It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II.

2003-12-01·Pediatric research3区 · 医学

Na+-Channel Modulation, a New Principle of Inotropic Intervention: Effects on Hemodynamic and Myocardial Energetics in the Immature Rabbit Heart

3区 · 医学

Article

作者: Lueers, Frank ; Pfahlberg, And Annette ; Rizouli, Vicky ; Schiffmann, Holger ; Hoebel, Dyrken ; Hellige, Gerhard ; Hackmann, Frank

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.

2002-01-01·Basic research in cardiology1区 · 医学

Effects of different inotropic interventions on myocardial function in the developing rabbit heart

1区 · 医学

Article

作者: Bohm, Michael ; Schiffmann, Holger ; Hauseler, Claudia ; Pfahlberg, Annette ; Flesch, Markus ; Hellige, Gerhard

The development of the mammalian heart is characterized by substantial changes in myocardial performance. We studied the ontogeny of myocardial function with and without various inotropic interventions in the developing isolated, antegrade-perfused rabbit heart (2d, 8d, 14d, 28d, n = 96). Myocardial function was related to the protein expression of the sarcolemmal Na(+)-Ca2+ exchanger and to the sarcoplasmic Ca(2+)-ATPase. In neonatal hearts an age-dependent increase in maximal developed pressure velocity (dP/dtmax) by 45% and peak negative pressure velocity (dP/ dtmin) by 75% within days 2 to 8 were observed. In response to inotropic intervention with isoproterenol, ouabain, calcium and the Na(+)-channel modulator BDF 9148, dP/dtmax and dP/dtmin increased in a concentration dependent manner. Significant differences between neonatal, juvenile and adult hearts could be demonstrated in a repeated measurement ANOVA model on the concentration-response curves for BDF 9148 (dP/dtmax and dP/dtmin), ouabain (dP/dtmin) and calcium (dP/dtmin), but not for isoproterenol. At the maximum isoproterenol concentration of 1 micromol/l, the increase in dP/dtmax and dP/dtmin was significantly higher in adult compared to neonatal hearts (t-test, p < 0.01). The significant decline of the Na(+)-Ca2+ exchanger protein expression from neonatal (1822 +/- 171) to adult hearts (411 +/- 96 S.E.M. [units per 20 microg protein], p < 0.01) was related to an increase in myocardial function (dP/dtmax r = 0.63, p < 0.01, dP/dtmin r = 0.62, p < 0.01). Contractility, relaxation and the observed positive inotropic effects were in general significantly lower in neonatal compared to adult hearts. In the individual heart an increase in contractility and relaxation was related to a decrease in Na(+)-Ca2+ exchanger expression.

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