Phosphodiesterase inhibitors and the cardiac sarcoplasmic reticulum calcium release channel: differential effects of milrinone and enoximone.
OBJECTIVE
The aim was to investigate possible interactions between milrinone or enoximone and the calcium release channel from cardiac sarcoplasmic reticulum.


METHODS
A membrane preparation enriched with "heavy" sarcoplasmic reticulum vesicles containing the calcium release channel was prepared from sheep myocardium. The incorporation of these vesicles into artificial lipid bilayers permitted investigation of the effects of the drugs on single calcium release channels under voltage clamp conditions. The effects of the drugs on radiolabelled ryanodine binding were also investigated as a functional probe for the activity of large populations of channels.


RESULTS
Milrinone (100 microM-2 mM) caused a reversible activation of channel opening when added at the cytoplasmic face of the channel. Lifetime analysis suggests this activation is synergistic with the effects of calcium on the channel. Milrinone also stimulated [3H]ryanodine binding, consistent with the proposition that it is an activating ligand of the calcium release channel. Enoximone (100 microM-1 mM) was without effect on both single channel activity and [3H]ryanodine binding.


CONCLUSIONS
Activation of the calcium release channel probably contributes to the positive inotropic action in vivo of milrinone but not enoximone. Other drugs which activate the calcium release channel have been shown to be cardiotoxic, but it is not known whether this is a specific effect of channel activation or a more general result of raising cytoplasmic calcium concentration within the myocyte. Further research is required to determine accurately the mechanism of action of drugs with phosphodiesterase inhibitory activity.
Holmberg
S R
SR
Department of Cardiac Medicine, National Heart and Lung Institute, London, United Kingdom.
Williams
A J
AJ
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D017335:Enoximone; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D020105:Milrinone; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012756:Sheep
D015220:Calcium Channels; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D012433:Ryanodine; D017335:Enoximone; D020105:Milrinone