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Involvement of cyclic AMP in the direct inotropic action of amrinone

Biochemical and functional evidence

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Summary

Using the isolated guinea-pig papillary muscle and conventional methods for recording isometric force and transmembrane electrical activity we analysed the positive inotropic effect of the bipyridine derivative amrinone at a contraction frequency of 0.2 Hz. The drug produced a concentration-dependent (0.06–8.0 mmol/l), reversible increase in force of contraction associated with an abbreviation of relaxation time at low concentrations and an increase of this parameter at high concentrations. Part of the inotropic effect was manifested by the rested-state contraction. In muscles depolarized by 24 mmol/l [K]0, amrinone increased the maximum rate of depolarization and overshoot of the slow responses. Carbachol reduced the inotropic effect of amrinone, and this antagonism was removed by the additional application of atropine. The inotropic effect of amrinone was not affected by propranolol or phentolamine and only slightly inhibited by cimetidine. Amrinone potentiated the positive inotropic effects of isoprenaline or histamine but interacted additively with dihydroouabain; the −log EC50 of isoprenaline was increased by 0.803±0.077 and that of histamine by 1.14±0.054 logarithmic units in the presence of 0.2 mmol/l amrinone. Abbreviation of relaxation time, increase in force of the rested-state contraction, atropine-sensitive antagonism by carbachol, and the effects on the slow response are characteristic of the class of cardiotonic drugs thought to act by increasing the cellular concentration of cyclic AMP. Direct support for this hypothesis was provided by the demonstration that inotropically effective concentrations of amrinone produced an up to 3.5-fold increase in cyclic AMP content of guinea-pig papillary muscles. In addition, amrinone was found to inhibit phosphodiesterase in a crude enzyme preparation from guinea-pig ventricular strips. Lack of specific antagonism by propranolol or cimetidine and potentiation of the effects of isoprenaline or histamine are consistent with an inhibitory effect on cyclic nucleotide phosphodiesterase. At high concentrations, amrinone was shown to exert an additional theophylline-like effect on the contour of the isometric contraction that cannot be attributed to cyclic AMP accumulation.

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  1. Institut für Pharmakologie und Toxikologie der Technischen Universität München, Biedersteiner Str. 29, D-8000, München 40, Germany

    P. Honerjäger, M. Schäfer-Korting & M. Reiter

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  1. P. Honerjäger
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  2. M. Schäfer-Korting
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  3. M. Reiter
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Honerjäger, P., Schäfer-Korting, M. & Reiter, M. Involvement of cyclic AMP in the direct inotropic action of amrinone. Naunyn-Schmiedeberg's Arch. Pharmacol. 318, 112–120 (1981). https://doi.org/10.1007/BF00508835

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  • DOI: https://doi.org/10.1007/BF00508835

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