Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Comparative cardiac effects of milrinone and sodium nitroprusside in conscious rats. 776 99

Milrinone is an inotropic and vasodilator agent proven to be effective in the treatment of heart failure. This study evaluated whether milrinone produces inotropic and hemodynamic effects independent of reflex adrenergic stimulation. Eleven stable heart failure patients (New York Heart Association class II to III) undergoing cardiac catheterization received intravenous (i.v.) milrinone (50 micrograms/kg for 10 minutes followed by 0.5 micrograms/kg/min for 50 minutes) during beta-adrenergic blockade. After beta-blockade with a 50-mg oral dose of metoprolol, heart rate decreased by a mean of 16.6%. The peak inotropic response to i.v. milrinone measured using the maximum rate of rise of left ventricular pressure (LV dP/dt) was fully developed at 20 minutes. Mean absolute inotropic response of LV dP/dt from baseline was statistically significant at 10, 20, 30, and 40 minutes (P < 0.05). Mean percentage increase in cardiac index from baseline was statistically significant at 20 and 30 minutes, and mean absolute decline from baseline for pulmonary capillary wedge pressure was statistically significant at 20 and 40 minutes (P < 0.05). The inotropic and hemodynamic effects of i.v. milrinone were thus preserved during beta-adrenergic blockade. This finding is consistent with a mechanism of action of i.v. milrinone--myocardial phosphodiesterase inhibition--that is independent of reflex adrenergic stimulation.
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PMID:The inotropic and hemodynamic effects of intravenous milrinone when reflex adrenergic stimulation is suppressed by beta-adrenergic blockade. 785 37

Glucagon has been reported to be one of the most effective treatments for severe beta-blocker poisoning. Recently, amrinone was suggested as an alternative therapeutic choice for beta-blocker poisoning. Milrinone, a derivative of amrinone, acts independently of beta-adrenoceptors and increases cyclic AMP. Therefore milrinone may also be effective in the treatment of beta-blocker poisoning. In the present study, we compared the effect of glucagon and milrinone in treating severe beta-blocker poisoning. Following the administration of 10 mg/kg propranolol i.v. over 10 min, heart rate, cardiac output, mean arterial pressure, stroke volume, and end tidal CO2 were depressed, while central venous pressure, and pulmonary capillary wedge pressure increased significantly (p < 0.05). Following the administration of saline (Group S, N = 3), glucagon 20 micrograms/kg (Group G, N = 5), and milrinone 300 micrograms/kg (Group M, N = 5), hemodynamic parameters were observed for 30 min. In group M, mean arterial pressure, cardiac output and stroke volume recovered to their baseline values, while central venous pressure and pulmonary capillary wedge pressure decreased. Although there were no significant differences between groups G and M, the heart rate, central venous pressure and pulmonary capillary wedge pressure, mean arterial pressure and stroke volume did not return to baseline values in group G. Milrinone administration produced a significant hemodynamic improvement without increasing the heart rate in the canine model of severe heart failure caused by propranolol. In the glucagon treatment group, central venous pressure and pulmonary capillary wedge pressure improved less than the milrinone group. Although more data are needed before a clinical recommendation, milrinone might be an effective drug to treat beta-blocker poisoning.
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PMID:Milrinone versus glucagon: comparative hemodynamic effects in canine propranolol poisoning. 800 35

It has been clearly established that ischemic heart disease, hypertension and ageing affect diastolic function before any change is observed in contractile function. Though an increasingly recognised clinical entity, cardiac failure with normal systolic function still does not have any specific treatment. Phosphodiesterase inhibitors which increase AMPc, in addition to their inotropic and vasodilator effects, accelerate relaxation. Major and isolated abnormalities of relaxation have been demonstrated in vitro in non necrosed tissues of both the dilated and hypertrophic forms of advanced cardiomyopathy. The myocardium seems unable to restore rapidly the low cytosolic calcium concentrations required for the deactivation of the contractile proteins. The underlying mechanisms are probably very complex but a deficit in AMPc production has been demonstrated in very advanced stages of cardiomyopathy. In ischemia, however, the abnormalities of relaxation seem to be directly related to a defect in free energy production inhibiting the sarcoplasmic reticulum calcium pump. If abnormalities of relaxation due to ischemia and those due essentially to a passive mechanism are excluded, phosphodiesterase inhibitors would seem to have pharmacological effects likely to improve diastolic function. Clinical studies confirm the beneficial effects of Milrinone and Enoximone on relaxation and the rapid phase of diastolic filling, both in acute and chronic studies. However, it has not yet been clearly established whether improved diastolic function is due to a direct action on the myocardium or an indirect action due to improved conditions of load. In order to determine the specific effects of phosphodiesterase inhibitors on diastolic function, further research is required.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

Milrinone is shown in 10 patients to be a valuable pharmacological bridge to heart transplantation; it can stabilize and improve decompensated chronic heart failure (CHF) in cases where the response to beta-agonists is inadequate. One patient who had suffered an acute myocardial infarction with heart failure resistant to vasodilators, beta-agonists, and balloon counterpulsation was stabilized with milrinone for 21 days. He was then maintained on ACE inhibitors until heart transplantation 3 months later. The other nine patients with severe decompensated CHF were stabilized on milrinone for between 11 and 51 days. Seven of them received a donor heart. Two patients died of bacteremic shock and terminal heart failure before a suitable organ could be found (31 and 51 days). All patients were clinically improved within 48 hours of the addition of IV milrinone to their therapy. In 55 patients following cardiac surgery, the efficacy and safety of milrinone in the treatment of low cardiac output states is demonstrated. Milrinone has a useful role in the management of patients with circulatory failure both before and after cardiac surgery, and this paper reviews the relevant current literature.
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PMID:Use of milrinone in cardiac surgical patients. 824 Oct 10

Myocardial contractility is dependent on available intracellular calcium and this can be enhanced by increasing intracellular cyclic adenosine monophosphate. One way of achieving this is by inhibiting the phosphodiesterase III enzyme. Over the last 15 years, a number of new drugs with this mechanism of action have been studied in man and have been found not only to have a positive inotropic action on the heart but also a vasodilating action on peripheral blood vessels. This combination of effects produces favourable haemodynamic improvement in patients with chronic heart failure. While some smaller studies showed that this did translate into an improvement in symptoms and functional capacity, a large well-designed and controlled clinical trial showed that survival was decreased when milrinone was used in target daily doses of 40 mg. For this reason, chronic long-term oral therapy with phosphodiesterase III inhibitors is not currently being actively pursued. They may still have a role as acute short-term therapy in severely ill patients who do not respond adequately to optimal standard drug therapy. Milrinone has been one of the most widely studied drugs in this regard. Even during short-term administration, its use should be closely monitored for any evidence of an increase in ventricular arrhythmias or decrease in ventricular function.
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PMID:The role of phosphodiesterase inhibitors in heart failure. 836 91

The effects of HN-10200 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo(4,5-c)-pyridine HCl) and its derivatives HN-10201-sulfide and HN-10202-sulfone on the activities of the phosphodiesterase (PDE) isoenzyme activities isolated from ventricular myocardium of failing human hearts (end-stage myocardial failure, NYHA IV) were investigated. Four PDE isoenzymes (PDE I-IV) were separated by DEAE-sepharose chromatography. Milrinone, 3-isobutyl-1-methylxanthine (IBMX), and a derivative of pimobendan (2-(4-hydroxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)- benzimidazole HCl, PiD) were studied for comparison. Furthermore, the influence of HN-10200 on force of contraction and cAMP content of ventricular trabeculae of these hearts were determined. HN-10200 inhibited the activities of PDE I-IV concentration-dependently. The IC50 values were (mumol/l): 218.7, 283.1, 119.6, and 85.8 for PDE I-IV, respectively. The IC50 values of its derivatives were in the same range, i.e. the parent compound or its derivatives inhibited the PDE isoenzymes nonselectively. IBMX also inhibited PDE I-IV nonselectively, but was about ten times more potent based on IC50 values. In contrast, PiD was the most selective and potent PDE III inhibitor tested. Milrinone inhibited both, PDE III and IV, up to two orders of magnitude more potently than PDE I and II, HN-10200 (30 mumol/l) only marginally and insignificantly increased force of contraction and cAMP content of the ventricular trabeculae. Thus, HN-10200 and it's derivatives HN-10201-sulfide and HN-10202-sulfone are nonselective inhibitors of myocardial PDE I-IV. HN-10200 revealed only neglectable positive inotropic effects in preparations from failing human heart.
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PMID:Characterization of the phosphodiesterase inhibition by 2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo-(4,5-c)-pyridine HCl and its sulfide- and sulfone derivatives in myocardial preparations from failing human hearts. 857 20

Milrinone (Inocor-Sanofi-Winthrop) represents a second generation phosphodiesterase inhibitor currently approved for intravenous administration in the treatment of decompensated congestive heart failure. By inhibiting Type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate. This results in a positive inotropic effect on the heart and vasodilatation in the periphery. The hemodynamic consequences of this action produce left ventricular afterload reduction, with an increase in cardiac output and a reduction in total peripheral resistance. Unlike the sympathomimetic amines, milrinone produces no tolerance and possesses the distinct advantage of directly decreasing pulmonary vascular resistance. Short-term intermittent infusion by peripheral administration, continuous infusion, long-term therapy, and intermittent outpatient therapy was demonstrated to be safe, efficacious, and cost effective. It is hypothesized that intravenous milrinone, by producing biventricular afterload reduction, offers an efficacious, cost-effective tool for the treatment of decompensated heart failure.
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PMID:Milrinone: basic and clinical pharmacology and acute and chronic management. 865 56

1. In this study, we investigated the influence of the inotropic agent and coronary vasodilator milrinone on platelet aggregation and intracellular levels of 3',5' cyclic adenosine monophosphate (cAMP) in human platelet-rich plasma (PRP) and whole blood (WB). Furthermore, we evaluated the influence of milrinone on the effects of adenosine, which reduces the platelet aggregation through an elevation of intraplatelet cAMP levels. 2. Milrinone decreased the platelet aggregation in response to agonists in both PRP and WB. A dose-dependent increase of intraplatelet cAMP levels was demonstrated: this result is in accordance with an effect on platelet phosphodiesterases. 3. Milrinone at low concentration and adenosine exerted additive effects on platelet aggregation and intraplatelet cAMP levels. 4. An interplay between milrinone and adenosine was shown in WB. Furthermore, dipyridamole, which prevents the uptake of endogenous adenosine, markedly enhanced the milrinone antiaggregating effect, whereas the adenosine receptor blocker, theophylline, decreased it. 5. The present data provide evidence that milrinone modulates the platelet function through an influence on intraplatelet levels of cAMP and it is able to interplay with substances stimulating adenylyl cyclase. 6. The interplay between milrinone and adenosine in the inhibition of the human platelet function could be effective during milrinone administration in the treatment of heart failure, when blood adenosine levels are significantly increased. These milrinone effects could be advantageous from a therapeutic point of view, since patients with heart failure are at risk of thrombosis and ischemic heart disease.
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PMID:Interplay between milrinone and adenosine in the inhibition of human platelet response. 898 Oct 60

Advanced heart failure (AHF) is a serious cause of mortality and morbidity in the United States. The treatment of AHF exacts a great financial and manpower toll on the healthcare infrastructure. The quality of life of patients with AHF also is reduced severely. When it is infused at home, Milrinone, which is an intravenous inodilator agent, reduces the number of hospitalizations. Milrinone decreases the overall treatment costs of AHF. Highly skilled home nursing care is required in the treatment of patients. The home care nurse plays a major role in the outcome of a patient with AHF.
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PMID:Infusion therapy with milrinone in the home care setting for patients who have advanced heart failure. 921 27


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