Hemodynamic Effects of a Novel Sodium Channel Activator in Dogs With Chronic Heart Failure

  title={Hemodynamic Effects of a Novel Sodium Channel Activator in Dogs With Chronic Heart Failure},
  author={Mitsuhiro Tanimura and Takayuki Mishima and Mitchell I. Steinberg and Steven Borzak and Sidney O. Goldstein and Hani N. Sabbah},
  journal={Cardiovascular Drugs and Therapy},
The use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemodynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with dobutamine (DOB), in eight dogs with HF produced by intracoronary microembolizations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline… Expand
Combined inotropic and bradycardic effects of a sodium channel enhancer in conscious dogs with heart failure: a mechanism for improved myocardial efficiency compared with dobutamine.
The data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O(2) utilization in the failing heart while providing inotropic support comparable to a beta-receptor-mediated agonist. Expand
Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure.
The Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function. Expand
Cardiac Contractility Modulation With the Impulse Dynamics Signal: Studies in Dogs With Chronic Heart Failure
Pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Expand
A sodium channel enhancer, LY341311, increases myocardial contractile performance without increasing heart rate in conscious normal dogs: a comparison with dobutamine.
The novel Na+ channel enhancer LY341311 caused significant increases in myocardial contractility and contractile performance without increasing heart rate and had a beneficial energetic effect on the heart with significantly less O2 cost and improved cardiac mechanical efficiency. Expand
First Report on an Inotropic Peptide Activating Tetrodotoxin-Sensitive, “Neuronal” Sodium Currents in the Heart
The pilot experiments suggest that selective activation of tetrodotoxin-sensitive neuronal sodium channels can safely increase cardiac contractility, and the peptide described here may become a lead compound for a new class of positive inotropic agents. Expand
Exciting treatment of reentrant arrhythmias
This editorial refers to ‘Expression of skeletal muscle sodium channel (Nav1.4) or connexin32 prevents reperfusion arrhythmias in murine heart’ by E.P. Anyukhovsky et al. , doi:10.1093/cvr/cvq284. Expand
Exciting treatment of reentrant arrhythmias.
Interventions that suppress the reduction of excitability or electrical coupling during acute ischaemia may prevent slow conductionrelated arrhythmias and open avenues for therapies with enhancers of the endogenous Na+ channel. Expand


Electrophysiologic and proarrhythmic effects of intravenous inotropic agents.
In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients, and the primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythias have been reported less commonly. Expand
Cardiac Sodium Channels as Targets for New Inotropic Agents
In ischemic CHF animal models, stroke volume and output are enhanced in the absence of positive chronotropic or arrhythmogenic activity and the unfavorable systolic and diastolic force–frequency relationships of isolated papillary muscle in advanced CHF are improved by some agents in this class. Expand
Hemodynamic response of a canine model of chronic heart failure to intravenous dobutamine, nitroprusside, enalaprilat, and digoxin
The data indicate that this canine model of CHF responds to acute pharmacologic intervention in a manner comparable to that seen in patients with CHF and may be a useful tool for the preclinical evaluation of new drugs targeted toward the treatment ofCHF and for investigating the mechanisms of action of drugs currently used for the Treatment of this disease state. Expand
The effect of a new inotropic agent, DPI 201-106, on systolic time intervals and the electrocardiogram in healthy subjects.
It is concluded that DPI has positive inotropic and negative chronotropic properties which make it potentially useful for the treatment of heart failure. Expand
Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishing hype from hope.
  • M. Packer
  • Medicine
  • Journal of the American College of Cardiology
  • 1988
It is suggested that correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder. Expand
Effect of Inotropic Stimulation on the Negative Force‐Frequency Relationship in the Failing Human Heart
These findings suggest that hitherto unknown changes in the intracellular ionic homeostasis occur in the failing human heart, leading to the negative force-frequency relationship in terminally failing human myocardium. Expand
Positive inotropic effects of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium.
The novel Na+-channel modulator BDF 9198 increases force of contraction to the same extent as calcium and with a higher potency than BDF9148, which might be the result of an altered Na+ homeostasis in human heart failure. Expand
Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction.
In dogs with reduced LVEF, long-term therapy with enalapril or metoprolol prevents the progression of LV systolic dysfunction and LV chamber dilation and does not prevent progressive LV enlargement. Expand
Characterization of the inotropic and arrhythmogenic action of the sodium channel activator BDF 9148: a comparison to its S-enantiomer BDF 9196, to its congener DPI 201-106, to norepinephrine, and to ouabain
It is demonstrated that the three Na+-channel activators exert a profound positive inotropic action with little intrinsic arrhythmogenic action under normal and ischemic conditions. Expand
Intermittent infusion of dobutamine in the therapy of severe congestive heart failure-long-term effects and lack of tolerance
Intermittent therapy with dobutamine seems to be a promising concept in the management of refractory severe heart failure and no excess mortality emerged during intermittentDobutamine therapy. Expand