Characterization of the Cardiotonic Effects of Milrinone, a New and Potent Cardiac Bipyridine, on Isolated Tissues from Several Animal Species

Alousi, Adawia A.; Stankus, Gerald P.; Stuart, James C.; Walton, Louise H.

doi:10.1097/00005344-198309000-00015

Cited by 151 publications

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“…Whatever the mechanisms involved, PDE III inhibitors are potent relaxant agents in the aorta, in spite of their relative inability to produce positive inotropy in rat cardiac tissue compared to their cardiac effect in other species (Alousi et al, 1983;Kobylarz et al, 1985;Weishaar et al, 1987). In agreement with the results of Martin et al (1986a,b), we have found that the selective PDE V inhibitor, zaprinast, induced a relaxation that was endothelium-dependent.…”

Section: Discussionmentioning

confidence: 99%

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

Komas

Lugnier²,

Stoclet³

1991

British J Pharmacology

138

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1 The effects of selective inhibitors of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) and guanosine 3': 5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 pM) precontracted rat aortic rings, with and without functional endothelium. 2 Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I. 3 The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (aM concentration producing 50% relaxation) : LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither N0-monomethyl-L-arginine (L-NMMA, 300pM), an inhibitor of the Larginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (1OpM) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930. 4 The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10piM). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine. 5 The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC5o values 1.7 and 12puM, respectively) or SNP (EC50 values 12.3 and 124pM, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 JM and for rolipram: 7, 13, 7 and 1.2 pM). 6 These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.

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Section: Discussionmentioning

confidence: 99%

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

Komas

Lugnier²,

Stoclet³

1991

British J Pharmacology

138

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“…These actions, demonstrated in a variety of animal preparations1 2 and recently in man, indicate an important potential use for milrinone in the long-term treatment of congestive heart failure.…”

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confidence: 88%

The effects of milrinone on conduction, reflection, and automaticity in canine Purkinje fibers.

Davidenko¹,

Antzelevitch²

1984

Circulation

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Milrinone is a newly developed analogue of amrinone possessing potent positive inotropic action. Electrophysiologic actions of the drug have not been reported. In this study microelectrode techniques were used to assess the electrophysiologic effects of milrinone in canine false tendons homogeneously superfused with either normal or high-K Tyrode's solution and in Purkinje fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Milrinone (0.2 to 20 gug/ml) caused no major changes in the action potential characteristics, refractoriness, or conduction velocity in fibers exposed to normal Tyrode's solution, but markedly improved conduction and abbreviated or eliminated postrepolarization refractoriness in the ischemic gap preparations. The drug also exerted important effects on reflected reentry generated in these preparations. Depending on the initial level of block, milrinone (1) suppressed the arrhythmia, (2) shifted its frequency dependence, or (3) created the conditions that allowed reflection to occur. Similar results were obtained in homogeneously depressed fibers. At similar concentrations, milrinone caused a relatively small enhancement of automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may exert either antiarrhythmic or arrhythmogenic effects. Circulation 69, No. 5, 1026No. 5, -1035No. 5, , 1984 MILRINONE (Win 47203), a new analogue of the cardiac bipyridine amrinone, has been shown to exert potent inotropic and vasodilatory effects. These actions, demonstrated in a variety of animal preparations1 2 and recently in man, indicate an important potential use for milrinone in the long-term treatment of congestive heart failure.Although the effects of milrinone on the mechanical properties of cardiac and smooth muscle have been investigated in some detail, studies of the actions of the drug on the electrical properties of heart tissues are lacking.Our study was designed to assess the effects of milrinone on action potential morphology, impulse conduction, automaticity, and arrhythmias in normal and depressed preparations of isolated cardiac Purkinje fibers. The effect of the drug on reflected reentry was evaluated with the use of the "ischemic gap" preparation previously developed in our laboratory.6The results demonstrate an important effect of this

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“…This occurred despite a significant fall in the mean pulmonary capillary wedge pressure (the driving force for left ventricular filling) in these patients ( figure 3). Furthermore, this increase in left ventricular peak filling rate was observed in all but one 1 It is probable that left ventricular systolic and diastolic function and dysfunction are "coupled" physiologic processes"2 and that the biochemical processes underlying some types of heart failure might affect myocardial relaxation as well as contraction. 23 Furthermore, it is also likely that failure of complete left ventricular myocardial relaxation could contribute to the abnormality seen in left ventricular systolic func-PRE POST MILRINONE A previous study reported altered early relaxation in patients with congestive (dilated) cardiomyopathy and heart failure, as supported by markedly depressed values for both peak negative dP/dt and velocity of circumferential fiber lengthening in early diastole.…”

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confidence: 91%

Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone.

Monrad¹,

McKay²,

Baim³

et al. 1984

Circulation

186

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To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased ( + 18%; p < .01 ) and T decreased (-30%; p < .01), while heart rate increased by only 8% (87 + 12 to 94 + 15 beats/min; p < .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p < .01). Left ventricular peak filling rate increased (1.2 + 0.6 to 1.7 + 0.7 end-diastolic volumes/sec; p .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 ± 7 to 18 9 mm Hg; p < .01). There was a fall in left ventricular end-diastolic pressure (28.6 + 6 to 19 + 7 mm Hg; p ' .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases. These changes in parameters of left ventricular diastolic relaxation and chamber distensibility after administration of milrinone suggest that improved diastolic function may contribute to the beneficial hemodynamic effect of milrinone in patients with congestive heart failure. Circulation 70, No. 6, 1030-1037, 1984 MILRINONE, a derivative of the bipyridine inotrope amrinone, has previously been shown to have a profound effect on myocardial contractile function in isolated muscle' and animal preparations.2 The clinical response of patients with congestive heart failure who are treated with this agent has been ascribed to readily demonstrable improvements in indexes of left ventric- Received Feb. 22, 1984; revision accepted Sept. 6, 1984. Presented in part at the 56th Annual Scientific Sessions of the American Heart Association. Anaheim, November 1983. 1030 ular systolic function (including increases in peak positive dP/dt and in left ventricular ejection fraction) and concurrent arteriolar vasodilation.3However, possible effects of milrinone on ventricular diastolic function, which might also contribute to the hemodynamic response to this agent, have not been evaluated. In particular, improved diastolic relaxation and distensibility might lead to more effective sarcomere stretch within the ventricular myocardium and to better systolic performance.6 7 Thus it is possible that improved systolic pump function in patients with heart failure treate...

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Characterization of the Cardiotonic Effects of Milrinone, a New and Potent Cardiac Bipyridine, on Isolated Tissues from Several Animal Species

Cited by 151 publications

References 0 publications

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

The effects of milrinone on conduction, reflection, and automaticity in canine Purkinje fibers.

Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone.

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