Phosphodiesterase Isozyme Inhibition, Activation of the cAMP System, and Positive Inotropy Mediated by Milrinone in Isolated Guinea Pig Cardiac Muscle

Silver, Paul J.; Harris, Andrea; Canniff, Paul C.; Lepore, Rhonda E.; Bentley, Ross; Hamel, L T; Evans, Dale B.

doi:10.1097/00005344-198904000-00004

Cited by 23 publications

(13 citation statements)

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“…However, the large difference in the EC50 value for positive inotropy and the IC50 concentration for PDE 111 inhibition with amrinone indicates that there is no direct correlation between these two parameters. Similar disparities between EC50 and IC50 values have been reported for other PDE 111 selective inhibitors (Brunkhorst et a1 1989;Silver et al 1989;Shahid & Nicholson 1991). The exact reasons for this discrepancy are not clear but it is possible that increases in cAMP produced by PDE 111 inhibition alone may be limited by the relative activities and distribution of PDE I, PDE I1 and PDE IV.…”

Section: Discussionsupporting

confidence: 52%

Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes

Shahid

Rodger²

1991

Journal of Pharmacy and Pharmacology

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The inotropic activity of amrinone and its effects on cyclic nucleotide levels in rabbit papillary muscles with normal and depressed contractile function have been compared. The effects of amrinone on the cyclic (c) AMP hydrolytic activity of cyclic nucleotide phosphodiesterase (PDE) isoenzymes were also examined. Amrinone (2.4 x 10(-4) - 1.2 x 10(-3) M) produced a relatively weak (maximal increase 11%) positive inotropic effect in papillary muscles stimulated at the near optimal stimulation frequency of 1 Hz. In contrast, large positive inotropic responses (maximal 138-200%) were obtained with amrinone in papillary muscles in which contractile force had been depressed by: (a) lowering stimulation frequency to 0.4 Hz, (b) reducing extracellular Ca2+ concentration from 2.5 x 10(-3) M to 6.3 x 10(-4) M, (c) prior addition of sodium pentobarbitone (6.5 x 10(-4) M). The EC50 values for amrinone under conditions (a), (b), and (c) were 3.0 x 10(-3), 2.6 x 10(-3), and 2.8 x 10(-3) M, respectively. Force-frequency curves in rabbit papillary muscles were compared at normal (2.5 x 10(-3) M) and low (6.3 x 10(-4) M) extracellular Ca2+ concentration. Contractions at low frequencies of stimulation (less than 0.4 Hz) were less sensitive to removal of extracellular Ca2+ than higher stimulation rates indicating that in the former situation, recycling of intracellular Ca2+ is more important for maintaining contractile force.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 52%

Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes

Shahid

Rodger²

1991

Journal of Pharmacy and Pharmacology

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“…Milrinone is a selective PDE3 inhibitor with pharmacological effects, including relaxation of vascular smooth muscle, enhanced myocardial contractility (inotropy) and improved myocardial relaxation (lusitropy). 19,20 In the newborn lamb model, intravenous milrinone augments the action of PGl 2 (prostaglandins) on pulmonary vasculature by significantly shortening the onset and prolonging the duration and degree of pulmonary vasodilation produced by PGI 2 . 21,22 Milrinone may also exhibit synergistic effects with iNO in lowering PVR.…”

Section: Discussionmentioning

confidence: 99%

Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series

et al. 2014

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“…PDE inhibitors affect myocardial function in multiple ways: (1) increased inotropy as a result of cyclic adenosine monophosphatemediated increase in trans-sarcolemmal calcium influx [21], (2) peripheral vasodilatation secondary to removal of free intracellular calcium by causing its uptake by sarcoplasmic reticulum [4], and (3) myocyte relaxation (lusitropy) possibly due to improved actin-myosin complex dissociation [23]. These non-glycoside non-catecholamine agents improve myocardial performance without raising myocardial oxygen consumption [11].…”

Section: Milrinone As Inodilatormentioning

confidence: 99%

Use of milrinone in the management of haemodynamic instability following duct ligation

2010

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Haemodynamic instability affects 22% to 29% of very low birth weight infants in the acute period following ligation of the ductus arteriosus and contributes to the mortality seen in this group. Since the sudden elevation of systemic vascular resistance has been recognised to be one of the factors contributing to this instability, milrinone, an afterload reducing agent, might potentially be of significant therapeutic benefit. This report presents the clinical course of an infant born at 26 weeks gestation who required surgical ligation of a haemodynamically significant patent ductus arteriosus after two unsuccessful 6-day courses of intravenous indomethacin. The post-operative period was characterized by oxygenation failure, rising blood pressure and echocardiographic signs indicative of diastolic dysfunction. The infant was successfully managed with milrinone, a phosphodiesterase inhibitor, which acts both as an "inodilator" and has lusitropy properties. Post-duct ligation haemodynamic instability in a preterm infant was successfully managed with milrinone. The role of afterload-reducing agents such as milrinone in this setting should, therefore, be systematically analyzed.

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Phosphodiesterase Isozyme Inhibition, Activation of the cAMP System, and Positive Inotropy Mediated by Milrinone in Isolated Guinea Pig Cardiac Muscle

Cited by 23 publications

References 0 publications

Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes

Enhancement of Amrinone-induced Positive Inotropy in Rabbit Papillary Muscles with Depressed Contractile Function: Effects on Cyclic Nucleotide Levels and Phosphodiesterase Isoenzymes

Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series

Use of milrinone in the management of haemodynamic instability following duct ligation

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