Pharmacological properties of the positive inotropic and alpha 1-adrenoceptor blocking agent saterinone.
The pharmacological properties of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) were investigated in isolated organs of the guinea pig and in human platelets. Saterinone was found to be a potent antagonist at vascular alpha 1-adrenoceptors with a pA2-value of 8.46 +/- 0.12. Besides its affinity for alpha 1-adrenoceptors saterinone exerted a positive inotropic effect in the isolated papillary muscle at an EC50-value of 3.2 X 10(-6)mol/l indicating 10-fold greater potency than milrinone. Comparable EC50-values were also found for the inotropic, chronotropic and bronchodilatory actions of the drug, indicating a common mechanism for these effects. The inotropic effects were not mediated by beta-adrenergic or H2-histaminergic receptors, but were shown to involve an elevation of myocardial cyclic adenosine monophosphate (cAMP) content. Saterinone also inhibited crude cAMP phosphodiesterase (PDE) activity in homogenates obtained from guinea pig right ventricles. The IC50-value for PDE-inhibition was 2.3 X 10(-5) mol/l and thus at a higher concentration than the inotropic effect. Saterinone was a potent inhibitor of human platelet aggregation induced by adenosine diphosphate, collagen and arachidonate. Against the latter agonist, saterinone was about 40-fold more effective than acetylsalicylic acid. In conclusion, saterinone exhibited a dual mechanism of action--direct inotropic effects in the myocardium and alpha 1-receptor blockade in the guinea pig vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)
Armah
B I
BI
Department of Pharmacology, BDF Research Laboratories, Beiersdorf AG, Hamburg, Fed. Rep. of Germany.
Hofferber
E
E
Stenzel
W
W
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011728:Pyridones; D011941:Receptors, Adrenergic; D000242:Cyclic AMP; C058572:saterinone