentration-dependent manners (IC50: milrinone, 2.6 x 10(-6) M; IBMX, 4.6 x 10(-6) M). Milrinone and IBMX increased cAMP levels when stimulated by a single concentration (0.3 microM) of iloprost. EC50:milrinone, 5.6 x 10(-5) M; IBMX, 3 x 10(-5) M. Milrinone was a potent inhibitor of platelet thromboxane A2 (TXA2) synthesis when stimulated by median stimulatory doses of collagen (IC50: 3 x 10(-7) M), sodium fluoride (NaF) (a non-specific G protein activator; IC50: 3 x 10(-7) M) and phorbol ester myristate acetate (PMA) (a protein kinase C activator; IC50: 2.2 x 10(-7) M). In contrast, at median stimulatory doses of A23187 and arachidonate there was a marked decrease in the potency of milrinone in inhibiting TXA2 synthesis. Milrinone had a weak inhibitory effect on TXA2 synthesis when elicited by freeze fracturing. In all experiments IBMX was a weaker inhibitor of TXA2 synthesis, although the general pattern of effects was similar to milrinone. Milrinone inhibited both collagen- and adrenaline-stimulated 45Ca2+ uptake by human platelets in dose-dependent manners. Since platelet TXA2 synthesis is dependent on Ca2+, and milrinone inhibited 45Ca2+ uptake, it is concluded that milrinone exerts its inhibitory effect on platelet activity, principally through an action on Ca2+ mobilisation/binding to effector proteins (protein kinase C and/or phospholipase A2).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Structure-activity relationships of milrinone analogues determined in vitro in a rabbit heart membrane Ca(2+)-ATPase model.

The cardiac activity of a series of analogues of the positive inotropic bipyridines amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) and milrinone (2-methyl-5-cyano-[3,4'-bipyridin]-6(1H)-one) was evaluated in vitro in a rabbit myocardial membrane Mg(2+)-dependent, Ca(2+)-stimulable adenosine triphosphatase (Ca(2+)-ATPase) model and structure-activity relationships were compared for nine closely related derivatives. In the present studies, a 5-bromo analogue of milrinone stimulated myocardial membrane Ca(2+)-ATPase significantly (10(-7) M; P < 0.001 vs control, with 67% of the activity of milrinone), whereas a 2'-methyl-2H-milrinone derivative was inactive. Although amrinone was inactive in this assay, its 2-methyl analogue was stimulatory. However, analogues lacking a 2-substituent (with or without a 5-cyano group) or with the 3-N position blocked by a methyl group did not stimulate myocardial membrane Ca(2+)-ATPase activity. Structural data for these bipyridines show that those with either a 2- or 2'-methyl substituent have a twist conformation, whereas those without are nearly planar. Activity data reveal that those bipyridines with a nonplanar conformation are more active in the Ca(2+)-ATPase assay. Further study of milrinone analogues with a 2'-methyl substituent shows that even though the effect on the twist angle is equivalent to that of 2-methyl substitution, these analogues are less potent. Data for this series reveal that the prerequisites for Ca(2+)-ATPase stimulation include not only a 2-methyl to maintain a twist conformation but also a free 3-N position and a 5-substituent. This model for optimal activity in the myocardial membrane Ca(2+)-ATPase system differs from those proposed for phosphodiesterase enzyme receptor recognition only in the requirement for a nonplanar molecule. We have previously shown that milrinone, but not amrinone, shares structural homology with thyroxine and was able to stimulate myocardial membrane Ca(2+)-ATPase activity in a manner similar to the thyroid hormone. Additionally, milrinone, but not amrinone, was an effective competitor for thyroxine binding to the serum transport protein transthyretin. Analysis of the milrinone-transthyretin crystal complex confirms the structural homology between milrinone and thyroid hormone which is not shared by amrinone. Modeling studies of the binding interactions of milrinone analogues indicate that the 2-desmethylmilrinone analogue, the most inhibitory analogue, lacks the hydrophobic contacts present in milrinone in its transthyretin-bound complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Amrinone↗
PubMed1989

Myocardial and vascular actions of milrinone.

Milrinone exerts potent positive inotropic and direct vasodilator properties in vitro. Several studies have been undertaken to elucidate the relative contributions of each of these actions to the overall haemodynamic effect of milrinone in patients with congestive heart failure. Intracoronary infusion of milrinone to patients with congestive heart failure results in a dose-related increase in left ventricular filling pressure, +dP/dt, indicating a positive inotropic effect due to direct myocardial stimulation. Infusion of milrinone into the brachial artery increases forearm blood flow and decreases forearm vascular resistance, indicating a direct vasodilator action in patients with congestive heart failure. The relative contribution of milrinone's positive inotropic and vasodilator actions has been assessed by two approaches. First, the haemodynamic effects of nitroprusside and milrinone were compared at doses that caused equal reductions in arterial pressure. Under this condition, the improvement in left ventricular pump function caused by milrinone exceeded that caused by nitroprusside, suggesting that a significant portion of milrinone's overall effect could not be attributed merely to vasodilatation. Second, the haemodynamic effects of intracoronary and intravenous milrinone administration were compared in the same subjects. Under these conditions, the haemodynamic effect of intracoronary drug infusion accounted for a substantial portion of the improvement in left ventricular pump function. The conclusion from these studies, taken together, is that the overall haemodynamic effect of milrinone is due to significant contributions from both its positive inotropic and its vasodilator actions. Consequently, milrinone differs significantly from pure vasodilators, such as nitroprusside, and relatively pure positive inotropic agents, such as dobutamine.

Cardiotonic Agents↗
PubMedDate not supplied

The effect of milrinone (Win 47203) on the in vitro electropharmacological properties of mammalian cardiac tissue.

The electropharmacological effects of milrinone (Win 47203), a new positive inotropic agent of the bipyridine class, were studied on dog and guinea pig cardiac muscle by means of microelectrode techniques. In dog Purkinje fibers perfused with a Krebs solution containing 4 mM K+, milrinone did not produce any changes in action potential configuration. However, rate of discharge from spontaneously active Purkinje fibers was increased by milrinone. In dog auricular and ventricular trabeculae, milrinone increased action potential amplitude, overshoot, and phase 2 of the action potential. The duration of the action potential and the effective refractory period were decreased. In guinea pig papillary muscle, the changes in the action potential produced by milrinone consisted of a slight increase in overshoot and a reduction in the duration of the action potential. Dog Purkinje fibers depolarized with 20 mM K+ did not respond to milrinone. When such depolarized Purkinje tissue was treated with norepinephrine, slow action potentials appeared, and these could be increased by milrinone. Depolarized dog trabeculae were quiescent and addition of milrinone produced a slow action potential; the amplitude, rate of depolarization, and duration of the slow action potentials were dependent on the milrinone concentration. In depolarized guinea pig papillary muscles, milrinone induced dose-dependent slow action potentials and contractions which could be reversed on washing. Preexisting slow action potentials induced by tetraethylammonium plus high [Ca]o were potentiated by milrinone in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

Central and regional vascular hemodynamics following intravenous milrinone in the conscious rat: comparison with dobutamine.

This study examined the hemodynamic and regional vascular profile of intravenous (i.v.) milrinone during increasing doses (3, 6, 12 micrograms/kg/min, n = 8) and by intraindividual comparison of milrinone and dobutamine (n = 10) in normal conscious rats. At 3 micrograms/kg/min, Milrinone increased coronary and cerebral blood flow (radioactive microspheres 15 +/- 5 microns) (7.7-9.8 and 1.05-1.27 ml/min/g respectively, both p less than 0.05) without significant changes in systemic hemodynamics. At 6 micrograms/kg/min milrinone increased skeletal muscle blood flow (0.19-0.24 ml/min/g, p less than 0.05) along with increases in cardiac output, stroke volume, and stroke work (all p less than 0.05), while systemic vascular resistance decreased (-51%, p less than 0.05). When compared with dobutamine, milrinone caused a greater increase in cardiac output (+26% vs. +17%) and a greater reduction in systemic vascular resistance. Milrinone and dobutamine increased renal, intestinal, cerebral, and coronary flow to a similar extent, but only milrinone enhanced hepatic arterial blood flow (+26%, p less than 0.05) and tended to increase flow to skeletal muscle (+35%, p = 0.07). We conclude that milrinone exerts significant regional vasodilating effects in a conscious rat model, being most prominent in the coronary and cerebral circulations at a dosage that does not alter central hemodynamics. At higher doses, milrinone causes a balanced increase in regional blood flow including enhanced flow to skeletal muscle. The hemodynamic (particularly as compared with dobutamine) and regional vascular profile of milrinone suggests a predominant vasodilating effect in the rat. Given a similar limited response of rat and diseased human myocardium to milrinone, these findings may have important clinical implications.

Animals↗
PubMed1999

The in vivo effects of milrinone on the airways of cystic fibrosis mice and human subjects.

Previous studies have indicated that milrinone, a specific type III phosphodiesterase inhibitor, may be able to induce chloride secretion in cystic fibrosis (CF) tissues. We have now assessed the effect of this agent in vivo on the nasal epithelium of CF mutant mice and also in the nose and lungs of human subjects with CF. Wild-type mice showed a small hyperpolarization of the nasal potential difference (PD) in response to milrinone (100 microM, 1.6 +/- 0.6 mV, n = 8, P < 0.05). In contrast, CF mice carrying either the most common human mutation of the gene for the CF transmembrane regulator (CFTR), DeltaF508 (protein mislocalized), or the G551D mutation (protein normally localized) failed to demonstrate this response. Milrinone perfused alone had no significant effect on the baseline nasal PD of human subjects without CF (14.7 +/- 4.0 mV preperfusion; 15.3 +/- 4.6 mV postperfusion), but significantly (P < 0.05) augmented the hyperpolarization induced by a subsequently perfused low-chloride solution (with milrinone, 36.8 +/- 3.0 mV, n = 6; without milrinone, 18.1 +/- 2.2 mV, n = 19). In contrast, in human subjects with CF (n = 6), milrinone alone significantly (P < 0. 05) altered the nasal baseline PD (52.2 +/- 3.3 mV preperfusion; 57. 4 +/- 4.2 mV, postperfusion) but not the subsequent responses to the low-chloride solution (with milrinone, 1.1 +/- 2.2 mV, n = 4; without milrinone, 0.6 +/- 0.5 mV, n = 28) or to isoproterenol (100 microM). In a separate study in subjects (n = 6) with the DeltaF508 mutation, nasal coadministration of milrinone with isoproterenol produced no effect in the presence of amiloride and a low-chloride solution (-0.8 +/- 0.5 mV). This was also the case in the nasal epithelium of CF subjects (n = 4) carrying at least one G551D allele (-0.3 +/- 0.8 mV). Similarly, milrinone did not hyperpolarize the PD of either the tracheal (n = 6) or segmental (n = 6) airways of CF subjects (DeltaF508) when applied topically in vivo in the presence of amiloride, isoproterenol, or adenosine triphosphate (all 100 microM) in a low-chloride solution. These data do not support the use of milrinone to induce chloride secretion in CF airways in vivo.

Amiloride↗
PubMed1985

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.

Adult↗
PubMed1996

Pharmacodynamics and pharmacokinetics of milrinone administration to increase oxygen delivery in critically ill patients.

OBJECTIVES: The positive inotropic and vasodilator actions of phosphodiesterase (PDE) inhibitor drugs may offer therapeutic alternatives to beta-agonists in critically ill patients. We hypothesized that milrinone administration would increase cardiac index (CI) and oxygen delivery (Do2) in ICU patients, and that a pharmacokinetic model previously developed in cardiac surgery patients may be used to predict milrinone plasma concentrations in a medical-surgical ICU population. SETTING: ICU in two tertiary-care, university medical centers. DESIGN AND INTERVENTIONS: A prospective, open-label, multicenter, dose-escalating study in three successive groups of eight ICU patients who received a 10-min loading dose of milrinone (25 micrograms/kg [LOW], 50 micrograms/kg [MED], and 75 micrograms/kg [HIGH]). In addition, all patients then received a milrinone infusion of 0.5 microgram/kg/min for 1 h. MEASUREMENTS: Hemodynamic measurements included heart rate (HR); mean arterial, pulmonary artery, central venous, and pulmonary artery occlusion pressures; and thermodilution cardiac output. Oxygen transport indexes included arterial and venous blood oxygen tensions to determine Do2 and oxygen consumption (Vo2). Data were analyzed by univariate repeated measures analysis of covariance, with baseline values utilized as covariate regressors. RESULTS: Twenty-four adult ICU patients 20 to 84 years of age completed the study. The three groups did not differ, except that the patients in the MED group were significantly older (67 +/- 4 years, mean +/- SEM) compared with either the patients in the LOW (48 +/- 7 years) or HIGH (47 +/- 6 years) group. While HR did not change in the LOW group (90 +/- 4 to 93 +/- 3 beats/min), HR increased significantly in the HIGH group (94 +/- 5 to 112 +/- 8 beats/min) (baseline to 60 min infusion time points). All milrinone doses increased both CI and Do2. At the end of the 10-min loading dose, CI increased 0.3 L/min/m2 in the LOW group, 1.1 L/min/m2 in the MED group, and 0.9 L/min/m2 in the HIGH group. Do2 increased 8% in the LOW group, 33% in the MED group, and 23% in the HIGH group, similar to the changes in CI. Mixed venous oxygen saturation increased 3 to 5% during the 10-min loading dose of milrinone. During this same time period, mean arterial pressure decreased 6 to 16% and pulmonary artery pressures decreased 9 to 15%. Peak plasma milrinone concentrations increased as a function of the loading dose (159 +/- 9 ng/mL in the LOW group, 302 +/- 33 ng/ml in the MED group, and 411 +/- 45 ng/mL in the HIGH group). However, milrinone concentrations were similar in all three groups after the 1-h infusion; 113 +/- 14 ng/ml (LOW), 147 +/- 22 ng/mL (MED), and 119 +/- 14 ng/ml (HIGH). In all patients with final plasma milrinone concentrations greater than 100 ng/mL (15/23), the CI increased by at least 0.4 L/min/m2 (range, 0.4 to 1.8 L/min/m2). CONCLUSIONS: Our study confirms that a milrinone loading dose of 50 micrograms/kg/min followed by an infusion of 0.5 microgram/kg/min achieves adequate plasma concentrations of 100 ng/mL or greater, which significantly increases both CI and Do2. In addition, a previously established pharmacokinetic model of milrinone disposition is confirmed in this mixed ICU population.

Adult↗
PubMed1988

Milrinone. A preliminary review of its pharmacological properties and therapeutic use.

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Positive inotropic effects of milrinone, sulmazole and AR-L100 on isolated normal and infarcted hearts of the rat.

The recent development of new positive inotropic agents, such as milrinone, sulmazole and AR-L100 might provide new insights for the treatment of congestive heart failure. Although it has been reported that milrinone and sulmazole have cardiac phosphodiesterase III inhibiting properties, the pharmacological action of these drugs cannot be explained by these mechanisms alone. Despite the presence of cardiac phosphodiesterase III in the rat, the effect of milrinone on the rat heart has been reported to be small or even absent. In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction. A perfused heart preparation was used to assess the direct positive inotropic effect of milrinone, sulmazole and AR-L100 as well as their effect on isoprenaline-evoked increase of contractile force. The increase in left ventricular systolic pressure (LVP) in hearts of control animals amounted to 42.0 +/- 3.9 mm Hg, 18.2 +/- 2.4 mm Hg and 8.0 +/- 1.7 mm Hg for AR-L100, milrinone and sulmazole, respectively. The average initial LVP was 70.4 +/- 5.3 mm Hg. In infarcted hearts, the increase in LVP was 25.5 +/- 5.9 mm Hg, 12.6 +/- 2.3 mm Hg and 6.7 +/- 1.2 mm Hg for AR-L100, milrinone and sulmazole, respectively. In infarcted hearts, the average initial LVP was 38.6 +/- 1.6 mm Hg. These data show that these drugs have positive inotropic effects on rat hearts, although the effects of milrinone and AR-L100 on hearts from myocardial infarcted rats are smaller. However, interaction studies with isoprenaline showed a stronger potentiating effect of milrinone and sulmazole in infarcted hearts than in control hearts. Only in this respect sulmazole was more active than milrinone, while AR-L100 had no potentiating effect at all. These results suggest that milrinone and sulmazole are effective agents in conditions where higher levels of circulating catecholamines exist. Therefore, they might be particularly effective in the treatment of congestive heart failure.

Animals↗
PubMed1986

Effects of [Na+] and [Ca2+] on the responses to milrinone in rat cardiac preparations.

In the present investigation we have studied the influence of changing the [Ca2+] and [Na+] on the cardiac responses to milrinone in various preparations of rat heart. Milrinone (5 X 10(-5) to 8 X 10(-4) M) produced a dose-dependent positive chronotropic effect on right atrium and a positive inotropic effect on left atrium and papillary muscle of the rat. A decrease in [Ca2+] (from 2.2 to 1.1 mM) or an increase in [Na+] (from 120 to 60 mM) increased the milrinone-induced inotropic effect in left atrium and papillary muscle. However, in right atrium the chronotropic effect of milrinone was significantly decreased under these conditions. Opposite changes to milrinone-induced responses were observed when [Ca2+] was increased (to 3.3 mM) or when the [Na+] was decreased to 60 mM. Nifedipine (3 X 10(-3) M), a selective Ca2+ channel blocker, significantly inhibited the chronotropic response to milrinone in right atrium. However, the inotropic response to milrinone was found to be significantly greater in the presence of nifedipine. A veratridine-induced positive inotropic effect in the left atrium was also significantly increased in the presence of nifedipine. Tetrodotoxin (TTX, 1 X 10(-6) M), a fast sodium channel blocker, significantly reduced the inotropic response to milrinone in left atrium and papillary muscle. A milrinone-induced dose-dependent increase in the baseline tension was observed in the right atrium which was abolished in low [Ca2+] and significantly increased in high [Ca2+]. Our data suggest the possibility that milrinone increases Ca2+ influx in the right atrium to cause the chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Beneficial hemodynamic effects of two weeks' milrinone treatment in conscious rats with heart failure.

Milrinone is a phosphodiesterase inhibitor which combines vasodilating effects with inotropic effects. Hemodynamic improvement after acute administration and increased survival with chronic milrinone therapy in rats with heart failure have been reported before, and suggest long-term hemodynamic improvement. However, no detailed hemodynamic studies are available on prolonged milrinone therapy in rats with heart failure. Therefore, the hemodynamic effects of 2 weeks' milrinone therapy were now investigated in conscious rats with heart failure due to myocardial infarction. The effects were compared to hemodynamic changes after acute administration. Acute milrinone increased the baseline cardiac output in infarcted rats by increasing heart rate rather than stroke volume. However, the maximal cardiac output achieved when the heart was stimulated through a volume load was improved due to increased stroke volume as well as increased heart rate. The increase in maximally stimulated cardiac output after acute milrinone was found to be related to infarct size. Two weeks' milrinone therapy in chronically infarcted rats dose dependently restored the hemodynamic changes which were caused by infarction. In contrast to acute administration, two weeks' milrinone restored cardiac function without an increase in heart rate. The effects were achieved at a rate of administration which presumably has no acute inotropic effects. The data indicate that acute milrinone in infarcted rats has vasodilating effects. Positive inotropic effects, possibly masked by concomitant venodilatation at baseline conditions, became overt after stimulation by volume loading. Long-term milrinone dose dependently restored cardiac function in infarcted rats without effects on heart rate or mean arterial pressure, suggesting that different mechanisms may be involved.

Animals↗
PubMed2006

Effects of milrinone on blood flow of the Y-graft composed with the radial and the internal thoracic artery in patients with coronary artery disease.

OBJECTIVE: Milrinone has been known to dilate the internal thoracic artery (ITA) and the radial artery (RA). The effect of milrinone, however, on each graft is unclear when the left ITA (LITA) and the RA form a Y-graft. This study evaluated the changes in blood flow of a composite Y-graft in response to milrinone. METHODS: Thirty-two patients undergoing an isolated coronary artery bypass graft surgery were included in this study. A Y-graft was created with an in situ LITA and free RA graft attached to the proximal side of the LITA. Graft flow was measured by opening the graft end for 30s, and is expressed in 'ml/min'. Graft flow and hemodynamic data were recorded before and 10 min after intravenous milrinone (50 microg/kg) administration. RESULTS: Milrinone significantly increased the RA graft flow, measured while the LITA graft end was clamped, and total Y-graft flow. Respective graft flows were not increased by milrinone when both clamps were released simultaneously, in spite of a significant decrease in the resistance of both grafts. The ratio of flows through the RA and the LITA grafts was not changed by milrinone. CONCLUSION: Milrinone significantly reduced RA and LITA resistances and increased the total Y-graft flow. Milrinone might dilate each individual arterial graft to a different degree. Milrinone did not, however, change the flow ratio through the RA to LITA grafts when they were measured simultaneously. Therefore, it would not significantly divert graft flow to one side in a composite Y-graft.

Aged↗