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PubMed1997

A placebo-controlled trial verifying the efficacy of milrinone in weaning high-risk patients from cardiopulmonary bypass.

OBJECTIVE: To establish the efficacy of the phosphodiesterase inhibitor milrinone in facilitating weaning from cardiopulmonary bypass of high-risk patients with left ventricular dysfunction and/or pulmonary hypertension. DESIGN: A double-blinded, placebo-controlled longitudinal study. SETTING: A university teaching hospital. PARTICIPANTS: Thirty-two patients with preoperative left ventricular ejection fraction < or = 35% and/or mean pulmonary artery pressure > or = 20 mmHg were studied after their written informed consent. INTERVENTION: Patients were randomized to commence either intravenous milrinone, 50 micrograms/kg loading dose over 20 minutes followed by 0.5 microgram/kg/min infusion, or matching placebo 15 minutes before withdrawal of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Two patients were withdrawn from the study and their results not analyzed: one because of early failure of hemodynamic monitoring and the other because of gross surgical bleeding. In the remaining 30 patients, who were well matched for clinical and baseline hemodynamic variables, bypass support was successfully withdrawn in all 15 patients randomized to receive milrinone but in only 5 of the 15 patients randomized to receive placebo. In the 10 patients who initially failed to wean from bypass while on placebo, bypass was reinstituted and open-label milrinone was administered in the dose outlined. After treatment with open-label milrinone, these patients could also be withdrawn from bypass support. During the period of hemodynamic monitoring, cardiac index increased in both milrinone- and placebo-treated patients, although this change was greater in those treated with milrinone. Perhaps related to routine clinical treatment, there were no significant differences between the two groups with mean pulmonary artery or pulmonary capillary wedge pressures, the other major hemodynamic endpoints. There were no significant adverse effects related to milrinone. CONCLUSIONS: This placebo-controlled, double-blind study has conclusively demonstrated the benefits of milrinone in facilitating weaning of high-risk patients from cardiopulmonary bypass.

Aged↗
PubMed2003

Anti-thrombotic effect of milrinone is caused by inhibition of calcium release from the dense tubular system in human platelets.

AIM: Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic effects which induce an increase in the intracellular calcium concentration by raising the cyclic adenosine monophosphate level in cardiac muscle. Milrinone was also reported to inhibit platelet aggregation, however, its mechanism remains unknown. Therefore, we investigated the effects of milrinone on intracellular calcium mobilization when platelets were activated. METHODS: Washed platelets, obtained from six healthy volunteers, were preincubated with milrinone (0.9 micro M) for 1 min and then exposed to 0.015 i micro ml-1 thrombin for 5 min. The effect of milrinone on changes in the intracellular calcium level using a fluorescent dye, fura-2, was also observed. Calcium mobilizations via plasma membrane calcium channels and the dense tubular system were assessed differentially. RESULTS: Milrinone (0.9 micro M) significantly suppressed the aggregation ratios at 5 min compared with those in controls (86+/-5%) to 75+/-8%. The increase in the intracellular calcium concentration was also significantly suppressed (controls, 915+/-293 nM vs. 405+/-240 nM) when stimulated by thrombin. Milrinone also significantly inhibited the release of calcium from the dense tubular system (controls, 284+/-111 nM vs. 158+/-51 nM). Calcium influx through the plasma membrane was suppressed by milrinone 2.4 micro M. CONCLUSION: Milrinone (0.9 micro M) inhibited thrombin-induced platelet aggregation. This inhibitory effect was mainly mediated by suppressing calcium release from the dense tubular system.

Adult↗
PubMed2001

Comparison of milrinone versus nitroglycerin, alone and in combination, on grafted internal mammary artery flow after cardiopulmonary bypass: effects of alpha-adrenergic stimulation.

OBJECTIVES: To compare changes in blood flow in a grafted internal mammary artery (IMA) after cardiopulmonary bypass (CPB) in response to the administration of milrinone or nitroglycerin and to establish the effects of alpha-adrenergic stimulation. DESIGN: Randomized study. SETTING: A university medical center hospital and a Veterans Affairs Medical Center hospital. PARTICIPANTS: Thirty consenting adults scheduled for elective coronary artery bypass graft surgery. INTERVENTIONS: Patients were randomized to receive a 2 microg/kg/min infusion of nitroglycerin (n = 10), a loading dose of 50 microg/kg of milrinone (n = 10), or both drugs combined (n = 10) shortly after CPB. Intravenous phenylephrine was administered to increase mean arterial pressure by 20%. IMA flow was measured with a calibrated laser Doppler flow probe. Hemodynamic and flow measurements were obtained before and after every intervention. MEASUREMENTS AND MAIN RESULTS: Nitroglycerin and milrinone increased mean IMA flow, but the increase was greater with milrinone. Both drugs combined were superior to nitroglycerin alone but not to milrinone. The addition of phenylephrine to nitroglycerin increased IMA flow in 6 of 10 patients. IMA flow decreased in 4 of 10 patients, however. Phenylephrine significantly increased IMA blood flow in patients receiving milrinone or in those given both drugs combined. CONCLUSION: After CPB, milrinone and nitroglycerin vasodilate the IMA; however, the combination of both drugs was not superior to milrinone alone. When using alpha-adrenergic stimulation, milrinone proved superior to nitroglycerin in preserving IMA flow.

Adrenergic alpha-Agonists↗
PubMed2001

Milrinone echocardiographic viability test: a pilot study.

We assessed the utility of milrinone to predict recovery of function after surgical myocardial revascularization in patients with severe baseline left ventricular systolic dysfunction caused by coronary artery disease (CAD). Prediction of viable myocardial segments that will regain function after revascularization may help in the selection of patients who will benefit from coronary artery bypass graft surgery (CABG) as well as aid in the choice of target sites for coronary revascularization. We investigated 20 consecutive patients with CAD and left ventricular ejection fraction < or = 40% who had evidence of myocardial viability by either thallium scan or dobutamine viability test and were candidates for elective CABG. Left ventricular regional wall motion and global ejection fraction were assessed by transesophageal echocardiography in the operating room. Measurements were done before and 10 minutes after milrinone infusion, and immediately after CABG. Left ventricular wall motion score was derived by means of a 12-segment model. Functional improvement for each segment was defined as a wall motion change > 1. Baseline ejection fraction was 27% +/- 5% (mean +/- SD). Ejection fraction increased to 35% +/- 5% after milrinone infusion (P < .0001) and to 36% +/- 6% after CABG (P < .0001). Post-CABG ejection fraction was significantly correlated with postmilrinone ejection fraction (r = 0.65, P < .0001). Milrinone infusion resulted in augmentation of contraction in 98 of the 209 abnormal segments (wall motion score > or = 2); 91 (92.9%) of these improved after CABG. One hundred nine of the 111 segments that showed no improvement with milrinone did not improve after revascularization (98.2%). Seventy-three segments were akinetic or dyskinetic at baseline; 46 (63.0%) of these improved with milrinone. Improvement in regional wall motion after revascularization was detected in 84.8% of the segments that improved with milrinone versus only 3.7% of the segments that did not improve with milrinone. In patients with ischemic cardiomyopathy, improvement in left ventricular function (segmental wall motion and global ejection fraction) during milrinone infusion is highly predictive of improvement after CABG.

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

A pharmacokinetic and pharmacodynamic evaluation of milrinone in adults undergoing cardiac surgery.

Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients. Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 micrograms/kg) in an open-label, dose-escalating study if their cardiac index was < 3 L.min-1.m-2 after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices < 3 L.min-1.m-2 after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-micrograms/kg doses produced significantly larger increases in cardiac index than the 25-micrograms/kg dose; however, the 75-micrograms/kg dose did not produce a significantly larger increase in cardiac index than did the 50-micrograms/kg dose. Two of 10 patients receiving milrinone 25 micrograms/kg, but no patient receiving either 50 or 75 micrograms/kg, required early epinephrine rescue when the cardiac index failed to increase by > 15%. The 75-micrograms/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-micrograms/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V1 = 11.1 L, V2 = 16.9 L, and V3 = 363 L. Similarly, the following clearances were estimated for the three compartments: Cl1 = 0.067 L/min, Cl2 = 1.05 L/min, and Cl3 = 0.31 L/min. The 50-micrograms/kg loading dose appeared more potent than the 25-micrograms/kg dose, and, as potent, but with possibly fewer side-effects than the 75-micrograms/kg dose. The short context-sensitive half-times of 6.7 or 10.2 min after 1- or 10-min bolus infusions underscore the need for prompt institution of a maintenance infusion when milrinone concentrations must be maintained.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2000

Milrinone attenuates serotonin-induced pulmonary hypertension and bronchoconstriction in dogs.

UNLABELLED: We determined whether milrinone, a phosphodiesterase III inhibitor, attenuates serotonin-induced (5-hydroxytryptamine [5HT]) pulmonary hypertension (PH) and bronchoconstriction. Dogs were anesthetized with pentobarbital (30 mg/kg + 2 mg. kg(-1). h(-1)). Bronchoconstriction and PH were elicited by 5HT (10 microg/kg + 1.0 mg. kg(-1). h(-1)). Pulmonary vascular resistance was used to assess PH. Bronchoconstriction was also assessed by changes in bronchial cross-sectional area obtained from our bronchoscopic method. At 30 min after 5HT infusion started, seven dogs were given milrinone: 0 (saline), 5, 50, 500, and 5000 microg/kg at 10-min intervals. The other 12 dogs were given milrinone 5000 microg/kg 30 min after 5HT infusion, and 5 min later were given propranolol 0.2 mg/kg (n = 6) or saline (n = 6) IV. The 5HT significantly increased percentage of pulmonary vascular resistance to 208% +/- 27% and decreased percentage of bronchial cross-sectional area to 52% +/- 5% of the basal. Milrinone significantly attenuated both PH and bronchoconstriction in a dose-dependent manner. However, -log 50% effective concentration (mean ED(50) in microg/kg) of milrinone for bronchoconstriction: 4.32 +/- 0.13 (47.6) was significantly smaller than that for PH: 3.84 +/- 0.29 (144.9) (P < 0.01). In addition, the spasmolytic effects of milrinone (5000 microg/kg) were not antagonized by propranolol, although this dose significantly increased plasma catecholamines. In conclusion, milrinone attenuates 5HT-induced PH and bronchoconstriction; however, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than in pulmonary vascular smooth muscle. In addition, the relaxant effects could not be caused by beta-adrenoceptor activation because beta-blocker did not antagonize. IMPLICATIONS: We studied the effects of milrinone on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Milrinone produces pulmonary vasodilation and bronchodilation, whose effects may not be caused by beta-adrenoceptor activation. In addition, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than that in pulmonary vascular smooth muscle.

Animals↗
PubMed2001

The effects of alpha-human atrial natriuretic peptide and milrinone on pial vessels during blood-brain barrier disruption in rabbits.

UNLABELLED: The effects of alpha-human atrial natriuretic peptide (HANP) and milrinone on cerebral pial vessels, especially during blood-brain barrier (BBB) disruption, are not clear. We studied topical HANP (10(-14), 10(-12), and 10(-10) M) or milrinone (10(-7), 10(-5), and 10(-3) M), and IV HANP (0.1, 0.2, and 1.0 microg. kg(-1). min(-1)) or milrinone (0.5, 5.0, and 20.0 microg. kg(-1). min(-1)) with or without hyperosmolar BBB disruption, using a rabbit cranial window preparation. At 10(-12) and 10(-10) M topical HANP produced significant arteriolar (16%, 20%, respectively), but no venular dilation. Topical milrinone (10(-3) M) produced significant arteriolar and venular dilation (21%, 8%, respectively). IV HANP produced no arteriolar or venular changes at any dose except during BBB disruption, when it caused a significant arteriolar (16%, 16%, and 17%, respectively), but no venular dilation. In contrast, IV milrinone caused small but significant arteriolar and venular dilation without BBB disruption (arterioles, 6%, 7% and 8%, respectively; venules, 6% at 20.0 microg. kg(-1). min(-1)). During BBB disruption, these responses to milrinone were similar. Although HANP and milrinone each have a direct vasodilator effect on arterioles, their systemic administration at clinical doses could induce different effects. BBB disruptive conditions could increase the response of pial vessels to systemically administered HANP. IMPLICATIONS: Although alpha-human atrial natriuretic peptide (HANP) and milrinone each have a direct vasodilator effect on cerebral pial arterioles, their systemic administration at clinical doses could have different effects and blood-brain-barrier disruptive conditions could alter the response of pial vessels to HANP, but not to milrinone.

Animals↗
PubMed1995

Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery.

OBJECTIVE: To evaluate the hemodynamic effects of intravenous milrinone in neonates with low cardiac output after cardiac surgery. DESIGN: Prospective cohort study. SETTING: Pediatric cardiac intensive care unit. PATIENTS: Ten neonates with low cardiac output (cardiac index of < or = 3.0 L/min/m2) after corrective cardiac surgery were enrolled in the study. The neonates' ages ranged from 3 to 27 days (median 5) and their weights ranged from 2.0 to 4.8 kg (median 3.7). The diagnoses were: transposition of the great arteries (n = 6, including two with ventricular septal defect), tetralogy of Fallot (n = 2), truncus arteriosus (n = 1), and total anomalous pulmonary venous connection (n = 1). INTERVENTIONS: Milrinone was intravenously administered in three stages: a) baseline stage, in which patients had a stable hemodynamic status, ventilation and gas exchange, hemostasis, and body temperature; b) loading stage, in which a 50 microgram/kg intravenous loading dose of milrinone was administered over 15 mins; and c) infusion stage, in which milrinone was continuously infused at 0.50 microgram/kg/min for 30 mins. MEASUREMENTS AND MAIN RESULTS: The mean heart rate increased after the loading stage (149 +/- 13 to 163 +/- 12 beats/min, p < .01) but slowed during the infusion stage (154 +/- 11 beats/min, p < .01 vs. loading stage). Both right and left atrial pressures were lowered in all ten neonates. Compared with baseline, mean arterial pressure decreased after the loading stage (66 +/- 12 to 57 +/- 10 mm Hg, p < .01) but did not decrease further at the infusion stage (59 +/- 12 mm Hg); changes in mean pulmonary arterial pressure were comparable. Cardiac index increased from a baseline mean of 2.1 +/- 0.5 to 3.0 +/- 0.8 L/min/m2 (p < .01) with the loading stage, and was maintained at 3.1 +/- 0.6 L/min/m2 during the infusion stage. Systemic vascular resistance index decreased below baseline values with loading, from 2136 +/- 432 to 1336 +/- 400 dyne.sec/cm5.m2 (p < .01), and pulmonary vascular resistance index also decreased with loading dose of milrinone, from 488 +/- 160 to 360 +/- 120 dyne.sec/cm5.m2 (p < .01). There was no change in the rate pressure index, an indirect measurement of myocardial oxygen consumption, throughout the study. CONCLUSIONS: Administration of milrinone in neonates with low cardiac output after cardiac surgery lowers filling pressures, systemic and pulmonary arterial pressures, and systemic and pulmonary vascular resistances, while improving cardiac index. Milrinone increases heart rate without altering myocardial oxygen consumption. While milrinone appears to be effective and safe during short-term use, the relative distribution of inotropic and vasodilatory properties of milrinone remains to be elucidated.

Cardiac Output, Low↗
PubMed1989

Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction.

The effects of milrinone and pimobendan upon the initiation of programmed ventricular stimulation-induced ventricular tachycardia (VT) and the incidence of lethal ischemic ventricular arrhythmias were assessed in conscious dogs with recent anterior myocardial infarctions. Based upon the results of previous studies, the animals which were entered into this investigation were nonresponsive to baseline programmed stimulation and, therefore, considered to be at "low risk" toward the development of subsequent lethal ischemic arrhythmias. Milrinone (200 micrograms/kg/h continuous i.v. infusion) and pimobendan (300 micrograms/kg i.v.) were administered in dosing regimens shown to produce equivalent and sustained increases in left ventricular (LV) + dP/dt. At the time of repeat electrophysiologic testing, 9 of 9 pimobendan-, 9 of 10 milrinone-, and 12 of 12 concurrent vehicle-treated animals remained nonresponsive to programmed ventricular stimulation. Compared to a total control population of 39 "low risk" postinfarction dogs; however, both milrinone and pimobendan administration increased the incidence of sudden ventricular fibrillation occurring in response to the development of acute posterolateral ischemia (milrinone 4 of 10 [40%] and pimobendan 4 of 10 [40%] versus "low risk" control population 4 of 39 [10.3%]; p = 0.038). The incidence of ischemic mortality at 24 h after the development of posterolateral myocardial ischemia was increased in the milrinone-treated group (6 of 10 [60%]) compared to the "low risk" control population (6 of 39 [15.2%]; p = 0.007), whereas the incidence of 24-h ischemic mortality in the pimobendan-treated group (4 of 10 [40%]) was only of borderline statistical significance when compared to that of the "low risk" control population (p = 0.083). Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs. The predominant electrophysiologic effects of both milrinone and pimobendan were decreases in ventricular refractoriness in both non-infarct (NZ) and in infarct zones (IZ), as well as reductions in electrocardiographic QTc or QT intervals. These findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. The enhanced susceptibility toward the development of ischemic ventricular arrhythmias in the presence of the inotropic interventions is not predicted by programmed ventricular stimulation testing prior to the ischemic event.

Animals↗
PubMed1996

Inhibition of vasoconstriction by phosphodiesterase III inhibitor milrinone in human conduit arteries used as coronary bypass grafts.

We wished to determine the effect of phosphodiesterase III (PDE III) inhibitor milrinone on human arteries used as coronary bypass grafts. Human internal mammary artery segments (IMA, n = 109) taken from 25 patients were studied. Concentration-relaxation curves for milrinone were established in IMA precontracted with four vasoconstrictors [K+, endothelin-1 (ET-1), U46619, and phenylephrine (PE)]. In IMA rings incubated with therapeutic plasma concentrations of milrinone (7 and 70 microM) for 10 min, concentration-contraction curves for the four vasoconstrictors were constructed. Milrinone caused a complete relaxation in U46619, ET-1, PE (100%), or K+ (97.7%)-precontracted IMA. The EC50 value was higher against K+ (-5.31 +/- 0.27 log M) than PE (-6.20 +/- 0.25 log M, p = 0.036) or endothelin-1 (-6.41 +/- 0.28 log M, p = 0.018). Pretreatment with milrinone decreased the contraction induced by ET-1 from 186.0 +/- 23.3 to 66.9 +/- 9.6% (p = 0.002) and that induced by PE from 140.6 +/- 27.6 to 54.1 +/- 7.0% (p = 0.03) and shifted the EC50 7.6-fold higher (p = 0.003). Treatment of milrinone reduced the K+ and U46619 contraction (p < 0.05) at lower concentrations (between 10 and 80 mM for K+ and -8.5 and -7.5 log M for U46619) and shifted the concentration-contraction curves rightward (2.56-fold higher for K+, p < 0.0001; 3.18-fold higher for U46619, p = 0.007). Denudation of endothelium did not affect the milrinone-induced relaxation. These results demonstrate that milrinone is a potent vasodilator of human conduit arteries used as coronary bypass grafts and may have a slight selectivity with greater potency to receptor stimulants than to the depolarizing agent K+. The results may prove a particular indication for milrinone for use in patients receiving arterial grafts for coronary bypass.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Prevention of chronic cerebral vasospasm in dogs with milrinone.

OBJECTIVE: Delayed cerebral ischemia resulting from vasospasm is a major cause of morbidity and death in patients with aneurysmal subarachnoid hemorrhage. Milrinone, because it inhibits Type IV cyclic adenosine monophosphate-specific phosphodiesterase enzyme in both cardiac and vascular smooth muscle, is a powerful inotrope and vasodilator, but it has little effect on heart rate or blood pressure. Because of these properties, milrinone is an attractive potential therapy after subarachnoid hemorrhage. The purpose of the present study was to investigate the effect of milrinone on chronic experimental cerebral vasospasm. METHODS: A double-hemorrhage canine model of vasospasm was used to study the efficacy of milrinone. Angiographic vasospasm and systemic hemodynamics were compared in a treatment group of animals that received a loading dose of milrinone (0.05 mg/kg, intravenously) and then slow-release (0.05 microgram/kg/min) milrinone pellets (n = 10) and a control group that received placebo pellets (n = 9), over an 8-day period after the initial subarachnoid hemorrhage. The hemorrhage was created by injection of 4 ml of autologous, nonheparinized, arterial blood into the cisterna magna on Days 1 and 3. Hemodynamic measurements, including cardiac output determinations, were made on Days 0, 1, 3, 6, and 8 with a pulmonary artery catheter, and angiographic vasospasm was assessed on Day 8 by comparison with baseline angiograms. RESULTS: Treatment with milrinone caused no significant changes in systemic hemodynamics. Angiographic vasospasm, however, was significantly reduced in the Day 8 angiograms for the treated group, compared with the control group (98.28 +/- 14.06 and 67.89 +/- 13.06% of original vessel cross-sectional area, respectively; P < 0.001). CONCLUSION: Milrinone is effective in preventing chronic cerebral vasospasm in a canine model of experimental chronic cerebral vasospasm. This effect is independent of changes in systemic hemodynamics. Milrinone and related drugs warrant further investigation for the treatment of cerebral vasospasm.

Animals↗
PubMed2005

Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone.

Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% +/- 3.36% versus 91.03% +/- 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% +/- 5.37%; milrinone, 77.65% +/- 4.42% versus vehicle: 74.42% +/- 7.54%). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.

Animals↗
PubMed1987

Effects of milrinone on contractility of the rat diaphragm in vitro.

We studied the effects of the phosphodiesterase inhibitor, milrinone, on isometric force production in the isolated, directly stimulated rat diaphragm. Milrinone (500 micrograms/ml) significantly increased force during twitch stimulation and submaximal tetanic stimulation (p less than 0.05); force during maximal tetanic stimulation was significantly reduced by milrinone (p less than 0.05). The force-augmenting effects of milrinone were not abolished by pretreatment with indomethacin (10(-5)M). Baseline force production decreased when diaphragmatic strips were placed in a calcium-free bathing solution; force potentiation by milrinone, however, persisted in this medium. Pretreatment with milrinone more than doubled the mean time to fatigue (10.8 +/- 1.0 versus 5.1 +/- 0.6 min) during repetitive submaximal stimulation (p less than 0.01). In diaphragmatic strips fatigued by repetitive submaximal stimulation until force production was 60% of baseline, milrinone promptly improved force production; the magnitude of force potentiation after milrinone was quite similar in fresh and fatigued muscle. In conclusion, milrinone enhances diaphragmatic contractility during the most forms of direct stimulation, and delays and reverses diaphragmatic fatigue.

Animals↗
PubMed1995

Comparative cardiac effects of milrinone and sodium nitroprusside in conscious rats.

The rat has been shown to be resistant to the inotropic action of milrinone. We compared in conscious rats, the effects of an i.v. infusion of milrinone (0.3 mg/kg/min), a phosphodiesterase (PDE) inhibitor to those of nitroprusside (50 micrograms/kg/min), a pure vasodilator, on blood pressure and dP/dtmax to determine whether or not an inherent positive inotropic effect of milrinone is offset by its powerful hypotensive action. For the first 10 min of infusion, we found no differences in dP/dtmax, (the first derivative of the left ventricular pressure (LVP), an index of contractility) for equihypotensive doses of milrinone or nitroprusside. A second objective of this study was to determine if milrinone-induced ventricular fibrillation (VF) is due to cardiac ischemia which could be associated with the profound hypotension induced by the drug. Milrinone infusion was accompanied by a significant QTc interval (QT corrected for heart rate) prolongation. VF and death occurred in 5/6 rats at total doses varying from 3.6 to 20.1 mg/kg infused over 12 to 67 min respectively. Premature ventricular contractions (PVCs) were noted in all 6 milrinone infused rats during the first min. of infusion. No arrhythmias were noted during the 2 hour i.v. infusion with nitroprusside. A direct action on the heart is postulated to explain, at least partially, the milrinone-induced VF since nitroprusside had a similar hypotensive action but no effect on the ECG. We conclude that the rat, in analogy to patients with severe cardiac failure, might be resistant to the inotropic action of milrinone but is sensitive to its vasodilatory and arrhythmogenic effects.

Animals↗
PubMed1999

[Influence of milrinone on internal mammary artery grafts].

To evaluate the effects of milrinone on blood flow in the left internal mammary artery (LIMA) grafts and hemodynamic variables, we conducted a prospective randomized study. Twenty-four patients undergoing coronary artery bypass grafting were randomized to receive milrinone treatment (Milrinone; n = 12) or no milrinone treatment (Control; n = 12). Milrinone was given after induction of anesthesia at a speed of 0.5 microgram/kg/min for 24 hours. After start of cardiopulmonary bypass (CPB), CPB perfusion flow was adjusted to 2.4 l/m2 and LIMA blood flow was measured. Blood samples for determination of plasma cAMP levels were collected and hemodynamic measurements were also assessed perioperatively. LIMA blood flow was significantly greater in Milrinone than that in Control (40 +/- 4 vs 29 +/- 4 ml/min/m2, p < 0.05). Plasma levels of cAMP were significantly (p < 0.05) greater in Milrinone than those in Control at tha start of CPB (18 +/- 1 vs 13 +/- 1 pmol/ml) and at the end of CPB (24 +/- 2 vs 17 +/- 2 pmol/ml). Systemic vascular resistance was significantly (p < 0.05) lower and cardiac index was significantly (p < 0.05) greater in Milrinone than those in Control postoperatively. With its positive inotropic and systemic vasodilator activities, milrinone may have direct vasodilator effect on LIMA.

Aged↗
PubMed2003

Intravenous milrinone in treatment of advanced congestive heart failure.

Phosphodiesterase inhibitors such as milrinone can relieve symptoms and improve hemodynamics in patients with advanced congestive heart failure. We retrospectively evaluated the hemodynamic and clinical outcomes of long-term combination therapy with intravenous milrinone and oral beta-blockers in 65 patients with severe congestive heart failure (New York Heart Association class IV function and ejection fraction <25%) refractory to oral medical therapy. Fifty-one patients successfully began beta-blocker therapy while on intravenous milrinone. Oral medical therapy was maximized when possible. The mean duration of milrinone treatment in this combination-treatment group was 269 days (range, 14-1,026 days). Functional class improved from IV to II-III with milrinone therapy. Twenty-four such patients tolerated beta-blocker up-titration and were successfully weaned from milrinone. Sixteen patients (31%) died while receiving combination therapy; one died of sudden cardiac death (on treatment day 116); the other 15 died of progressive heart failure or other complications. Hospital admissions during the previous 6 months and admissions within 6 months after milrinone initiation stayed the same. Meanwhile, the total number of hospital days decreased from 450 to 380 (a 15.6% reduction), and the mean length of stay decreased by 1.4 days (a 14.7% reduction). We conclude that 1) milrinone plus beta-blocker combination therapy is an effective treatment for heart failure even with beta-blocker up-titration, 2) weaning from milrinone may be possible once medications are maximized, 3) patients' functional status improves on the combination regimen, and 4) treatment-related sudden death is relatively infrequent during the combination regimen.

Adrenergic beta-Antagonists↗
PubMed1989

Phosphodiesterase isozyme inhibition, activation of the cAMP system, and positive inotropy mediated by milrinone in isolated guinea pig cardiac muscle.

The purpose of the present study was to examine the interrelationships among phosphodiesterase (PDE) isozyme inhibition, cAMP formation, activation of cAMP-dependent protein kinase (cAPK), and positive inotropy in isolated guinea pig cardiac muscle mediated by the cardiotonic/vasodilator agent, milrinone. Milrinone was a potent and selective inhibitor of the "low Km" cAMP PDE isozyme (peak III) isolated by diethylaminoethyl ether cellulose chromatography, with IC50 values of 0.7 microM for peak III PDE and 100 microM for peak I PDE. In isolated papillary muscles frozen at peak inotropic responses, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.72, p less than 0.05) or cAPK activity ratio, an index of activation of cAPK (r = 0.79, p less than 0.001), for concentrations of milrinone from 0.1-1000 microM. Similar correlations were evident in muscles frozen at peak inotropic responses for the beta-adrenoreceptor agonist isoproterenol (r = 0.96, p less than 0.001; r = 0.98, p less than 0.001, respectively), but not for ouabain or Bay K-8644. The temporal sequence of these events was also quantitated for concentrations of milrinone (100 microM) and isoproterenol (3 nM) that produced approximately a 100% increase in isometric force. Whereas early time interval of force development (30 s, 1 min, isoproterenol; 30 s milrinone) were not accompanied by significant increases in either cAMP content or cAPK activity ratio, peak increases in force development for both isoproterenol (2 min) and milrinone (1 min) were related to peak increases in cAPK activity ratios. In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with positive inotropy in isolated guinea pig papillary muscles with milrinone. These correlations occur at concentrations of milrinone that inhibit cardiac PDE isozymes and are similar to the known cAMP-dependent cardiostimulant isoproterenol. These data support the hypothesis that selective PDE isozyme inhibition is a mechanism by which milrinone effects positive inotropy.

Animals↗
PubMed1988

Stability of milrinone and digoxin, furosemide, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate, or verapamil hydrochloride in 5% dextrose injection.

The stability of milrinone and digoxin, furosemide, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate, or verapamil hydrochloride in 5% dextrose injection containing milrinone was studied. Milrinone admixtures with digoxin, furosemide, propranolol hydrochloride, quinidine gluconate, and verapamil hydrochloride were studied at two concentrations. Admixtures of milrinone and procainamide hydrochloride were studied at four concentrations. Duplicate solutions of each admixture and each control were prepared and stored in glass containers for four hours at room temperature (22-23 degrees C), under normal fluorescent lights. The samples were analyzed immediately by visual inspection, tested for pH, and assayed by high-performance liquid chromatography (HPLC). Milrinone 0.35 mg/mL-furosemide 4 mg/mL and milrinone 0.1 mg/mL-furosemide 5 mg/mL admixtures precipitated immediately after preparation and were not studied by HPLC. No changes in pH or visual appearance were observed in the remaining admixtures after storage at room temperature for four hours. Admixtures containing milrinone 0.175 or 0.2 mg/mL and procainamide hydrochloride 1, 2, or 4 mg/mL satisfied the USP standard for procainamide hydrochloride injection USP assay after one hour but failed this test in all cases after four hours. No degradation of milrinone was observed in any of the admixtures containing procainamide hydrochloride. Milrinone and furosemide are incompatible in 5% dextrose injection and should be administered separately. The remaining admixtures were compatible, and all except those containing procainamide hydrochloride were stable for four hours at room temperature.

Digoxin↗