title: A dual-component positive inotropic effect of endothelin-1 in guinea pig left atria: a role of protein kinase C.
abstract: This study was designed to analyze the mechanism(s) underlying the positive inotropic effect (PIE) of endothelin-1 (ET-1) in the guinea pig left atrium. ET-1 exhibited a greater PIE at lower frequencies of pacing and potentiated significantly the postrest contraction similar to isoproterenol. However, ET-1 prolonged the duration of a single contraction, whereas isoproterenol shortened it. ET-1 was similar to methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate in the prolonged duration of a single contraction but different from this drug in the force-frequency relationship. ET-1 at concentrations of 10 nM and higher caused a dual-component PIE composed of an initial increasing phase (early component) and a second greater positive inotropic phase (late component). The early component was correlated to the ET-1-induced prolongation of the duration of the action potential in the time course. Both nifedipine and ryanodine suppressed the late component much more than the early component. ET-1 (> or = 3 nM) produced significant stimulation of phosphoinositide hydrolysis as measured by [3H]inositol monophosphate accumulation. ET-1 was found to activate protein kinase C (PKC) instantaneously but transiently (evaluated by the translocation of PKC activity to the particulate fraction). Pretreatment with 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine and staurosporine, PKC inhibitors, markedly inhibited the late component of the PIE of ET-1 without affecting the early component. These data indicate that the two components of the PIE induced by ET-1 in the guinea pig left atrium may be mediated by different mechanisms. The early component may be attributed to the increased Ca++ influx as a result of the prolongation of the duration of the action potential, whereas the late component may be linked to stimulation of phosphoinositide hydrolysis and subsequent PKC activation.
authors.affiliation: Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hattori
authors.forename: H
authors.initials: H
authors.lastname: Nakaya
authors.forename: J
authors.initials: J
authors.lastname: Nishihira
authors.forename: M
authors.initials: M
authors.lastname: Kanno
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D016279:Atrial Function, Left / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004594:Electrophysiology; D016232:Endothelins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006868:Hydrolysis; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D009543:Nifedipine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D016232:Endothelins; D010716:Phosphatidylinositols; D012433:Ryanodine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011493:Protein Kinase C; D009543:Nifedipine; D007545:Isoproterenol