Ion channel modulators as potential positive inotropic compound for treatment of heart failure.
1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life-threatening toxicity while beta-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.
Doggrell
S
S
Department of Pharmacology, University of Auckland, New Zealand.
Hoey
A
A
Brown
L
L
D000818:Animals; D002120:Calcium Channel Agonists / Q000737:chemistry* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007474:Ion Exchange; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers
D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers