No2

Figure 20 Polypeptide structure of gap junction activators: (a) AAP-10 and (b) ZP123. A stretch-activated channel (ICl,swell) blocker: (c) DCPIB. Sodium-calcium exchanger blockers: (d) KB-R7943 and (e) SEA0400.

6.33.7.3.3.1 Sodium-calcium exchanger blockers

The sodium-calcium exchanger is a particularly interesting target due to its role in arrhythmic situations where there is calcium overload, after potentials and other arrhythmic changes. The function of the sodium-calcium exchanger is perturbed by ischemia, heart failure, and by other pathological conditions of the heart, including the excessive action potential prolongation seen with IKr blockers. Experimental studies have shown that sodium-calcium exchanger blockers, such as KB-R7943 (66) and SEA0400 (67), prevent arrhythmias due to ischemia and reperfusion.38

6.33.7.3.3.2 Sodium-hydrogen exchanger blockers

There have been many studies with the sodium-hydrogen exchanger (NHE) and the effects of drugs upon its activity. This exchanger is essential in cardiac cells since it moderates intracellular acidosis by exchanging one extracellular sodium ion for one intracellular hydrogen ion. In animals with infarction and ventricular hypertrophy, the level and activity of the exchanger are elevated. This increased activity may also lead to increases in intracellular sodium, which in turn increase intracellular Ca2 +, via the sodium-calcium exchanger, and result in Ca2 + overload. In rabbits, treatment with cariporide, an NHE inhibitor, attenuates the development of cardiac hypertrophy and failure, ionic remodeling, and arrhythmias.

Cariporide (68) was amongst the first blockers of the sodium-hydrogen exchanger. Cariporide and HOE-694 (69) are analogs of the diuretic amiloride (70) (Figure 21). Others include compounds such as eniporide (71) and BIIB-513 (72) (Figure 21), with the latter shown to be cardiac protective in a canine model of myocardial ischemia.39

6.33.7.3.3.3 Fatty acid and fish oil

There has been interest over the years regarding arrhythmogens released from endogenous fatty acids, and attempts have been made to manipulate the endogenous fatty acid composition by dietary means leading to sporadic experimental and clinical studies into the potential antiarrhythmic effects of diet. In a randomized control trial,40 fish oil supplementation in patients with an ICD was associated with more episodes of recurrent VT/VF, thereby suggesting that, rather than reduce arrhythmias, fish oil might be proarrhythmic in some patients.

The mechanism by which long-chain o-3 polyunsaturated fatty acids (PUFAs), like eicosapentaenoic acid (EPA, 73) and docosahexaenoic acid (DHA, 74) (Figure 22), affect arrhythmias is not known with any certainty, but Na+ and K+ channel blockade/modification is probably responsible for its potential class 1 and 3 effects.41'42

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