Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium.
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).
Takahashi
R
R
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Talukder
M A
MA
Endoh
M
M
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
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