Na(+)-channel modulation, a new principle of inotropic intervention: effects on hemodynamic and myocardial energetics in the immature rabbit heart.
Na+-channel modulators exert their positive inotropic action without affecting the adenylate-cyclase pathway by an increase in the open probability of the sarcolemmal Na+ channels. Although inotropic effects in neonatal hearts are less pronounced compared with adult hearts, the Na+-channel modulator BDF 9148 increases contractility and relaxation velocity in immature myocardium. Effects on hemodynamics and myocardial energetics are not known. Therefore, we studied the Na+-channel modulator BDF 9148 in isolated antegrade perfused rabbit hearts of different ages (2-28 d) and compared the effects with isoproterenol, enoximone, and ouabain. ANOVA showed significant effects in the concentration response curves for heart rate, stroke volume, cardiac output, and oxygen consumption but not for myocardial efficiency (p = 0.06). Age-dependent differences were observed for heart rate and stroke volume. Administration of BDF 9148 resulted in a maximal increase in stroke volume and cardiac output up to 25% in neonatal and 40% to 60% in adult preparations. Heart rate decreased by 15% in adult hearts only. Myocardial oxygen consumption was increased in a concentration-dependent manner between 25% in neonatal and 50% in adult hearts. Myocardial efficiency was increased by 35% in adult and by 10% in neonatal preparations. Although positive hemodynamic and energetic effects were less pronounced in immature compared with adult hearts, neonatal hearts also profited from the administration of the Na+-channel modulator BDF 9148. Further studies are necessary to clarify the risk of arrhythmia during application of Na+-channel modulators such as BDF 9148.
Schiffmann
Holger
H
Department of Pediatric Cardiology and Intensive Care, University of Goettingen, Goettingen D-37075, Germany. schiffi@med.uni-goettingen.de
Rizouli
Vicky
V
Luers
Frank
F
Hackmann
Frank
F
Hoebel
Dyrken
D
Pfahlberg
Annette
A
Hellige
Gerhard
G
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001384:Azetidines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017335:Enoximone / Q000494:pharmacology; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology; D011247:Pregnancy; D011817:Rabbits; D015222:Sodium Channels / Q000378:metabolism*
D001384:Azetidines; D002316:Cardiotonic Agents; D015222:Sodium Channels; C071117:BDF 9148; D010042:Ouabain; D017335:Enoximone; D000242:Cyclic AMP; D007545:Isoproterenol