Pharmacological Interventions at Gap Junctions

On the other hand arrhythmia due to uncoupling may be prevented. If coupling is enhanced selectively in the previously uncoupled area only within that area cellular uncoupling would be antagonized, which means that the surrounding tissue would not be affected in the way described above. There might be a similar effect in the close border zone between diseased and normal tissue, but the effect would be confined to that zone. Inhomogeneities within the diseased zone would be smoothened whereas the normal tissue behavior would probably be less affected. This could especially smooth differences in action potential duration and thereby prevent, in some situations, from reentrant arrhythmia, since this is often related to differences in action potential duration, to dispersion. Another important factor in the initiation of reentry 

enhancing intercellular coupling may exert a prophylactic effect against arrhythmia if arrhythmia is due to uncoupling. However, if the coupling effect is unselective, it would probably postpone an impairing effect as discussed above for ischemia. From this theoretical point of view selective couplingenhancing effects on the previously uncoupled tissue would be desirable rather than unselective. 

However, it should be considered that in both cases one has to distinguish whether a substance uncouples or couples the whole tissue or only those parts with altered intercellular communication. Thus, the question arises what is presently known about the pharmacology of gap junction channels  

In the following a survey is given of the substances which have been found to alter intercellular coupling. First drugs will be considered which uncouple gap junctions. A number of lipophilic compounds have been described to reduce gap junctional coupling. These substances include alcohols like hep-tanol and octanol, saturated and unsaturated fatty acids, and alcohols and 

However, some authors showed that heptanol and octanol can also inhibit the cardiac sodium current [Nelson and Makielski, 1990] and that general anesthetics like octanol and decanol can interfere with the cardiac Na+/Ca2+ exchange [Haworth et al., 1989] at concentrations below those required for gap junctional uncoupling. This action is considered to contribute to their well-known negative inotropic effect. 

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Furthermore, synchronization of contraction is facilitated by gap junctional communication as well as synchronization of electrical activation. The electrical coupling between cardiomyocytes mitigates differences in the membrane potential between these cells, for example in the course of an action potential if both cells repolarize at different timepoints. This results in smaller differences in the repolarization times thereby causing a reduction in the dispersion of the action potential duration. Since increased dispersion is known to make the heart more prone to reentrant arrhythmia, sufficient gap junctional communication can be considered as an endogenous arrhythmia-preventing mechanism. For a detailed discussion of the role of gap junctional communication in the biophysics of cardiac activation as related to anisotropy, nonuniformity and stochastic phenomena, see chapter 1 for a discussion of their role in arrhythmia, see chapter 6, and for a possible pharmacological intervention at the gap junctions for suppression of arrhythmia, refer to chapter 7. 

Fig. 23. Survey of the various pharmacological interventions at the gap junctional coupling. For details see text. 

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