hmr-1098 and Heart-Failure

Inhibition of cardiomyocyte-specific ATP-sensitive potassium (K(ATP)) channels prolongs the action potential during intense ischaemia with attendant antiarrhythmic effects. However, this is accompanied by contractile depression in some models. These changes may be particularly troublesome in dilated cardiomyopathic hearts that display basal systolic dysfunction, limited energy reserve, and prolonged repolarization favouring arrhythmia. Mechanical effects of selective myocyte K(ATP) channel blockade on basal, beta-adrenergic stimulated, and ischemic responses were therefore tested in dogs with cardiac failure induced by tachypacing. Cardiovascular function was assessed by pressure - dimension relationships in 10 conscious, chronically instrumented dogs (sonomicrometry/micromanometry), with or without cardiac failure. Cardiomyocyte K(ATP) channels were inhibited by HMR 1098, and data obtained under basal conditions, during epinephrine infusion to raise metabolic demand, during regional ischaemia, and with combined ischaemia+epinephrine. HMR 1098 had no effect on baseline cardiac function nor did it induce arrhythmia in normal or failing hearts. Epinephrine raised cardiac work 65% and oxygen consumption 55%, yet HMR 1098 had no functional effect in either heart condition. Regional ischaemia with or without epinephrine co-stimulation depressed regional and global function, yet both were also unaffected by HMR 1098. There was minimal arrhythmia without HMR 1098, and drug infusion did not alter this. Thus, myocyte-K(ATP) channels play a negligible role modulating intact in vivo cardiac contraction or arrhythmia in normal and failing heart with and without increased metabolic demand and/or regional ischaemia. This supports the feasibility of administering such agents to depressed hearts, despite underlying contractile and electrophysiologic abnormalities.

Topics: Animals; Benzamides; Cardiotonic Agents; Dogs; Electrocardiography; Heart Failure; Myocardial Ischemia; Potassium Channel Blockers; Potassium Channels