title: Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO--AE1--329 in the halothane-anesthetized dogs.
abstract: Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Honda
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Katagi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.affiliation: Yamanashi Research Center of Clinical Pharmacology, 73-5 Hatta, Isawa-cho, Fuefuki-city, Yamanashi 406-0023, Japan.
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Yamanashi Research Center of Clinical Pharmacology, 73-5 Hatta, Isawa-cho, Fuefuki-city, Yamanashi 406-0023, Japan. Electronic address: atsushi.sugiyama@med.toho-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000200:Action Potentials; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004334:Drug Administration Schedule; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006221:Halothane; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D008738:Methyl Ethers; C461399:ONO-AE1-329; D058309:Receptors, Prostaglandin E, EP4 Subtype; D006221:Halothane
keywords: EP(4); Electro-mechanical relationship; Halothane-anesthetized dog; ONO-AE1-329; ONO-AE1-329 (PubChem CID: 5311230); Positive inotropic effect; Vasodilation