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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Effects of Paclitaxel and Derivatives on Guinea Pig Isolated Heart and Papillary Muscle

Giuseppe Alloatti, Claudia Penna, Maria Pia Gallo, Renzo C. Levi, Ezio Bombardelli and Giovanni Appendino
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 561-567;
Giuseppe Alloatti
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Claudia Penna
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Maria Pia Gallo
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Renzo C. Levi
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Ezio Bombardelli
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Giovanni Appendino
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Abstract

Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5–20 μM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.

Footnotes

  • Send reprint requests to: Giuseppe Alloatti, Laboratorio di Fisiologia Generale, Dipartimento di Biologia Animale e dell’Uomo, Università degli Studi di Torino, Via Santa Croce 8 10123 Torino, Italy.

  • ↵1 This research was supported by grants from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) and from Indena SpA.

  • ↵2 M.P. Gallo is recipient of a grant from Indena SpA-Milano.

  • Abbreviations:
    LVSP
    left ventricular systolic pressure
    LVDP
    left ventricular diastolic pressure
    DMSO
    dimethylsulfoxide
    CF
    coronary flow
    HR
    sinus heart rate
    A-V
    atrioventricular conduction time
    Q-T
    Q-T interval
    QRS
    duration of QRS complex
    Tmax
    peak tension
    +dT/dt
    maximal rate of increase of developed tension
    −dT/dt
    maximal rate of decrease of developed tension
    VPB
    ventricular premature beat
    VT
    ventricular tachycardia
    AVR
    accelerated ventricular rhythm
    • Received July 9, 1997.
    • Accepted October 28, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Effects of Paclitaxel and Derivatives on Guinea Pig Isolated Heart and Papillary Muscle

Giuseppe Alloatti, Claudia Penna, Maria Pia Gallo, Renzo C. Levi, Ezio Bombardelli and Giovanni Appendino
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 561-567;

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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Effects of Paclitaxel and Derivatives on Guinea Pig Isolated Heart and Papillary Muscle

Giuseppe Alloatti, Claudia Penna, Maria Pia Gallo, Renzo C. Levi, Ezio Bombardelli and Giovanni Appendino
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 561-567;
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