Skip to main content
SpringerLink
Log in

Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

1. The positive inotropic effects of the dihydropyridine calcium activator Bay K 8644 were studied in guinea-pig isolated contracting myocardium and human papillary muscle strips obtained from patients undergoing mitral valve replacement or cardiac transplantation. 2. Bay K 8644 produced a slowly developing, concentration-dependent positive inotropic response in all cardiac tissues studied. In guinea-pig papillary muscle, the increase in force of contraction was half-maximal at 3.9 × 10−8 mol/l and the maximal inotropic effect was comparable to that obtained with ouabain, dobutamine or calcium. The guinea-pig left atrium (EC50, 2.1 × 10−7 mol/l) was fivefold less sensitive than the papillary muscle. 3. The maximal inotropic response to dihydroouabain was significantly increased after preincubation with Bay K 8644 (1 × 10−6 mol/l) in papillary muscles from both guinea-pig and human. In guinea-pig papillary muscles, the maximal inotropic response to dobutamine was not changed by preincubation with Bay K 8644 whereas in human papillary muscle strips, Bay K 8644 increased the inotropic response to dobutamine. 4. Bay K 8644 increased force of contraction (EC50, 4 × 10−8 mol/l) in human papillary muscle strips from patients undergoing mitral valve replacement. However, the maximal inotropic response to Bay K 8644 was reduced to 32 ± 4.4% that of calcium (15 mmol/l) measured in the same muscle strips. 5. A further reduction in maximal inotropic response to Bay K 8644 to 13 ± 1.2% that of calcium (15 mmol/l) with no change in potency was measured in human papillary muscle strips taken from terminally failing hearts of cardiac transplant recipients. 6. There was a significant correlation between the preoperative left ventricular ejection fraction and the maximal inotropic response to Bay K 8644 in isolated human papillary muscle strips. 7. These results suggest that Bay K 8644 affects excitation-contraction coupling of cardiac muscle so as to increase the maximal inotropic effect of the digitalis glycosides. Further, the inotropic response of human myocardial tissue to calcium channel activator Bay K 8644 may be reduced in states of pathological heart function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Akera T (1986) The function of Na+, K+-ATPase and its importance for drug action. In: Erdmann E, Greeff K, Skou JC (eds) Cardiac glycosides 1785–1985. Steinkopff, Darmstadt, pp 19–25

    Google Scholar 

  • Akera T, Brody TM (1985) Sodium ion and the cardiac actions of digitalis. Trends Pharmacol Sci 6:156–159

    Google Scholar 

  • Allen DG, Eisner DA, Pirolo JS, Smith GL (1985) The relationship between intracellular calcium and contraction in calcium-over-loaded ferret papillary muscles. J Physiol (Lond) 364:169–182

    Google Scholar 

  • Bean BP, Nowycky MC, Tsien RW (1984) β-Adrenergic modulation of calcium channels in frog ventricular myocardium. Nature 307:371–375

    Google Scholar 

  • Brandt W, Reiter M, Seibel K (1972) “Supramaximal“ enhancement of the inotropic effect of noradrenaline by tyramine. Naunyn-Schmiedeberg's Arch Pharmacol 273:294–306

    Google Scholar 

  • Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sagemann WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. New Engl J Med 307:205–211

    Google Scholar 

  • Brown AM, Kunze DL, Yatani A (1984) The agonist effect of dihydropyridines on Ca channels. Nature 311:570–572

    Google Scholar 

  • Brown L, Erdmann E (1985) Concentration-response curves of positive inotropic agents before and after ouabain pretreatment. Cardiovasc Res 19:288–298

    Google Scholar 

  • Brown L, Lorenz B, Erdmann E (1986) Reduced positive inotropic effects in diseased human ventricular myocardium. Cardiovasc Res 20:516–520

    Google Scholar 

  • Capasso JM, Malhotra A, Scheuer J, Sonnenblick EH (1986) Myocardial biochemical, contractile, and electrical performance after imposition of hypertension in young and old rats. Circ Res 58:445–460

    Google Scholar 

  • Eisner DA, Valdeolmillos M, Lederer WJ, Cannel MB (1986) Electrophysiological effects of cardiac glycosides. In: Erdmann E, Greeff K, Skou JC (eds) Cardiac glycosides 1785–1985. Steinkopff, Darmstadt, pp 69–78

    Google Scholar 

  • Endoh M, Yanagisawa T, Taira N, Blinks JR (1986) Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 73 (suppl III): III-117-III-133

    Google Scholar 

  • Erdmann E, Schoner W (1974) Ouabain-receptor interactions in (Na+ + KOuabain-receptor interactions in (Na+ + K+)-ATPase preparations. IV. The molecular structure of different cardioactive steroids and other substances and their affinity to the glycoside receptor. Naunyn-Schmiedeberg's Arch Pharmacol 283:335–356

    Google Scholar 

  • Erdmann E, Philipp G, Scholz H (1980) Cardiac glycoside receptor, (Na+ + K+)-ATPase activity and force of contraction in rat heart. Biochem Pharmacol 29:3219–3229

    Google Scholar 

  • Fabiato A (1983) Calcium-induced release of calcium from the sarcoplasmic reticulum. Am J Physiol 245:C1-C14

    Google Scholar 

  • Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP (1987) Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end stage heart failure. Circulation 75:331–339

    Google Scholar 

  • Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166

    Google Scholar 

  • Franckowiak G, Bechem M, Schramm M, Thomas G (1985) The optical isomeres of the 1,4-dihydropyridine Bay K 8644 show opposite effects on Ca channels. Eur J Pharmacol 114:223–226

    Google Scholar 

  • Garcia AG, Sala F, Reig JA, ViniegraS, Frias J, Fonteriz R, Gandia L (1984) Dihydropyridine Bay K 8644 activates chromaffin cell calcium channels. Nature 309:69–71

    Google Scholar 

  • Glossmann H, Ferry DR, Goll A, Striessnig J, Zernig G (1985) Calcium channels and calcium channel drugs: recent biochemical and biophysical findings. Arzneim Forsch 35:1917–1935

    Google Scholar 

  • Godfraind T, Miller R, Wibo M (1986) Calcium antagonism and calcium entry blockade. Pharmacol Rev 38:321–416

    Google Scholar 

  • Hess P, Lansman JB, Tsien RW (1984) Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–544

    Google Scholar 

  • Honerjäger P, Heiss A, Schaefer-Korting M, Schönsteiner G, Reiter M (1984) UD-CG 115 — a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guinea pig papillary muscles. Naunyn-Schmiedeberg's Arch Pharmacol 325:259–269

    Google Scholar 

  • Ishii K, Taira N, Yanagisawa T (1985) Differential antagonism by Bay K 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle. Br J Pharmacol 84:577–584

    Google Scholar 

  • Kenakin TP, Ferris R (1983) Effects of in vivo β-adrenoceptor down-regulation on cardiac responses to prenalterol and pirbuterol. J Cardiovasc Pharmacol 5:90–97

    Google Scholar 

  • Kennedy RH, Seifen E (1985) Stimulation frequency alters the inotropic response of atrial muscle to Bay K 8644. Eur J Pharmacol 107:209–214

    Google Scholar 

  • Kokubun S, Reuter H (1984) Dihydropyridine derivatives prolong the open state of Ca channels in cultured cardiac cells. Proc Natl Acad Sci USA 81:4824–4827

    Google Scholar 

  • Langer GA (1980) The role of calcium in the control of myocardial contractility: An update. J Mol Cell Cardiol 12:231–239

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurements with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • McDonald TF (1982) The slow inward calcium current in the heart. Ann Rev Physiol 44:425–434

    Google Scholar 

  • Millard RW, Grupp G, Grupp IL, DiSalvo J, DePover A, Schwartz A (1983) Chronotropic, inotropic, and vasodilator actions of diltiazem, nifedipine and verapamil. Circ Res 52 (suppl 1):29–39

    Google Scholar 

  • Morad M, Tung L (1983) Ionic events responsible for the cardiac resting and action potential. Am J Cardiol 49:584–594

    Google Scholar 

  • Näbauer M, Brown L (1986) The calcium agonist Bay K 8644: Positive inotropy on isolated, contracting guinea pig and human myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 332:R44

    Google Scholar 

  • Reuter H (1967) The dependence of slow inward current in Purkinje fibres on the extracellular calcium concentration. J Physiol (Lond) 192:479–492

    Google Scholar 

  • Reuter H, Scholz H (1977) The regulation of the calcium conductance of cardiac muscle by adrenaline. J Physiol (Lond) 264:49–62

    Google Scholar 

  • Rogg H, Criscione L, Truog A, Meier M (1985) In vitro comparative studies of the calcium-entry activators YC-170, CGP 28392, and Bay K 8644. J Cardiovasc Pharmacol 7 (suppl 6):S31-S37

    Google Scholar 

  • Sanguinetti MC, Kass RS (1984) Regulation of cardiac calcium channel current and contractile activity by the dihydropyridine Bay K 8644 is voltage-dependent. J Mol Cell Cardiol 16:667–670

    Google Scholar 

  • Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672

    Google Scholar 

  • Scholz H (1984) Inotropic drugs and their mechanism of action. J Am Coll Cardiol 4:389–397

    Google Scholar 

  • Schoner W, von Ilberg C, Kramer R, Seubert W (1967) On the mechanism of Na+- and K+-stimulated hydrolysis of adenosine triphosphate. 1. Purification and properties of a Na+- and K+-activated ATPase from ox brain. Eur J Biochem 1:334–343

    Google Scholar 

  • Schramm M, Thomas G, Towart R, Franckowiak G (1983a) Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature 303:535–537

    Google Scholar 

  • Schramm M, Thomas G, Towart R, Franckowiak G (1983b) Activation of calcium channels by novel 1,4-dihydropyridines. Arzneim-Forsch 33:1268–1272

    Google Scholar 

  • Schwartz A, Grupp IL, Grupp G, Williams JS, Vaghy PL (1984) Effects of dihydropyridine calcium channel modulators in the heart. Biochem Biophys Res Comm 125:386–394

    Google Scholar 

  • Thomas G, Groß R, Schramm M (1984) Calcium channel modulation: ability to inhibit or promote calcium influx in the same dihydropyridine molecule. J Cardiovasc Pharmacol 6:1170–1176

    Google Scholar 

  • Thomas G, Groß R, Pfitzer G, Rüegg LC (1985) The positive inotropic dihydropyridine Bay K 8644 does not affect calcium sensitivity or calcium release of skinned cardiac fibres. Naunyn-Schmiedeberg's Arch Pharmacol 328:378–381

    Google Scholar 

  • Trautwein W, Cavalie MS (1985) Cardiac calcium channels and their control by neurotransmitters and drugs. J Am Coll Cardiol 6:1409–1416

    Google Scholar 

  • Vaghy PL, Grupp IL, Grupp G, Schwartz A (1984) Effects of Bay K 8644, a dihydropyridine analog, on 3H-nitrendipine binding to canine cardiac sarcolemma and the relationship to a positive inotropic effect. Circ Res 55:549–553

    Google Scholar 

  • Wada Y, Satoh K, Taira N (1985) Cardiovascular profile of Bay K 8644, a presumed calcium channel activator, in the dog. Naunyn-Schmiedeberg's Arch Pharmacol 328:382–387

    Google Scholar 

  • Wier WG, Yue DT (1985) The effects of 1,4-dihydropyridine type Ca+-channel antagonists and agonists on intracellular Ca2+ transients accompanying twitch contraction of heart muscle. In: Fleckenstein A, van Breemen C, Groß R, Hoffmeister F (eds) Cardiovascular effects of dihydropyridine-type calcium antagonists and agonists. Springer, Berlin Heidelberg, pp 188–194

    Google Scholar 

  • Wilmshurst PT, Walker LM, Fry CH, Mounsey JP, Twort CHC, Williams BT, Davies MJ, Webb-Peploe MM (1984) Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovasc Res 18:302–309

    Google Scholar 

  • Williams JS, Grupp IL, Grupp G, Vaghy PL, Dumont L, Schwartz A (1985) Profile of the oppositely acting enantiomeres of the dihydropyridine 202–791 in cardiac preparations: receptor binding, electrophysiological, and pharmacological studies. Biochem Biophys Res Comm 131:13–21

    Google Scholar 

Download references

Author information

Author notes

  1. Lindsay Brown

    Present address: Department of Physiology and Pharmacology, University of Queensland, St. Lucia 4067, Queensland, Australia

Authors and Affiliations

  1. Medizinische Klinik I der Universität, Klinikum Grosshadern, D-8000, München 70, Federal Republic of Germany

    Michael Näbauer, Lindsay Brown & Erland Erdmann

Authors
  1. Michael Näbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lindsay Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erland Erdmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

The human heart papillary muscles were provided by Prof. E. Kreuzer, Prof. B. Kemkes, Dr. C. Weinhold and their colleagues, Herzchirurgische Klinik der Universität, Klinikum Grosshadern, D-8000 München 70, Federal Republic of Germany

Send offprint requests to E. Erdmann

Rights and permissions

Reprints and permissions

About this article

Cite this article

Näbauer, M., Brown, L. & Erdmann, E. Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 337, 85–92 (1988). https://doi.org/10.1007/BF00169482

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00169482

Key words

Search

Navigation