Hemodynamic effects of a novel sodium channel activator in dogs with chronic heart failure

The use of positive inotropic agents, such as sympathomimetics and phosphod iesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemod ynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with d obutamine (DOB), in eight dogs with HF produced by intracoronary microembol izations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline measurements, infusion of DOB w as initiated at a dose of 2 mu g/kg/min and increased until an increase of heart rate (HR) > 30% of baseline or ventricular arrhythmias developed. Onc e hemodynamics returned to baseline, LY was infused at a dose of 2 mu g/kg/ min and increased until the LV fractional area of shortening (FAS), determi ned echocardiographically, reached a similar level as with DOB. Both drugs increased FAS equivalently compared to baseline (DOB, 24 +/- 3 to 47 +/- 2; LY, 27 +/- 2 to 46 +/- 2%). DOB increased HR from 78 +/- 4 min(-1) at base line to 107 +/- 7 min(-1) at maximal dose (p < 0.05) and provoked serious a rrhythmias in one dog. In contrast, LY infusion did not increase HR (82 +/- 7 vs. 80 +/- 8 min(-1)) or elicit arrhythmias. After 1 week of oral digoxi n, dogs were infused again with LY. A lower dose of LY was needed to achiev e the same increase in FAS compared to LY alone, but this was not statistic ally significant. The combination of LY with digoxin did not increase HR or evoke arrhythmias. We conclude that in dogs with HF, intravenous LY improv es LV function to the same extent as DOB without increasing HR or evoking v entricular arrhythmias. The combination of LY with digoxin elicits a safe p ositive inotropic response.