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. 1992 Jul;106(3):511–516. doi: 10.1111/j.1476-5381.1992.tb14367.x

Differential inotropic effects of flosequinan in ventricular muscle from normal ferrets versus patients with end-stage heart failure.

C L Perreault 1, N L Hague 1, E Loh 1, I M Hunneyball 1, M F Sim 1, J P Morgan 1
PMCID: PMC1907553  PMID: 1324072

Abstract

1. In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Baker P. F., Schapira A. H. Anaesthetics increase light emission from aequorin at constant ionised calcium. Nature. 1980 Mar 13;284(5752):168–169. doi: 10.1038/284168a0. [DOI] [PubMed] [Google Scholar]
  2. Blinks J. R. Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J Pharmacol Exp Ther. 1966 Feb;151(2):221–235. [PubMed] [Google Scholar]
  3. Cohn J. N. Future directions in vasodilator therapy for heart failure. Am Heart J. 1991 Mar;121(3 Pt 1):969–974. doi: 10.1016/0002-8703(91)90228-a. [DOI] [PubMed] [Google Scholar]
  4. Corin W. J., Monrad E. S., Strom J. A., Giustino S., Sonnenblick E. S., LeJemtel T. Flosequinan: a vasodilator with positive inotropic activity. Am Heart J. 1991 Feb;121(2 Pt 1):537–540. doi: 10.1016/0002-8703(91)90723-u. [DOI] [PubMed] [Google Scholar]
  5. Erdmann E., Böhm M. Positive inotropic stimulation in the normal and insufficient human myocardium. Basic Res Cardiol. 1989;84 (Suppl 1):125–133. doi: 10.1007/BF02650352. [DOI] [PubMed] [Google Scholar]
  6. Falotico R., Haertlein B. J., Lakas-Weiss C. S., Salata J. J., Tobia A. J. Positive inotropic and hemodynamic properties of flosequinan, a new vasodilator, and a sulfone metabolite. J Cardiovasc Pharmacol. 1989 Sep;14(3):412–418. doi: 10.1097/00005344-198909000-00009. [DOI] [PubMed] [Google Scholar]
  7. Fann M. L., Souccar C., Lapa A. J. Phenthonium, a quaternary derivative of (-)-hyoscyamine, enhances the spontaneous release of acetylcholine at rat motor nerve terminals. Br J Pharmacol. 1990 Jul;100(3):441–446. doi: 10.1111/j.1476-5381.1990.tb15825.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Feldman M. D., Copelas L., Gwathmey J. K., Phillips P., Warren S. E., Schoen F. J., Grossman W., Morgan J. P. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation. 1987 Feb;75(2):331–339. doi: 10.1161/01.cir.75.2.331. [DOI] [PubMed] [Google Scholar]
  9. Greenberg S., Touhey B. Positive inotropy contributes to the hemodynamic mechanism of action of flosequinan (BTS 49465) in the intact dog. J Cardiovasc Pharmacol. 1990 Jun;15(6):900–910. doi: 10.1097/00005344-199006000-00007. [DOI] [PubMed] [Google Scholar]
  10. Gwathmey J. K., Copelas L., MacKinnon R., Schoen F. J., Feldman M. D., Grossman W., Morgan J. P. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987 Jul;61(1):70–76. doi: 10.1161/01.res.61.1.70. [DOI] [PubMed] [Google Scholar]
  11. Gwathmey J. K., Morgan J. P. The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret. Br J Pharmacol. 1985 May;85(1):97–108. doi: 10.1111/j.1476-5381.1985.tb08835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hajjar R. J., Gwathmey J. K., Briggs G. M., Morgan J. P. Differential effect of DPI 201-106 on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest. 1988 Nov;82(5):1578–1584. doi: 10.1172/JCI113769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kamaya H., Ueda I., Eyring H. Reversible and irreversible inhibition by anesthetics of the calcium-induced luminescence of aequorin. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5534–5537. doi: 10.1073/pnas.74.12.5534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kihara Y., Grossman W., Morgan J. P. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res. 1989 Oct;65(4):1029–1044. doi: 10.1161/01.res.65.4.1029. [DOI] [PubMed] [Google Scholar]
  15. Kihara Y., Gwathmey J. K., Grossman W., Morgan J. P. Mechanisms of positive inotropic effects and delayed relaxation produced by DPI 201-106 in mammalian working myocardium: effects on intracellular calcium handling. Br J Pharmacol. 1989 Apr;96(4):927–939. doi: 10.1111/j.1476-5381.1989.tb11904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kihara Y., Morgan J. P. A comparative study of three methods for intracellular loading of the calcium indicator aequorin in ferret papillary muscles. Biochem Biophys Res Commun. 1989 Jul 14;162(1):402–407. doi: 10.1016/0006-291x(89)92011-1. [DOI] [PubMed] [Google Scholar]
  17. MacKinnon R., Gwathmey J. K., Allen P. D., Briggs G. M., Morgan J. P. Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle. Circ Res. 1988 Dec;63(6):1080–1089. doi: 10.1161/01.res.63.6.1080. [DOI] [PubMed] [Google Scholar]
  18. Morgan J. P. Intracellular calcium in heart failure. Cardiovasc Drugs Ther. 1988 Mar;1(6):621–624. doi: 10.1007/BF02125749. [DOI] [PubMed] [Google Scholar]
  19. Morgan J. P., Morgan K. G. Calcium and cardiovascular function. Intracellular calcium levels during contraction and relaxation of mammalian cardiac and vascular smooth muscle as detected with aequorin. Am J Med. 1984 Nov 5;77(5A):33–46. doi: 10.1016/s0002-9343(84)80006-6. [DOI] [PubMed] [Google Scholar]
  20. Packer M. Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure. Am J Cardiol. 1989 Jan 3;63(2):41A–45A. doi: 10.1016/0002-9149(89)90392-5. [DOI] [PubMed] [Google Scholar]
  21. Packer M. Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope. J Am Coll Cardiol. 1988 Nov;12(5):1299–1317. doi: 10.1016/0735-1097(88)92615-0. [DOI] [PubMed] [Google Scholar]
  22. Perreault C. L., Hague N. L., Ransil B. J., Morgan J. P. The effects of cocaine on intracellular Ca2+ handling and myofilament Ca2+ responsiveness of ferret ventricular myocardium. Br J Pharmacol. 1990 Nov;101(3):679–685. doi: 10.1111/j.1476-5381.1990.tb14140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Resnick M. S., Maitland L. A., Morgan K. G. Flosequinan, a vasodilator with a novel mechanism of action. Br J Pharmacol. 1991 Apr;102(4):974–978. doi: 10.1111/j.1476-5381.1991.tb12286.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wier W. G. Cytoplasmic [Ca2+] in mammalian ventricle: dynamic control by cellular processes. Annu Rev Physiol. 1990;52:467–485. doi: 10.1146/annurev.ph.52.030190.002343. [DOI] [PubMed] [Google Scholar]
  25. Wilmshurst P. T., Walker J. M., Fry C. H., Mounsey J. P., Twort C. H., Williams B. T., Davies M. J., Webb-Peploe M. M. Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovasc Res. 1984 May;18(5):302–309. doi: 10.1093/cvr/18.5.302. [DOI] [PubMed] [Google Scholar]
  26. Wynne R. D., Crampton E. L., Hind I. D. The pharmacokinetics and haemodynamics of BTS 49 465 and its major metabolite in healthy volunteers. Eur J Clin Pharmacol. 1985;28(6):659–664. doi: 10.1007/BF00607911. [DOI] [PubMed] [Google Scholar]
  27. Yates D. B. Pharmacology of flosequinan. Am Heart J. 1991 Mar;121(3 Pt 1):974–983. doi: 10.1016/0002-8703(91)90229-b. [DOI] [PubMed] [Google Scholar]

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