Biomaterial Database

Phosphodiesterase inhibitors and the cardiac sarcoplasmic reticulum calcium release channel: differential effects of milrinone and enoximone. 1991

S R Holmberg, and A J Williams

Department of Cardiac Medicine, National Heart and Lung Institute, London, United Kingdom.

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.

UI	MeSH Term	Description	Entries
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D009206	Myocardium	The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.	Muscle, Cardiac,Muscle, Heart,Cardiac Muscle,Myocardia,Cardiac Muscles,Heart Muscle,Heart Muscles,Muscles, Cardiac,Muscles, Heart
D010726	Phosphodiesterase Inhibitors	Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases.	Phosphodiesterase Antagonists,Phosphodiesterase Inhibitor,Phosphoric Diester Hydrolase Inhibitors,Antiphosphodiesterases,Inhibitor, Phosphodiesterase
D011728	Pyridones	Pyridine derivatives with one or more keto groups on the ring.	Pyridinones
D004305	Dose-Response Relationship, Drug	The relationship between the dose of an administered drug and the response of the organism to the drug.	Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D012433	Ryanodine	A methylpyrrole-carboxylate from RYANIA that disrupts the RYANODINE RECEPTOR CALCIUM RELEASE CHANNEL to modify CALCIUM release from SARCOPLASMIC RETICULUM resulting in alteration of MUSCLE CONTRACTION. It was previously used in INSECTICIDES. It is used experimentally in conjunction with THAPSIGARGIN and other inhibitors of CALCIUM ATPASE uptake of calcium into SARCOPLASMIC RETICULUM.
D012519	Sarcoplasmic Reticulum	A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.	Reticulum, Sarcoplasmic,Reticulums, Sarcoplasmic,Sarcoplasmic Reticulums
D012756	Sheep	Any of the ruminant mammals with curved horns in the genus Ovis, family Bovidae. They possess lachrymal grooves and interdigital glands, which are absent in GOATS.	Ovis,Sheep, Dall,Dall Sheep,Ovis dalli
D015220	Calcium Channels	Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue.	Ion Channels, Calcium,Receptors, Calcium Channel Blocker,Voltage-Dependent Calcium Channel,Calcium Channel,Calcium Channel Antagonist Receptor,Calcium Channel Antagonist Receptors,Calcium Channel Blocker Receptor,Calcium Channel Blocker Receptors,Ion Channel, Calcium,Receptors, Calcium Channel Antagonist,VDCC,Voltage-Dependent Calcium Channels,Calcium Channel, Voltage-Dependent,Calcium Channels, Voltage-Dependent,Calcium Ion Channel,Calcium Ion Channels,Channel, Voltage-Dependent Calcium,Channels, Voltage-Dependent Calcium,Voltage Dependent Calcium Channel,Voltage Dependent Calcium Channels