title: Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium.
abstract: We performed experiments in rabbit ventricular papillary muscles loaded with aequorin to elucidate the mechanism of positive inotropic effect (PIE) of OR-1896, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic: PIE of OR-1896 reached a plateau at 10(-5) M (first phase), and the CRC became steeper at 10(-3) M and higher (second phase). Maximal response of the first phase was 11% of the maximal response to isoproterenol (ISOmax) and associated with an increase in Ca2+ transients of 5% of ISOmax. For a given degree of PIE, the increase in Ca2+ transients by OR-1896 was lower than that induced by elevation of [Ca2+]o. The PIE of OR-1896 was not associated with impairment of relaxation, and it was abolished by carbachol. In conclusion, OR-1896 has a PIE partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted through crosstalk with signal transduction mediated by cyclic adenosine monophosphate (cAMP).
authors.affiliation: Department of Pharmacology, Yamagata University School of Medicine, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Takahashi
authors.forename: M A
authors.initials: MA
authors.lastname: Talukder
authors.forename: M
authors.initials: M
authors.lastname: Endoh
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000331:Aequorin / Q000493:pharmacokinetics; D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006835:Hydrazones / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D000077464:Simendan; D013268:Stimulation, Chemical; D016278:Ventricular Function, Right / Q000187:drug effects* / Q000502:physiology
chemical_list: D000081:Acetamides; D002316:Cardiotonic Agents; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D000077464:Simendan; D000331:Aequorin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007545:Isoproterenol