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DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties

  • G. Scholtysik
  • R. Salzmann
  • R. Berthold
  • J. W. Herzig
  • U. Quast
  • R. Markstein
Article

Summary

The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated.

DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10−7 and 3×10−6 mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 μmol/l respectively.

In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 μmol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer.

DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecular septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 did not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria.

In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

Key words

DPI 201-106 Positive inotropic effect Cardiac electrophysiology Stereoselectivity Ca2+-sensitization 

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References

  1. Akera T, Brody TM (1977) The role of Na+, K+-ATPase in the inotropic action of digitalis. Pharmacol Rev 29:187–220Google Scholar
  2. Alabaster CT, Blackburn KJ, Joice JR, Massingham R, Scholfield PC (1977) UK-14, 275, a novel orally-active cardiac stimulant. Br J Pharmacol (Abstract) 60:284PGoogle Scholar
  3. Alousi AA, Canter JM, Montenaro MJ, Fort DJ, Ferrari RA (1983) Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals. J Cardiovasc Pharmacol 5:792–803Google Scholar
  4. Anno T, Furuta T, Itho M, Kodama I, Toyama J, Yamada K (1984) Effects of bepridil on the electrophysiological properties of guinea-pig ventricular muscles. Br J Pharmacol 81:589–597Google Scholar
  5. Bassingthwaighte JB, Fry CH, McGuigan JAS (1976) Relationship between internal calcium and outward current in mammalian ventricular muscle: a mechanism for the control of action potential duration? J Physiol (Lond) 262:15–37Google Scholar
  6. Beress L, Ritter R, Ravens U (1982) The influence of the rate of electrical stimulation on the effects of the anemonia sulcata toxin ATX II in guinea papillary muscle. Eur M Pharmacol 79:265–272Google Scholar
  7. Brückner R, Scholz H (1984) Effects of α-adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart. Br J Pharmacol 82:223–232Google Scholar
  8. Diederen W, Weisenberger H (1981) Studies on the mechanism of the positive-inotropic action of AR-L 115 BS, a new cardiotonic drug. Arzneimittelforsch/Drug Res 31:177–182Google Scholar
  9. Dudel J, Trautwein W (1958) Elektrophysiologische Messungen zur Strophantinwirkung am Herzmuskel. Naunyn-Schmiedeberg's Arch Pharmacol 232:393–407Google Scholar
  10. Erdmann E, Philipp G, Scholz H (1980) Cardiac glycoside receptor, (Na++K+)-ATPase activity and force of contraction in rat heart. Biochem Pharmacol 29:3219–3229Google Scholar
  11. Evans DB, Weishaar RE, Kaplan HR (1982) Strategy for the discovery and development of a positive inotropic agent. Pharmacol Ther 16:303–330Google Scholar
  12. Fabiato A (1981) Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle. J Gen Physiol 78:457–497Google Scholar
  13. Frandsen EK, Krishna G (1976) A simple ultrasensitive method for the assay of cyclic AMP and cyclic GMP in tissues. Life Sci 18:529–542Google Scholar
  14. Herzig JW, Rüegg JC (1980) Investigations on glycerinated cardiac muscle fibres in relation to the problem of regulation of cardiac contractility-effects of Ca++ and cAMP. Basic Res Cardiol 75:26–33Google Scholar
  15. Herzig JW, Feile K, Rüegg JC (1981a) Activating effects of AR-L 115 BS on the Ca2+ sensitive force, stiffness and unloaded shortening velocity (V max) in isolated contractile structures from mammalian heart muscle. Arzneimittelforsch/Drug Res 31: 188–191Google Scholar
  16. Herzig JW, Köhler G, Pfitzer G, Rüegg JC, Wölffle G (1981b) Cyclic AMP inhibits contractility of detergent treated glycerol extracted cardiac muscle. Pflügers Arch 391:208–212Google Scholar
  17. Herzig JW, Bormann G, Botelho L, Erdmann E, Salzmann R, Solaro RJ (1983) APP 201-533, a novel cardiotonic agent: In-crease in Ca++ sensitivity and economization of the myocardial contractile process. J Mol Cell Cardiol 15: (Suppl 1) 244Google Scholar
  18. Holroyde MJ, Howe E, Solaro RJ (1979) Modification of calcium requirements for activation of cardiac myofibrillar ATPase by cyclic AMP dependent phosphorylation. Biochem Biophys Acta 586:63–69Google Scholar
  19. Honerjäger P (1982) Cardioactive substances that prolong the open state of sodium channels. Rev Physiol Biochem Pharmacol 92:1–74Google Scholar
  20. Honerjäger P, Schäfer-Korting M, Reiter M (1981) Involvement of cyclic AMP in the direct inotropic action of amrinone. Naunyn-Schmiedeberg's Arch Pharmacol 318:112–120Google Scholar
  21. Honerjäger P, Heiss A, Schäfer-Korting M, Schönsteiner G, Reiter M (1984) UD-CG 115 — a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guineapig papillary muscle. Naunyn-Schmiedeberg's Arch Pharmacol 325:259–269Google Scholar
  22. Inoue F, McNeill JH, Pull E, Tenner TE Jr (1979) Electropharmacological analysis of the actions of histamine in cardiac tissue. Can J Physiol Pharmacol 57:778–786Google Scholar
  23. Isenberg G, Ravens U (1983) ATX II-induced enhancement of contractility in ventricular myocytes: Cellular sodium load or prolonged action potential duration? Naunyn-Schmiedeberg's Arch Pharmacol (Abstract) 324: R33Google Scholar
  24. Kanayama H, Ban M, Ogawa K, Satake T (1982) Myocardial concentration of norepinephrine and cyclic AMP in ventricular fibrillation during acute myocardial ischemia. J Cardiovasc Pharmacol 4:1018–1023Google Scholar
  25. Kariya T, Wille LJ, Dage RC (1982) Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043. J Cardiovasc Pharmacol 4:509–514Google Scholar
  26. Kariya T, Wille LJ, Dage RC (1984) Studies on the mechanism of the cardiotonic activity of MDL 19205: Effects on several biochemical systems. J Cardiovasc Pharmacol 6:50–55Google Scholar
  27. Korth M (1978) Effects of several phosphodiesterase-inhibitors on guinea-pig myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 302:77–86Google Scholar
  28. Ledda F, Mantelli L, Mugelli A (1980) Alpha-sympathomimetic amines and calcium-mediated action potentials in guinca-pig ventricular muscle. Br J Pharmacol 69:565–571Google Scholar
  29. Meszaros J, Kelemen K, Marko R, Kecsemeti V, Szegl J (1982) Inhibition of myocardial K+ channel by bromobenzoyl-methyladamantylamine, an adamantane derivative. Eur J Pharmacol 84:151–160Google Scholar
  30. Meyer W (1984) Effects of a new benzimidazole derivative (UD-CG 212) on force of contraction and phosphodiesterase activity in guinea-pig hearts. Naunyn-Schmiedeberg's Arch Pharmacol (Abstract) 325: R46Google Scholar
  31. Morad M, Trautwein W (1968) The effect of the duration of the action potential on contraction in the mammalian heart muscle. Pflügers Arch 299:66–82Google Scholar
  32. Opie LH, Lubbe WF (1979) Catecholamine-mediated arrhythmias in acute myocardial infarction. S Afr Med J 56:871–880Google Scholar
  33. Perrin DD, Sayce IG (1967) Computer calculation of equilibrium concentrations in mixtures of metal ions and complexing species. Talanta 14:833–842Google Scholar
  34. Pöch G (1971) Assay of phosphodiesterase with radioactively labeled cyclic 3′, 5′-AMP as substrate. Naunyn-Schmiedeberg's Arch Pharmacol 268:272–299Google Scholar
  35. Pollard TD (1982) Assays for myosin. Methods enzymol 85 (structural and contractile proteins, B). Academic Press, New York, pp 123–130Google Scholar
  36. Ray KP, England PJ (1976) Phosphorylation of the inhibitory subunit of troponin and its effects on the calcium dependence of cardiac myofibrillar ATPase. FEBS Lett 70:11–16Google Scholar
  37. Reiter M (1968) Versuche über die pharmakologische Beeinflussung der elektromechanischen Koppelung. In: Reindell H, Keul J, Doll E (eds) Herzinsuffizienz, Pathophysiologie und Klinik. Thieme, Stuttgart, pp 102–108Google Scholar
  38. Reiter M (1972) Differences in the inotropic cardiac effects of noradrenaline and dihydro-ouabain. Naunyn-Schmiedeberg's Arch Pharmacol 275:243–250Google Scholar
  39. Salzmann R, Bormann G, Herzig JW, Markstein R, Scholtysik G (1985) Pharmacological actions of APP 201-533, a novel cardiotonic agent. J Cardiovasc Pharmacol (in press)Google Scholar
  40. Scholtysik G, Schaad A (1983) Cardiac cellular electrophysiology as a tool to prove Ca++ slow channel inhibition by PY 108-068. Triangle 22:49–55Google Scholar
  41. Scholtysik G (1981) Retardation of aconitine-induced ECG-alterations in rats as an indication of membrane-stabilizing drug effects. In: Budden R, Detweiler DT, Zbinden G (eds) The rat electrocardiogram in pharmacology and toxicology. Pergamon Press, Oxford, pp 257–264Google Scholar
  42. Schuhmacher P, Greeff K, Noack E (1983) Zur Wirkung des Benzimidazol-Derivates AR-L 115 BS auf die myokardiate Adenylatcyclase und Phosphodiesterase. Arzneimittelforsch/Drug Res 32(I):80–82Google Scholar
  43. Sheu SS, Fozzard HA (1982) Transmembrane Na+ and Ca++ electromechanical gradients in cardiac muscle and their relationship to force development. J Gen Physiol 80:325–351Google Scholar
  44. Singh B (1983) Amiodarone: Historical development and pharmacologic profile. Am Heart J 106:788–797Google Scholar
  45. Solaro JR, Pang DC, Briggs N (1971) The purification of cardiac myofibrils with Triton X-100. Biochem Biophys Acta 245: 259–262Google Scholar
  46. Solaro RJ, Holroyde MJ, Herzig JW, Peterson JM (1980) Cardiac relaxation and myofibrillar interactions with phosphate and vanadate. Eur Heart J 1:21–27Google Scholar
  47. Steiger GJ (1971) Stretch activation and myogenic oscillation of isolated contractile structures of heart muscle. Pflüger's Arch 330:347–361Google Scholar
  48. Steiner AL, Kipnis DM, Utinger R, Parker C (1969) Radioimmunoassay for the measurement of adenosine 3′,5′-cyclic phosphate. Proc Nat Acad Sci USA 64:367–373Google Scholar
  49. Taira N, Endoh M, Iijimy T, Satoh K, Yanagisawa T, Yamashita S, Maruyama M, Kawada M, Morita T, Wada Y (1984) Mode and mechanism of action of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), a novel positive inotropic drug, on the dog heart. Arzneimittelforsch/Drug Res 34(I):347–355Google Scholar
  50. Weidmann S (1974) Heart: Electrophysiology. Ann Rev Physiol 36:155–169Google Scholar
  51. Weishaar RE, Quade MM, Schenden JA, Boyd DK, Evans DB (1983) Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent. Pharmacologist (Abstract) 25:207Google Scholar
  52. Witt JJ, Roskoski R Jr (1975) Rapid protein kinase assay using phosphocellulose absorption. Anal Biochem 66:253–258Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • G. Scholtysik
    • 1
  • R. Salzmann
    • 1
  • R. Berthold
    • 1
  • J. W. Herzig
    • 1
  • U. Quast
    • 1
  • R. Markstein
    • 1
  1. 1.Preclinical ResearchSandoz Ltd.BaselSwitzerland

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