Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium.
The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.Cl and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K1-values, the rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. The new inotropic agents also displaced the binding of 3H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean Ki-values were considerably higher at m-cholinoceptors than at A1 adenosine receptors. The rank order of potency was saterinone greater than sulmazole greater than UD-CG 212.Cl greater than milrinone. Competition of the A1 adenosine receptor agonist R-PIA to 3H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient nH = 0.63) and revealed two affinity states of the A1 adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient nH = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the super-high affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p.(ABSTRACT TRUNCATED AT 250 WORDS)
Ungerer
M
M
Medizinische Klinik I, Universität München, Federal Republic of Germany.
Böhm
M
M
Schwinger
R H
RH
Erdmann
E
E
D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors*; D004558:Electric Stimulation; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D020105:Milrinone; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects*; D014970:Xanthines
D002316:Cardiotonic Agents; D007093:Imidazoles; D010879:Piperazines; D011724:Pyridazines; D011728:Pyridones; D011950:Receptors, Cholinergic; D011983:Receptors, Purinergic; D014970:Xanthines; D006165:Guanylyl Imidodiphosphate; D011813:Quinuclidinyl Benzilate; C047936:UD CG 212 Cl; C051360:1,3-dipropyl-8-cyclopentylxanthine; C029758:sulmazole; D020105:Milrinone; C058572:saterinone