A sodium channel enhancer, LY341311, increases myocardial contractile performance without increasing heart rate in conscious normal dogs: a comparison with dobutamine.
BACKGROUND
Catecholamines and many inotropic agents increase cardiac contractility but also cause excessive myocardial O2 consumption (MVO2). We determined if the novel Na+ channel enhancer LY341311, which increases myocardial contractility independent of beta receptors, can produce significant cardiac inotropic effects compared with dobutamine but at lower oxygen cost in conscious dogs.


RESULTS
Mongrel dogs were chronically instrumented for measurement of arterial pressure, left ventricular (LV) pressure and internal diameter, coronary blood flow, and arterial and coronary sinus O2 content. Both LY341311 and dobutamine produced dose-dependent increases in LV dP/dt, dP/dt/40, fractional shortening, and cardiac stroke work and minute work estimated from the LV pressure-diameter loop. The major difference between LY341311 and dobutamine was an opposing effect on heart rate with LY341311 slightly reducing it but dobutamine markedly increasing it. LY341311 caused a significantly smaller increase in MVO2 than dobutamine (P <.05) and produced similar cardiac inotropic effects, yielding a higher cardiac mechanical efficiency than dobutamine. However, after pacing to match heart rate with dobutamine LY341311 increased MVO2 markedly, approaching the same level as with dobutamine.


CONCLUSIONS
The novel Na+ channel enhancer LY341311 caused significant increases in myocardial contractility and contractile performance without increasing heart rate. It had a beneficial energetic effect on the heart with significantly less O2 cost and improved cardiac mechanical efficiency.
Gill
Robert M
RM
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Jones
Bonita D
BD
Steinberg
Mitchell I
MI
Shen
Weiqun
W
D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003243:Consciousness; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects
D001384:Azetidines; D002316:Cardiotonic Agents; D015222:Sodium Channels; C071117:BDF 9148; D004280:Dobutamine