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Effects on atrioventricular conduction and blood flow of enantiomers of verapamil and of tetrodotoxin injected into the posterior and the anterior septal artery of the atrioventricular node preparation of the dog

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Summary

  1. 1.

    The present experiments were attempted to determine whether the (+)-enantiomer of verapamil would act predominantly as an inhibitor of the slow calcium channel or the fast sodium channel. For this purpose the effect of (+)-verapamil on atrioventricular (AV) conduction was compared with those of (-)-verapamil, a relatively pure inhibitor of the slow calcium channel, and of tetrodotoxin (TTX), a relatively pure inhibitor of the fast sodium channel by the use of the isolated, blood-perfused AV node preparation of the dog. To obtain a clue to settle the above question, their effects on blood flow through the nutrient arteries of the preparation were also investigated.

  2. 2.

    In the dog heart the upper part of the AV node is perfused through the posterior septal artery (PSA), whereas the more distal conduction system and the myocardium of the ventricular septum are supplied by the anterior septal artery (ASA). In conduction of cardiac impulses the slow calcium channel plays an important role in the upper part of the AV node whereas the fast sodium channel does so in the distal conduction system.

  3. 3.

    The isolated, blood-perfused AV node preparation consists of the right atrium and ventricular septum and permits administration of drugs individually into the PSA and the ASA. Changes in AV conduction time obtained with injection of drugs into the PSA reflect the effect on the slow calcium channel, whereas those obtained with injection into the ASA reflect the action on the fast sodium channel.

  4. 4.

    Single injections of (+)-verapamil (0.1–10 μg) into the PSA produced a dose-dependent increase in AV conduction time, and in high doses it caused a second or third degree block of AV conduction. Prolongation of AV conduction time was due entirely to that of the intervals between bipolar electrograms of the right atrium and those of the right bundle branch (A-B interval).

  5. 5.

    Single injection of (-)-verapamil (0.1–3 μg) into the PSA produced an effect on AV conduction qualitatively similar to that of (+)-verapamil. (-)-Verapamil was about 6 times more potent and far longer-acting than (+)-verapamil.

  6. 6.

    Single injection of (+)-verapamil (0.1–30 μg) into the ASA affected neither AV conduction time nor the shape of bipolar electrograms of the right bundle branch and of the underlying ventricular myocardium.

  7. 7.

    Essentially similar negative results were obtained with (-)-verapamil (0.1–30 μg) injected into the ASA.

  8. 8.

    TTX (1–30 μg) injected into the PSA or the ASA equally produced a dose-dependent increase in AV conduction time. Prolongation of AV conduction time caused by TTX injected into the PSA was due entirely to that of the A-B intervals, whereas that produced by injection into the ASA was due exclusively to that of intervals between bipolar electrograms of the right bundle branch and those of the underlying ventricular myocardium (B-V interval). The latter change was associated with alteration of the shape of bipolar electrograms of the right bundle branch and those of the ventricular septum.

  9. 9.

    Thus, it is unlikely that (+)-verapamil acts as an inhibitor of the fast sodium channel but rather likely that it acts as an inhibitor of the slow calcium channel like its (-)-enantiomer. Difference in action between them was only quantitative.

  10. 10.

    The results also suggest that in addition to the dominant slow calcium channel the fast sodium channel plays a subsidiary role in conduction through the AV node.

  11. 11.

    Both enantiomers of verapamil injected into the PSA or the ASA produced a dose-dependent increase in blood flow through the respective artery. In this regard (-)-verapamil was about 3 times as potent as (+)-verapamil.

  12. 12.

    Intra-arterial TTX was entirely ineffective in increasing blood flow through the PSA or the ASA.

  13. 13.

    The above results support the conlusion that (+)-verapamil is an inhibitor of the slow calcium channel.

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Authors and Affiliations

  1. Department of Pharmacology, Tohoku University School of Medicine, 980, Sendai, Japan

    K. Satoh, T. Yanagisawa & N. Taira

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  1. K. Satoh
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  2. T. Yanagisawa
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  3. N. Taira
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Satoh, K., Yanagisawa, T. & Taira, N. Effects on atrioventricular conduction and blood flow of enantiomers of verapamil and of tetrodotoxin injected into the posterior and the anterior septal artery of the atrioventricular node preparation of the dog. Naunyn-Schmiedeberg's Arch. Pharmacol. 308, 89–98 (1979). https://doi.org/10.1007/BF00499049

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  • DOI: https://doi.org/10.1007/BF00499049

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