Drugs that Block Other Ion Channels Pumps or Transporters

In addition to the classic ion channels for sodium, potassium, and calcium, there are other ion channels that are thought to play a role in arrhythmias. There are stretch receptors that are candidates for explaining how stretch might induce arrhythmias. A common observation, both in vivo and in vitro, is that stretch of cardiac tissue can induce various types of arrhythmias.

Current flow between cardiac cells is vital for conduction of the impulse through all types of cardiac tissue. This is primarily by low-resistance pathways providing for easy electronic spread of potential from one cell to another. During ischemia and other conditions, changes in these pathways lead to the impediment of the spread of currents between cells, resulting in poor conduction, a condition where re-entry circuits become more likely.

In addition to the critical role played by voltage and ligand dependent ion channels, the maintenance of appropriate cardiac electrophysiology depends upon the existence of appropriate ionic gradients across cardiac cell membranes. The maintenance of such ionic gradients depends upon pumps and transporters for ions, principally sodium, potassium, calcium, and hydrogen. Since disorders of these mechanisms are common in conditions that result in arrhythmias, it is no surprise that they are potential targets for antiarrhythmic drugs. Gap junction activators

Conduction though gap junctions is reduced during ischemia and contributes to re-entry arrhythmias. For example, expression of the gap junction protein connexin 43 (Cx43) is downregulated in guinea pigs with congestive heart failure and these animals are liable to arrhythmias. The reduction in gap junction conductance due to ischemia is related to intracellular acidosis. However, compounds that block gap junctions (16-doxyl-stearic acid (61) and 1-heptanol (62)) reduce the ventricular defibrillation threshold in isolated rabbit hearts.35 Therefore, the role of gap junctions in arrhythmias is not totally clear, and there is uncertainty as to whether uncoupling, or maintaining, gap junctions is antiarrhythmic.

The short polypeptides, ZP123 (63) and AAP-10 (64) (Figure 20), prevent the closure of gap junctions induced by prolonged acidosis in guinea pig hearts. As a result, they reduce the heterogeneity of repolarization induced by acidosis. AAP-10 is a natural amino acid hexapeptide unlike the longer ZP123 which contains D amino acids. Not surprisingly AAP-10 has the limitation of a short half-life as compared with ZP123.36 Stretch activated channel blockers

The stretching that occurs in damaged atria or following overload of atria is a well-known cause of arrhythmias. Therefore, stretch-induced channels are considered a source of arrhythmogenic currents, and as a result a target for new antiarrhythmic drugs. Compounds such as DCPIB (65) can be expected to have antiarrhythmic actions, since it selectively inhibits the swelling-induced chloride current (ICl,swell) and prevents swell-induced shortening of atrial action potential in guinea pigs.37 Unfortunately, there have been no studies into the effects of such blockers in arrhythmias. Pumps, exchangers, and transporters

Ion exchangers or transporters are a fairly obvious target for antiarrhythmic drug discovery since they are integral to ionic homeostasis in cells, and generate electrogenic pump currents that supplement and complement the classical currents due to the opening of ion channels. Overexpression, or inappropriate activity, of such mechanisms is postulated to be responsible for certain types of arrhythmias.

N-Ac-(D)-Tyr-(D)-Pro-(D)-Hyp-Gly-(D)-Ala-Gly-NH2 Gly-Ala-Gly-Hyp-Pro-Tyr-NH2

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