title: Effect of a novel inhibitor of cyclic AMP phosphodiesterase, E-1020, on cytosolic Ca++ level and contraction in vascular smooth muscle.
abstract: 1. The effects of a novel cyclic AMP phosphodiesterase inhibitor, E-1020 (1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate), on cytosolic Ca++ level ([Ca++]cyt) and muscle tension were examined in rat aorta using a fluorescent Ca++ indicator, fura-2. 2. The sustained contraction induced by norepinephrine was more strongly inhibited by E-1020 than that induced by high K+. The contraction induced by a higher concentration of the stimulant was less sensitive to E-1020 than that due to a lower concentration. 3. Contractions induced by high K+ and norepinephrine followed the increase in [Ca++]cyt. E-1020 inhibited the increments in [Ca++]cyt and muscle tension. A Ca++ channel blocker, verapamil, inhibited the norepinephrine-stimulated [Ca++]cyt more strongly than the contraction. E-1020 inhibited the verapamil-insensitive portion of the norepinephrine-stimulated [Ca++]cyt and contraction. 4. Norepinephrine transiently increased [Ca++]cyt and muscle tension in Ca(++)-free solution. E-1020 inhibited the transient contraction but not the stimulated [Ca++]cyt. 5. E-1020 increased the cyclic AMP content of the muscle. The effects of E-1020 on cyclic AMP content and contraction were potentiated by an activator of adenylate cyclase, forskolin. 6. These results suggest that E-1020 inhibits the vascular contractility by the decrease in [Ca++]cyt and decrease in Ca++ sensitivity of contractile elements. These effects may be mediated by the increase in cyclic AMP content of the muscle.
authors.affiliation: Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tajimi
authors.forename: H
authors.initials: H
authors.lastname: Ozaki
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Karaki
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; C059498:olprinone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002118:Calcium