title: The novel cardiotonic agent EMD 53 998 is a potent "calcium sensitizer".
abstract: EMD 53 998, a novel thiadiazinone derivative, increases the contractile force of cardiac tissue in vitro through both an inhibition of phosphodiesterase III (PDE III) and a sensitization of cardiac contractile proteins to Ca2+. Guinea pig ventricular PDE III is selectively inhibited by EMD 53 998 (IC50 = 60 nM) without major effects on other PDE isoenzymes. Consonant with this is an increase in cAMP content of rat ventricular cells and a potentiation by EMD 53 998 of the cAMP-elevating action of isoprenaline (increase by 50% at 1.3 microM). Sensitization to Ca2+ by EMD 53 998 (3-30 microM) finds its expression in a leftward shift of the Ca2+ response curve for force generation in skinned fibers from porcine ventricular muscle and failing human heart as well as for activation of bovine cardiac myofibrillar actomyosin ATPase. Interestingly, EMD 53 998 elevates the maximum of the Ca(2+)-response curve for both parameters. Pimobendan studied under identical conditions was 100 times less potent than EMD 53 998. EMD 53 998 increases force development of guinea pig papillary muscle in a concentration-dependent manner with an EC50 of 3.6 microM, thus being 10 times more potent than pimobendan. In contrast to pimobendan, the positive inotropic effect of EMD 53 998 is barely affected by carbachol. Further evidence for a Ca(2+)-sensitizing effect of EMD 53 998 is provided by an additional increase in force generation in the presence of supramaximal isoprenaline concentrations. It is concluded that the positive inotropic action of EMD 53 998 is mediated through both cAMP-independent and cAMP-dependent mechanisms, with the former probably prevailing. We are not aware of other compounds with a similarly high Ca(2+)-sensitizing potency. On these grounds. EMD 53 998 appears to be a promising inotropic agent.
authors.affiliation: Pharmaceutical Research Department, E. Merck, Darmstadt, F.R.G.
authors.forename: N
authors.initials: N
authors.lastname: Beier
authors.forename: J
authors.initials: J
authors.lastname: Harting
authors.forename: R
authors.initials: R
authors.lastname: Jonas
authors.forename: M
authors.initials: M
authors.lastname: Klockow
authors.forename: I
authors.initials: I
authors.lastname: Lues
authors.forename: G
authors.initials: G
authors.lastname: Haeusler
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects / Q000201:enzymology; D010210:Papillary Muscles / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013829:Thiadiazines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D007527:Isoenzymes; D011724:Pyridazines; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C041648:pimobendan; D002217:Carbachol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000251:Adenosine Triphosphatases; D007545:Isoproterenol; D002118:Calcium