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PubMedDate not supplied

Pharmacological comparison of CK-2289, an inodilator agent, with milrinone and enoximone.

CK-2289 is an inhibitor of type III cyclic 3'5'-adenosine monophosphate phosphodiesterase with potential utility in the treatment of congestive heart failure. We compared CK-2289 to milrinone and enoximone in several pharmacological models. Intravenous administration of CK-2289 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) produced dose-related increases in myocardial dP/dTmax and decreased mean arterial blood pressure, similar to milrinone and enoximone. However, CK-2289 was 3-9 times more potent than either agent as a positive inotrope. Intraperitoneal and oral administration of CK-2289 and milrinone to mice produced central nervous system depression. Administered intravenously. CK-2289 and milrinone (1 mg/kg) inhibited, whereas enoximone (1 mg/kg) enhanced, guinea-pig gastric acid secretion. CK-2289 (0.01 to 0.3 mg/kg) and milrinone (0.03 to 1 mg/kg), given intravenously, did not affect neurotransmission to the rabbit sciatic nerve-gastrocnemius muscle preparation. Neither CK-2289 nor milrinone (100 microM) inhibited sympathetic neurotransmission, alpha 1-, muscarinic and thromboxane receptors. Both compounds relaxed canine arteries and veins. CK-2289 was devoid of effects on non-vascular smooth muscles of guinea-pig vas deferens and uteri and rabbit bronchi. CK-2289 (1 to 100 microM), milrinone and enoximone inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. These data suggest that CK-2289 should be devoid of adverse renal, neural, smooth or skeletal muscle or gastrointestinal side effects associated with milrinone and enoximone therapy.

Animals↗
PubMedDate not supplied

Acute effects of milrinone on the electrocardiogram and the cardiac hemodynamics of rats with pressure overload-induced congestive heart failure.

The effects of i.v. bolus injections of milrinone on the electrocardiogram and cardiac hemodynamics were evaluated in old rats with chronic (82-93 weeks) pressure overload induced by aortic constriction. Based on the heart weight/body weight ratio and histopathological findings, the rats with aortic clips were divided into 2 groups: rats with (CHF group) or without (CLIP group) congestive heart failure (CHF). In CHF rats, the cardiac contractility, as measured by the peak of the first derivative of the left ventricular pressure (dP/dt max), was significantly lower than in CLIP rats, confirming the presence of heart failure in these rats. Three groups of anesthetized rats received boluses of milrinone of 0.1, 0.5, 1, 5 and 10 mg/kg: sham-operated rats (SHAM, n = 9), CLIP (n = 22) and CHF (n = 10). A control group of 3 CHF and 5 CLIP rats received only the vehicle. The major effect of milrinone at the 2 highest doses was the induction of ventricular fibrillation and death in approximately 25% of the rats (SHAM 2/9, CHF 1/10 and CLIP 7/22). A significant widening of the QRS complex (which includes ST segment) was also noted 3 min after each dose of milrinone in the SHAM group and at 5 and 10 mg/kg doses in the CHF group. These results were thought to be related to the marked hypotensive effect of milrinone possibly inducing myocardial ischemia. No positive inotropic effect, as indicated by the maximum rise of left ventricular pressure (dP/dt max) could be observed. This might have been because of (1) the marked vasodilating effect of milrinone on venous and arterial beds, negating a possible small positive inotropic effect, or (2) the lack of positive inotropic action of milrinone in rats. Our results thus indicate that, in anesthetized rats, milrinone is a powerful vasodilator but not a positive inotropic agent (or a very weak one).

Animals↗
PubMed1988

Effect of milrinone on ethanol and halothane induced cardiodepression.

The inotropic effect of milrinone was studied in isolated rat and cat heart preparations. In the spontaneously beating isolated rat atria a dose-related initial positive inotropic effect was observed, reaching the highest percent increase in tension developed (TD) of +26.5 +/- 2.8% with the dose of 25 micrograms/ml milrinone and a maximal increase in spontaneous rate of +60.2 +/- 6% with the dose of 80 micrograms/ml. However, in electrically driven rat atria, the maximal increase in TD was +39.2 +/- 3.4%. The difference of both preparations might be due to the negative staircase in rat limiting increase in TD in spontaneously beating atria. In electrically driven isolated cat atria the positive inotropic effect of milrinone appeared with 0.5 micrograms/ml and the maximal effect (36% increase in TD) with the dose of 8 micrograms/ml. In cat papillary muscle the dose-response relationship appeared upward and to the left as compared to rat atrial preparations and reached a maximal TD increase of around 90%. Ethanol (22 and 44 mM) induced a dose-related significant decrease of TD in isolated rat atrial preparations, that was reversed by milrinone, and its dose-effect relationship was similar in the presence as well as in ethanol-free medium. In the isolated cat heart papillary muscle, ethanol 44 mM decreased TD 15.1 +/- 1.8%. Milrinone in concentrations up to 8 micrograms/ml increased TD in a significantly lower magnitude than in ethanol-free medium. However, with higher milrinone concentrations (16-120 micrograms/ml) no difference was observed between both conditions. In spontaneously beating right atria halothane 20 micrograms/ml induced a negative inotropic effect revealed by a 33.8 +/- 4.2% decrease in TD, which was reversed by milrinone in a dose-dependent manner. This relative percent increase in TD was significantly greater in halothane exposed atria than in halothane-free experiments. Phosphodiesterase blockade increasing cyclic AMP, which appears to be the main mechanism for the inotropic effect of milrinone, might participate in the reversal of the cardiodepression by both ethanol and halothane or eventually by modifying directly calcium availability.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Effects of milrinone on contractile responses of guinea pig trachea, lung parenchyma and pulmonary artery.

The effects of milrinone, a bipyridine with known vasodilator activity, on guinea pig tracheal-spirals, lung parenchymal strips and pulmonary artery rings in vitro were compared with the effects of isoproterenol and aminophylline on these tissues. The concentration of milrinone that produced 50% relaxation (IC50) of tracheal spirals constricted by carbachol was 3.6 X 10(-5) M. Isoproterenol (IC50, 9.5 X 10(-8) M) was significantly (P less than .001) more potent and aminophylline (IC50, 1.2 X 10(-4) M) was significantly (P less than .001) less potent than milrinone in this effect. The IC50 for milrinone for lung parenchymal strips contracted by histamine was 3.2 X 10(-5) M, whereas the IC50 for isoproterenol was significantly (P less than .001) less, 1.4 X 10(-7) M; aminophylline produced only limited relaxation of lung parenchymal strips. Milrinone relaxed pulmonary artery rings constricted by norepinephrine with an IC50 of 3.8 X 10(-6) M, whereas neither isoproterenol nor aminophylline produced a 50% relaxation. Pretreatment of tracheal spirals, lung parenchymal strips and pulmonary artery rings with 1.6 X 10(-4) M milrinone inhibited subsequent contraction by carbachol, histamine and norepinephrine, respectively. The relaxant effects of milrinone were not influenced by treatment with atropine, cimetidine, mepyramine, phentolamine or propranolol. However, indomethacin blocked milrinone's relaxant effects on tracheal spirals effectively, but not on pulmonary artery rings or lung parenchymal strips, suggesting distinct modes of action on various tissue types.

Aminophylline↗
PubMed1990

Plasma elimination of milrinone in rats in relation to its hemodynamic effects.

Milrinone (1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile) is a cardiotonic drug, currently under clinical investigation for the treatment of congestive heart failure. Its positive inotropic properties and its strong vasodilative action contribute to a favorable therapeutic effect. Plasma elimination of milrinone is generally by renal excretion of the unchanged drug. Since hemodynamic effects might influence the pharmacokinetics of renally eliminated drugs, we have investigated the plasma elimination of milrinone after different iv bolus doses of the compound in healthy rats. Half-times were 20.6 +/- 5.5 min (0.3 mg/kg milrinone), 17.0 +/- 1.8 min (1.0 mg/kg), 31.4 +/- 4.5 min (3.0 mg/kg), and 95.5 +/- 18.4 min (10.0 mg/kg). Clearances of milrinone showed a positive correlation with doses. Hemodynamic effects were dose dependent and (plasma) concentration dependent, and the maximum decrease in diastolic blood pressure was 54.5 +/- 0.5 mmHg. The half-effective plasma concentration of milrinone was 1.0 +/- 0.2 microM. The maximum increase in heart rate was 15%. We conclude that milrinone plasma elimination in rats is dose dependent, probably resulting from its strong vasodilator properties.

Animals↗
PubMed2005

Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema.

Hand, foot, and mouth disease and herpangina are the major clinical manifestations of enterovirus 71 (EV71) infections. Brain-stem encephalitis and pulmonary edema are severe complications that can lead to death. This study was designed to evaluate the potential therapeutic effect of milrinone, a phosphodiesterase (PDE) inhibitor, in the treatment of patients with EV71-induced pulmonary edema. We conducted a historically controlled trial of 24 children with severe EV71-induced pulmonary edema from April 1998-June 2003 in southern Taiwan. Patients were divided into groups treated before and after the introduction of milrinone therapy. Etiological diagnosis was established by viral cultures and confirmed by specific immunofluorescence and neutralization tests. All 24 patients were below 5 years of age. The mortality was lower in the milrinone-treated vs. nontreated group (36.4% vs. 92.3%, P=0.005). Sympathetic tachycardia was decreased in patients treated with milrinone compared to controls (144 +/- 17/min vs. 206 +/- 26/min, P=0.004). A marked decrease in IL-13 (77 +/- 9 pg/ml vs. 162 +/- 88 pg/ml, P=0.001) was observed in milrinone-treated patients compared to controls. There was a significant reduction in white blood cell (10,838 +/- 4,537/mm3 vs. 19,475 +/- 7,798/mm3, P=0.009) and platelet (257 +/- 45 x 10(3)/mm3 vs. 400 +/- 87 x 10(3)/mm3, P=0.001) counts in milrinone-treated patients compared to controls. These results were associated with improvement in sympathetic regulation and decrease in IL-13 production. Milrinone therapy may provide a useful therapeutic approach for this highly lethal disorder.

Biomarkers↗
PubMed1994

The type III phosphodiesterase inhibitor milrinone and type V PDE inhibitor dipyridamole individually and synergistically reduce elevated pulmonary vascular resistance.

The effects of the phosphodiesterase (PDE) inhibitors milrinone and dipyridamole were studied in an in situ perfused rabbit lung model in which the pulmonary vascular resistance (PVR) was elevated by infusion of the thromboxane-A2 mimetic U46619. Dose-response curves for reduction of elevated PVR were generated for each of these drugs. The EC50 for milrinone was approximately 2 microM. The EC50 for dipyridamole was approximately 0.2 microM. In separate experiments, 0.1 microM milrinone was found to reduce elevated PVR by 4.6 +/- 2.4%, 0.06 microM dipyridamole reduced elevated PVR by 8.2 +/- 2.8%, whereas the combination of 0.1 microM milrinone and 0.06 microM dipyridamole reduced elevated PVR by 41.9 +/- 7.3%. In more limited experiments, it was determined that the PDE type V inhibitor zaprinast also caused a synergistic reduction of PVR when used with milrinone. We concluded that both the type III PDE inhibitor milrinone and the type V PDE inhibitors dipyridamole or zaprinast are effectively able to reduce elevated PVR and that the combination of PDE type III and type V inhibitors is synergistic in the ability to reduce elevated PVR. We speculate that type V PDE may play a more important role than type III PDE in the regulation of pulmonary vascular tone. It is proposed that the combination of milrinone and dipyridamole has the potential to be useful in the clinical treatment of elevated PVR.

Animals↗
PubMed1991

The effects of milrinone in the neonatal pig heart.

Milrinone, a selective inhibitor of phosphodiesterase (PDE), was examined in neonatal hearts and in ventricular myocytes. Isolated, paced (180 beats/min), isovolumically beating hearts from pigs, less than 3 days of age, were perfused with an erythrocyte-enriched solution. In one group (control, n = 6), milrinone was studied at perfusate concentrations of 1, 10, and 100 micrograms/ml. In a second group (postischemia, n = 10), hearts were subjected to 30 minutes of no-flow ischemic arrest, prior to the addition of milrinone. Left ventricular peak systolic pressure (PSP) and end-diastolic pressure, coronary flow (CF), heart rate (HR), and myocardial oxygen consumption (MVO2) were measured. The PSP averaged approximately 100 mmHg during the baseline periods for both groups and decreased to approximately 85 mmHg in those hearts subjected to ischemic arrest. In both groups, PSP increased approximately 14% at the 1 micrograms/ml concentration of milrinone. No additional increases in PSP were observed in the control group at the higher concentrations. However, PSP increased 28% and 41% (p less than 0.05), in the postischemia group at the 10 and 100 micrograms/ml concentrations, respectively. The CF averaged approximately 3 ml/min/g during the baseline periods of both groups and increased significantly at each milrinone concentration. The HR in both groups increased to approximately 200 and approximately 250 beats/min at the 10 and 100 micrograms/ml concentrations, respectively. Additionally, milrinone's effects in intact hearts were found to be comparable to those of isobutylmethyl xanthine (IBMX), a nonspecific PDE inhibitor. In isolated myocytes, however, milrinone produced only modest increases in cAMP levels, compared to IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1990

Comparison of cyclic nucleotide phosphodiesterase isoenzymes in rat and rabbit ventricular myocardium: positive inotropic and phosphodiesterase inhibitory effects of Org 30029, milrinone and rolipram.

The species dependent variation in the cardiotonic activity of selective cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors was examined by comparing the inotropic and PDE inhibitory effects of Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide HCl), 3-isobutyl-1-methyl-xanthine (IBMX), milrinone and rolipram in rat and rabbit ventricular myocardium. The relative activities of PDE isoenzymes in rat and rabbit cardiac ventricle were also examined to assess the role of the different PDE subtypes in modulating contractile force in the two species. In rabbit papillary muscles, IBMX, Org 30029 and milrinone increased contractile force whilst rolipram was inactive. The rank order of potency of the active compounds was Org 30029 greater than IBMX greater than milrinone. Only Org 30029 and IBMX produced significant positive inotropic responses in rat papillary muscles, milrinone and rolipram being inactive. However, large positive inotropic responses were obtained in rat papillary muscles when milrinone and rolipram were tested in combination. In rabbit papillary muscles, the positive inotropic action of milrinone was markedly potentiated by rolipram. Four main types of PDE (I, II, III, IV) isoenzymes were resolved, by DEAE-sepharose or Mono-Q ion-exchange chromatography, from both rat and rabbit cardiac ventricular tissue. In rabbit, Ca2+/calmodulin dependent PDE (PDE I) and cyclic GMP inhibited PDE (PDE III) were the dominant cAMP activities. In contrast, cyclic GMP stimulated PDE (PDE II), PDE III and cGMP insensitive PDE (PDE IV) represented the main cAMP activities in rat cardiac ventricle. The inhibitory effects of Org 30029, IBMX, milrinone and rolipram on PDE isoenzymes from rat and rabbit cardiac ventricle were essentially similar.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed2002

Dopamine may preserve the myocardial oxygen balance better than dobutamine when administered with milrinone.

PURPOSE: To compare the hemodynamic effects of dopamine with those of dobutamine when administered with milrinone in patients undergoing non-cardiac surgery. METHODS: In 14 patients undergoing major surgery during anesthesia with isoflurane, milrinone (50 microgram*kg(-1) followed by 0.25 microgram*kg(-1)*min(-1)) was administered. Hemodynamic baseline values were assessed 50 min after continuous infusion of milrinone. Additional infusion of either dopamine or dobutamine, randomly selected, was started at the rate of 4 and later 8 microgram*kg(-1)*min(-1); each hemodynamic variable was measured 20 min after changing the infusion rate. One hour after ceasing the infusion of one catecholamine (dopamine or dobutamine), the other was infused at the rate of 4 and 8 microgram*kg(-1)*min(-1). RESULTS: Milrinone increased heart rate (HR), but decreased mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P < 0.05 for each). Dopamine administered with milrinone significantly increased MAP and cardiac output (CO), whereas dobutamine significantly increased HR and CO, but decreased SVR. By comparison between dopamine and dobutamine administered at the rate of 8 microgram*kg(-1)*min(-1), there was a significant difference in HR, MAP, and SVR (P < 0.01, 0.01, and 0.05, respectively). CONCLUSION: Dopamine and dobutamine administered with milrinone induce different hemodynamic changes: dopamine increases MAP without affecting HR, whereas dobutamine increases HR. Our data suggest that the myocardial oxygen balance might be better preserved with dopamine than with dobutamine when administered with milrinone.

Aged↗
PubMed1987

Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To compare the effects of intravenous dobutamine and milrinone on right ventricular (RV) systolic function, 14 patients with severe congestive heart failure underwent simultaneous radionuclide-hemodynamic study. Patients were randomized to receive intravenous milrinone (50 micrograms/kg bolus then 0.5 microgram/kg/min) or dobutamine (2.5 to 15 micrograms/kg/min) to achieve equal increases in cardiac output. Both drugs significantly improved cardiac performance, with identical 24% increases in mean cardiac index (p less than 0.05 vs baseline; difference not significant for milrinone vs dobutamine) and no change in heart rate. Neither drug substantially altered RV preload, as reflected by mean right atrial pressure and RV end-diastolic volume. Both drugs caused similar increases in RV ejection fraction (mean +/- standard deviation; dobutamine: 0.32 +/- 0.09 to 0.40 +/- 0.11; p less than 0.05; milrinone: 0.35 +/- 0.19 to 0.43 +/- 0.21; p less than 0.05) resulting from reductions in RV end-systolic volume. RV afterload reduction contributed substantially to drug effect on RV systolic performance in patients treated with milrinone but not those treated with dobutamine. With doses effecting equal increases in cardiac index and RV systolic performance, pulmonary artery end-systolic pressure was significantly reduced by milrinone (40 +/- 12 to 33 +/- 12 mm Hg; p less than 0.05), but not by dobutamine. Thus, in patients with congestive heart failure milrinone's effect on RV systolic function is explainable, at least in part, by RV afterload reduction, whereas RV inotropic augmentation contributed more strongly to dobutamine's effect.

Adult↗
PubMed1987

Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy.

Milrinone and dobutamine are positive inotropic agents with beneficial hemodynamic effects in patients with congestive heart failure. This study was undertaken to compare the effects of intravenous milrinone and dobutamine in patients with stable New York Heart Association class III or IV congestive heart failure and to test the hypothesis that intravenous milrinone is at least as beneficial as dobutamine in this setting. Seventy-nine patients were randomized to either dobutamine therapy at incremental doses of 2.5, 5, 7.5, 10, 12.5 and 15 micrograms/kg/min, or milrinone as a bolus of 50 or 75 micrograms/kg followed by an infusion of 0.5 to 1.0 micrograms/kg/min. Both agents significantly increased heart rate, cardiac index and stroke volume index and decreased pulmonary artery wedge pressure and systemic vascular resistance compared with baseline levels (p less than 0.01). During sustained infusion for 48 hours, no difference in hemodynamic effects was observed between the 2 drugs. Ventricular tachycardia occurred in 5 patients (3 taking milrinone, 2 taking dobutamine); 1 patient taking milrinone had ventricular fibrillation. Milrinone and dobutamine elicited similar beneficial hemodynamic results with relatively few adverse effects.

Cardiomyopathy, Dilated↗
PubMed1986

Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure.

Administration of the positive inotropic vasodilator milrinone results in immediate improvement in the maximal and submaximal metabolic responses to exercise. To determine whether these effects persist during long-term therapy, nine patients with severe congestive heart failure were evaluated by upright maximal exercise testing before therapy (baseline), after 10 +/- 1 weeks of oral therapy, and during double-blind, placebo-controlled readministration of intravenous milrinone after withdrawal of oral drug for 24 hours. During long-term oral therapy, maximal oxygen uptake was unchanged (baseline 792 +/- 72 ml per minute, oral therapy 820 +/- 83 ml per minute), whereas the anaerobic threshold was increased significantly from 570 +/- 53 ml per minute to 681 +/- 61 ml per minute. After withdrawal of milrinone, maximal oxygen uptake and anaerobic threshold decreased significantly; subsequent intravenous administration caused significant increases in maximal oxygen uptake and anaerobic threshold, back to the values measured during oral therapy. After oral milrinone withdrawal, maximal oxygen uptake decreased below baseline values, suggesting progression of the underlying disease. The anaerobic threshold expressed as a percent of maximal oxygen uptake was significantly increased during oral therapy (baseline 73 +/- 2 percent, oral therapy 84 +/- 2 percent) and remained significantly increased after drug withdrawal, suggesting a peripheral circulatory effect. These results indicate that in selected patients with severe congestive heart failure, milrinone exerts persistent effects on the metabolic responses to both maximal and submaximal exercise. Because of progressive deterioration in exercise capacity during long-term oral therapy, the effects of milrinone may not be apparent unless it is withdrawn. The relation of milrinone therapy to disease progression is not known.

Administration, Oral↗
PubMed1988

Selective inhibition of cyclic AMP phosphodiesterase from various human tissues by milrinone, a potent cardiac bipyridine.

We observed the effects of milrinone, an inotropic agent prescribed to treat congestive heart failure, on cyclic nucleotide messenger systems in various human tissues in vivo. Cyclic nucleotide phosphodiesterases (PDEs) from the human heart were separated into three isoforms, FI, FII and FIII, by DEAE-cellulose chromatography. Milrinone proved to be a potent and selective inhibitor of human cardiac FIII PDE, a "low Km" enzyme for cyclic AMP (cAMP-PDE). The IC50 value for the inhibition of FIII PDE was 0.42 microM, while those of FI and FII PDEs, "high Km" enzymes, were 38 and 19 microM, respectively. Kinetic studies showed that milrinone inhibited the activity of FIII PDE, competitively with respect to cAMP, and the Ki was 0.15 microM. Milrinone in doses to 100 microM had no effect on human cardiac cAMP-dependent protein kinase and adenylate cyclase. The activity of cAMP-PDEs from human platelets and the aorta, as well as that from heart, were potently inhibited by milrinone, with much the same IC50 values. Cyclic AMP-PDEs from human kidney, liver and lung were not readily inhibited by milrinone, and the IC50 values of cAMP-PDEs from these tissues were about 7-30-fold higher than that from heart. On the other hand, papaverine had a relatively lesser selectivity for any of the cAMP-PDEs. All these results suggest that milrinone exerts inotropic effects by inhibiting cAMP-PDE selectively in the human heart tissues and that this compound can be used to evaluate different forms of cAMP-PDEs present in human tissues.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Effect of milrinone on contractility and 45Ca movements in the isolated rabbit aorta.

The effects of milrinone on 45Ca movements and on contractile responses were studied in rabbit aortic smooth muscle. Milrinone, 10(-7)-5 x 10(-4) M, inhibited the responses induced by high K and noradrenaline (NA). These effects were observed when milrinone was added before or after the induced contractions and were similar in aortas with or without endothelium. The Ca-induced contractions of K-depolarized aortas as well as the contractions induced by caffeine in normal and in Ca-free solution were also inhibited dose dependently by milrinone. Milrinone reduced the 45Ca influx in resting or non-stimulated aortic rings as well as in aortic rings stimulated by NA. On the other hand, neither the 45Ca influx stimulated by high K or the 45Ca efflux stimulated by NA were altered by pretreatment with milrinone. It is concluded that milrinone inhibits vascular smooth muscle contractility by probably acting at multiple sites to decrease the availability of intracellular free Ca required for activation.

Animals↗
PubMed1988

Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction.

The long-term survival of rats with healed myocardial infarction and congestive heart failure treated with milrinone, enalapril and the combination of milrinone plus enalapril, was documented. Seven days after sham or coronary ligation, 200 rats (99 sham and 101 myocardial infarcted) were randomized based on electrocardiographic criteria to receive tap water, milrinone (20-40 mg/l drinking water), enalapril (17-25 mg/l) or the combination of milrinone plus enalapril (20-40 mg/17-25 mg per l). The date of spontaneous death was recorded and heart weights and myocardial infarct size (by planimetry) were determined. Long-term enalapril therapy prolonged survival with a median 50% survival (MS50) of 233 days compared to 203 days in the tap water group. Milrinone therapy also prolonged survival with a MS50 of 297 days. The combination therapy prolonged survival with a MS50 of 277 days. In general, there were three times as many rats alive in the treatment groups at the end of one year compared to untreated control groups. Cardiac hypertrophy was evident in all myocardial infarcted groups and heart weights were significantly reduced by all treatments. The average myocardial infarct sizes and the distribution of infarct sizes were not different between groups (36.8-43% of left ventricle). This study demonstrates that long-term therapy with enalapril and milrinone prolongs survival in rats with healed myocardial infarctions. The prolongation of survival was comparable in the milrinone plus enalapril groups, indicating that there was no synergy with these two agents with survival as the end point.

Animals↗
PubMed2000

Vasorelaxant effect of phosphodiesterase-inhibitor milrinone in the human radial artery used as coronary bypass graft.

OBJECTIVE: The radial artery is a spastic coronary bypass graft. We investigated the effect of the phosphodiesterase III inhibitor milrinone on the human radial artery. METHODS: Radial artery segments (n = 76) taken from 15 patients were studied in an organ chamber. Concentration-relaxation curves for milrinone were established in the radial artery precontracted with 3 vasoconstrictors (phenylephrine, K(+), and U46619). In radial artery rings incubated with therapeutic plasma concentrations of milrinone (7 and 70 micromol/L) for 10 minutes, concentration-contraction curves for the 3 vasoconstrictors were constructed. RESULTS: Milrinone caused a submaximal relaxation in phenylephrine- (98.6% +/- 1.4%), K(+)- (89.1 +/- 4.5%), or U46619- (74.2 +/- 8.0%) precontracted radial arteries at -4.5 log(10) M. The EC(50) was higher against K(+) (-5.85 +/- 0.24 log(10) M, P =.02) or U46619 (-5. 21 +/- 0.61 log(10) M, P =.03) than phenylephrine (-6.68 +/- 0.11 log(10) M). Pretreatment with milrinone depressed the contraction by phenylephrine from 70.0% +/- 7.9% to 23.5% +/- 9.3% (P =.003) and by K(+) from 138.6% +/- 5.8% to 73.0% +/- 13.9% (P =.006) and shifted the EC(50) 3.8-fold higher (P =.03) for phenylephrine and 2.2-fold higher for K(+) (P =.01). Milrinone reduced the U46619 contraction at low concentration (-8.5 log(10) M) but had little effect on the maximal contraction. CONCLUSION: Milrinone is a potent vasodilator for the radial artery, with possibly higher potency in alpha-adrenoceptor- and depolarizing agent K(+)-mediated, but less potency in thromboxane A(2)-mediated, contraction. Because it also has a positive inotropic effect, this vasodilator may be particularly indicated for use in patients receiving radial artery grafts in coronary artery bypass grafting.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol.

OBJECTIVE: To compare the efficacy of milrinone and dobutamine in patients chronically treated with carvedilol. BACKGROUND: Milrinone and dobutamine are used to manage decompensated heart failure, but their efficacy in patients on beta-blocker therapy was unknown. METHODS: Twenty patients with decompensated heart failure were prospectively enrolled. Inotropic responses to milrinone (12.5, 25 or 50 microg/kg bolus infusions) or dobutamine (5, 10, 15 or 20 microg/kg/min infusions) were evaluated by right-heart catheterization. RESULTS: Milrinone increased cardiac index (2.0-2.6 l/min/m2, P=0.0001) without significantly altering heart rate (70-75 bpm, P=0.19). Milrinone decreased mean pulmonary artery pressure (36-29 mm Hg, P=0.0001), pulmonary capillary wedge pressure (24-18 mm Hg, P=0.0001) and mean arterial blood pressure (78-75 mm Hg, P=0.0002). Left ventricular stroke volume index increased in the milrinone group (31-35 ml/beat/m2, P=0.0001). Dobutamine produced an increase in cardiac index (2.4-3.3 l/min/m2, P=0.0001) only at doses that are not typically used to treat heart failure (15-20 microg/kg/min). At these doses, dobutamine increased heart rate (68-82 bpm, P=0.008), mean systemic pressure (90-117 mm Hg, P=0.0001) and mean pulmonary artery pressure (21-30 mm Hg, P=0.001). Dobutamine did not alter left ventricular stroke volume index or pulmonary capillary wedge pressure. CONCLUSIONS: Dobutamine and milrinone have different hemodynamic effects in patients treated chronically with carvedilol. These differences should be considered when selecting inotropic therapy for decompensated heart failure.

Adrenergic beta-Agonists↗