Klinische Wochenschrift

, Volume 62, Issue 15, pp 717–723 | Cite as

Negative inotropic effects of aldosterone antagonists in isolated human and guinea-pig ventricular heart muscle

  • A. Mügge
  • W. Schmitz
  • H. Scholz
Originalien

Summary

The effects of K+-canrenoate (Aldactone® pro inj.) and its metabolite canrenone on isometric force of contraction were measured in isolated guinea-pig and human papillary muscle preparations driven electrically at a frequency of 1 Hz. In guinea-pig hearts both substances exerted a concentration-dependent negative inotropic effect; the IC50 of K+-canrenoate and canrenone were 129±22 µmol l−1 (n=5) and 85±11 µmol l−1 (n=12), respectively. At the maximally tested concentration canrenone (250 µmol l−1) and K+-canrenoate (1,000 µmol l−1) reduced force of contraction by 68±4% (n=12) and 83±3% (n=5), respectively. The negative inotropic effects of canrenone and K+-canrenoate were not affected by 10 µmol l−1 atropine. The negative inotropic effect of canrenone was also not affected by 14 µmol l−1 aldosterone, but canrenone (10 µmol l−1) diminished the maximal positive inotropic effect of dihydro-ouabain from 554±75% (n=4) to 269±39% (n=4) of the predrug value.

In human heart muscles K+-canrenoate and canrenone also exerted a concentration-dependent negative inotropic effect. K+-canrenoate (1,000 µmol l−1) and canrenone (250 µmol l−1) reduced force of contraction by 57±7% (n=8) and 67±2% (n=6), respectively. A positive inotropic effect of both substances was never observed.

It is concluded that the improvement of cardiac performance after application of aldosterone antagonists observed in patients cannot be explained by a direct effect on the heart. K+-canrenoate and canrenone are devoid of any direct cardiotonic action. Instead, K+-canrenoate and canrenone have direct negative inotropic effects at high concentrations.

Key words

Aldosterone antagonists Canrenone K+-canrenoate Negative inotropic effect Human heart 

Abbreviations

Aldactone® pro inj

Aldactone® pro injection

g

gramm

Hz

Hertz

IC50

concentration of drugs which produce 50% inhibition of force of contraction

i.v.

intravenous

min

minutes

mm

millimeter

mm s−1

millimeter per second

mmol l−1

millimolar

mg

milligramm

mN

milli newton

ms

millisecond

SC 8109

spironolactone derivative

SEM

standard error of the mean

TRIS

Tris(hydroxymethyl)-aminomethan

v/v

volume per volume

µmol l−1

micromolar

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bachour G, Bender F, Most E (1978) Hämodynamische Wirkungen von Aldosteron-Antagonisten bei Patienten mit Mitralstenose. Z Kardiol 67:469–473Google Scholar
  2. Baskin SI, Akera T, Puckett CR, Brody SL, Brody TM (1973) Effect of potassium canrenoate on cardiac functions and (Na+/K+)-activated ATPase (37351). Proc Soc Exp Biol Med 143:495–498Google Scholar
  3. Briggs AH, Holland WC (1959) Effects of steroids, acetylcholine, quinidine and ionic environment on refractory period and K transport in isolated rabbit atria (Abstract). Fed Proc 18:371Google Scholar
  4. Coraboeuf E, Deroubaix E (1974) Effect of a spironolactone derivative, sodium canrenoate, on mechanical and electrical activities of isolated rat myocardium. J Pharmacol Exp Ther 191:128–138Google Scholar
  5. Erdman E, Krawietz W, Poppert D, Krüger R, v. Arnim T, Vogt W, Bolte HD (1977) Zur kardialen Wirkung antikaliuretischer Diuretika — klinische und biochemische Untersuchungen. Klin Wochenschr 55:985–994Google Scholar
  6. Finotti P, Palatini P (1981) Canrenone as a partial agonist at the digitalis receptor site of sodium-potassium-activated adenosine triphosphatase. J Pharmacol Exp Ther 217:784–790Google Scholar
  7. Fricke U (1978) Lack of interaction of spironolactone with ouabain in guinea-pig isolated heart muscle preparations. Eur J Pharmacol 49:363–371Google Scholar
  8. Hüttemann U, Schüren KP (1972) Zur Behandlung des chronischen Cor pulmonale mit Aldactone (Spironolacton, Canrenoat-Kalium). Dtsch Med Wochenschr 97:1533–1535Google Scholar
  9. Kauffmann N (1974) Über die positiv inotrope Wirkung von Theophyllin in Abhängigkeit vom pH-Wert der Extrazellulärflüssigkeit. Dissertation, MainzGoogle Scholar
  10. Klein WW, Pavek P, Brandt D, Fluch N, Goebel R (1975) Hämodynamische Wirkung von Spironolacton beim akuten Myokardinfarkt. Intensivmedizin 12:85–93Google Scholar
  11. Lucchesi BR, Haley NR (1973) Failure of potassium canrenoate to alter experimentally induced digitalis arrhythmias. Eur J Pharmacol 22:256–262Google Scholar
  12. Meinertz T, Nawrath H, Scholz H (1976) Possible role of cyclic AMP in the relaxation process of mammalian heart: Effects of dibutyryl cyclic AMP and theophylline on potassium contractures in cat papillary muscles. Naunyn Schmiedebergs Arch Pharmacol 293:129–137Google Scholar
  13. Piepenbrock S, Hempelmann G, Schwarz S, Oelert H (1979) Extrarenale Effekte von Canrenoat-Kalium. Anaesthesist 28:163–170Google Scholar
  14. Ramdohr B, Schüren KP, Schröder R (1975) Die Behandlung der Herzinsuffizienz mit Spironolacton und Canrenoat-Kalium. Therapie Woche 35:4598–4606Google Scholar
  15. Sadée W, Dagcioglu M, Schröder R (1973) Pharmacokinetics of spironolactone, canrenone and canrenoate-K in human. J Pharmacol Exp Ther 185:686–695Google Scholar
  16. Scholz H (1979) Pharmakologie und Klinik tödlich verlaufender Glykosidintoxikationen: Versuch eines pharmakologischen Nachweises von Herzglykosiden in Leichenteilen. In: Hierholzer K, Rietbrock N (eds) Physiologische und pharmakologische Grundlagen der Therapie. Viewig Braunschweig, pp 83–102Google Scholar
  17. Scholz H (1980) Effects of beta- and alpha-adrenoceptor activators and adrenergic transmitter releasing agents on the mechanical activity of the heart. In: Szekeres L (ed) Handbook of Experimental Pharmacology Vol. 54/I. Springer, Berlin Heidelberg New York, pp 651–733Google Scholar
  18. Schröder R, Biamino G, Meyer V, Ramdohr B, Sadée W, Schüren KP (1971) Positive inotropic effect of canrenoate-K in man. In: Extrarenal activity of aldosterone and its antagonists. Excerpta Medical Foundation, Amsterdam, pp 109–116Google Scholar
  19. Schröder R, Ramdohr B, Hüttemann U, Schüren KP (1972a) Direkte positiv-inotrope Herzwirkung von Aldactone (Spironolacton, Canrenoat-Kalium). Dtsch Med Wochenschr 41:1535–1538Google Scholar
  20. Schröder R, Ramdohr B, Hüttemann U, v. Leitner E, Schüren KP (1972b) Direkte positiv-inotrope Herzwirkung durch orale Spironolacton-Behandlung. Verh Dtsch Ges Herz Kreislaufforsch 38:349–353Google Scholar
  21. Seibel K, Hörmann G (1980) Potassium-canrenoate exerts a negative inotropic effect on guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol 313 (Suppl):R 42 (Abstract)Google Scholar
  22. Sponer G, Kaufmann B, Kuhr M (1976) Pharmakokinetik von Aldosteron-Antagonisten. Krankenhausarzt 49:569–575Google Scholar
  23. Strauer BE (1972) Myokardiale Aspekte der Aldactonewirkung. Verh Dtsch Ges Inn Med 78:1063–1066Google Scholar
  24. Strauer BE (1973) The influence of the aldosterone-antagonists spironolactone on myocardial contractility. Arch Int Pharmacodyn Ther 201:59–70Google Scholar
  25. Strauer BE, Avenhaus H, Nose M (1972) Evidence for a positive inotropic effect of aldadiene (-K, -Na) on the isolated ventricular myocardium. Klin Wochenschr 50:387–389Google Scholar
  26. Strauer BE, Scherpe A (1977) Intropic action of diuretic drugs, Summary of discussion. In: Siegenthaler W, Beckerhoff R, Vetter W (eds) Diuretics in research and clinics. Thieme, Stuttgart, p 142Google Scholar
  27. Tanz RD, Kerby CF (1961) The inotropic action of certain steroids upon isolated cardiac tissue; with comments on steroidal cardiotonic structure-activity relationship. J Pharmacol Exp Ther 131:56–64Google Scholar
  28. Waldorff S, Buch J (1979) Canrenoate-a spironolactone metabolite. Acute cardiac effects in digitalized patients. Eur J Cardiol 10:143–149Google Scholar
  29. Waldorff S, Berning J, Buch J, Steiness E (1982) Systolic time intervals during spironolactone treatment of digitalized and non-digitalized patients with ischaemic heart disease. Eur J Clin Pharmacol 21:269–273Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • A. Mügge
    • 1
  • W. Schmitz
    • 1
  • H. Scholz
    • 1
  1. 1.Abteilung Allgemeine PharmakologieUniversitäts-Krankenhaus Eppendorf, Universität HamburgGermany

Personalised recommendations