New inotropic agents: milrinone analogs.
1. Two new milrinone analogs, 3-acetyl-6-phenyl-2(1H)-pyridone (SF 348) and 3-acetyl-7-methyl-7,8-dihydro-2,5(1H, 6H) quinolinone (SF 349), increase the contractile activity of spontaneously beating and electrically driven atria isolated from reserpine-treated guinea-pigs. 2. Propranolol 0.1 microM drastically inhibits the contractile effect of SF 348, whereas that of SF 349 is unaffected. Preincubation of the atria with adenosine-deaminase suppresses the cardiac activity of SF 349, but does not affect that of SF 348. 3. SF 349 competitively antagonizes the negative inotropic effect induced by N6-(R-phenylisopropyl)-adenosine (R-PIA) and displaces N6-cyclohexyl[3H]-adenosine (3H-CHA) from its binding sites to A1 receptors in the guinea-pig heart. 4. The positive inotropic effect of SF 348 is largely sustained by activation of beta-adrenoceptors, whereas SF 349 acts by displacing endogenous adenosine from its inhibitory (A1) receptors in the atria.
Dorigo
P
P
Department of Pharmacology, University of Padova, Largo, Italy.
Fraccarollo
D
D
Gaion
R M
RM
Santostasi
G
G
Borea
P A
PA
Floreani
M
M
Mosti
L
L
Maragno
I
I
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D016275:Atrial Function; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone / Q000031:analogs & derivatives*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D015363:Quinolones; D011943:Receptors, Adrenergic, beta; D018047:Receptors, Purinergic P1; C107150:SF 348; C107151:SF 349; D010660:Phenylisopropyladenosine; C027513:N(6)-cyclohexyladenosine; D012110:Reserpine; D011433:Propranolol; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000243:Adenosine Deaminase; D020105:Milrinone; D000241:Adenosine