Effects of the phosphodiesterase inhibitor enoximone on the autonomic innervation of the isolated heart.
Enoximone is a selective inhibitor of a low Km, cyclic AMP-specific type of phosphodiesterase (PDE III). In guinea pig and chicken atria, enoximone (0.1-100 mumol/L) caused a weak increase in the force of contraction. The heart rate was slightly enhanced or was unchanged (chicken). Enoximone (30 mumol/L) also failed to shift the concentration-response curves for the positive inotropic and chronotropic effects of norepinephrine in guinea pig atria. Under almost the same conditions, enoximone and the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) markedly potentiated the forskolin-induced mobilization of choline from phospholipids. The concentrations of IBMX (100 mumol/L) and of enoximone (50 mumol/L) used were equieffective and did not enhance choline mobilization by themselves. Cardioinhibition caused by acetylcholine was unaffected by enoximone. In perfused guinea pig hearts, the release of [3H]norepinephrine evoked by field stimulation (5 Hz) was increased by 50 mumol/L enoximone both in the absence and presence of cocaine plus corticosterone. In contrast, enoximone failed to alter the release of acetylcholine in chicken hearts at rest and during field stimulation (5 Hz), which directly depolarizes the intrinsic post-ganglionic nerves. Similar results were obtained in guinea pig hearts using [3H]acetylcholine. In contrast, when the release of labeled or unlabeled acetylcholine was evoked by (preganglionic) vagal stimulation, enoximone (30 and 50 mumol/L) and IBMX (50 mumol/L) reduced the release in both species. Taken together, enoximone and IBMX apparently reduced ganglionic transmission. The results further indicate functional compartmentalization of PDE III in guinea pig myocardial cells. PDE III appears to be involved in the regulation of myocardial choline-phospholipid hydrolysis and of norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)
Löffelholz
K
K
Department of Pharmacology, University of Mainz, F.R.G.
Dressler
H
H
Lindmar
R
R
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D002645:Chickens; D005576:Colforsin / Q000494:pharmacology; D004558:Electric Stimulation; D017335:Enoximone; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D017335:Enoximone; D000109:Acetylcholine; D015056:1-Methyl-3-isobutylxanthine