ION CHANNEL MODULATORS AS POTENTIAL POSITIVE INOTROPIC COMPOUNDS FOR TREATMENT OF HEART FAILURE

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Abstract
SUMMARY: 1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life‐threatening toxicity while β‐adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation.2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201–106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction.3. Activation of L‐type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors.4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction.5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.