Abstract
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.
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Abbreviations
- CO:
-
cardiac output
- Eff:
-
myocardial efficiency
- HR:
-
heart rate
- pLV:
-
left ventricular pressure
- SV:
-
stroke volume
- Vcor:
-
coronary flow
REFERENCES
St John Sutton MG, Gewitz MH, Shah B, Cohen A, Reichek N, Gabbe S, Huff DS 1984 Quantitative assessment of growth and function of the cardiac chambers in the normal human fetus: a prospective longitudinal echocardiographic study. Circulation 69: 645–654
Teitel DF, Hoffman JI 1996 Coronary circulation and myocardial oxygen consumption. In: Gluckman PD, Heymann MA. Arnold (eds) Pediatrics and Perinatology. Arnold, London, pp 731–736.
Artman M, Kithas PA, Wike JS, Strada SJ 1988 Inotropic responses change during postnatal maturation in rabbit. Am J Physiol 255: H335–H342
Nishioka K, Nakanishi T, George BL, Jarmakani JM 1981 The effect of calcium on the inotropy of catecholamine and paired electrical stimulation in the newborn and adult myocardium. J Mol Cell Cardiol 13: 511–520
Feng ZP, Dryden WF, Gordon T 1989 Postnatal development of adrenergic responsiveness in the rabbit heart. Can J Physiol Pharmacol 67: 883–889
Osaka T, Joyner RW 1992 Developmental changes in the beta-adrenergic modulation of calcium currents in rabbit ventricular cells. Circ Res 70: 104–115
Park MK, Sheridan PH, Morgan WW, Beck N 1980 Comparative inotropic response of newborn and adult rabbit papillary muscles to isoproterenol and calcium. Dev Pharmacol Ther 1: 70–82
Szymanska G, Grupp IL, Slack JP, Harrer JM, Kranias EG 1995 Alterations in sarcoplasmic reticulum calcium uptake, relaxation parameters and their responses to β-adrenergic agonists in the developing rabbit heart. J Mol Cell Cardiol 27: 1819–1829
Teitel DF, Sidi D, Chin T, Brett C, Heymann MA, Rudolph AM 1985 Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res 19: 948–955
Teitel DF, Klautz R, Steendijk P, van der Velde ET, van Bel F, Baan J 1991 The end-systolic pressure-volume relationship in the newborn lamb: effects of loading and inotropic interventions. Pediatr Res 29: 473–482
Schiffmann H, Flesch M, Häuseler C, Pfahlberg A, Böhm M, Hellige G 2002 Effects of different inotropic interventions on myocardial function in the developing rabbit heart. Basic Res Cardiol 97: 76–87
Artman M 1992 Sarcolemmal Na+-Ca2+ exchange activity and exchanger immunoreactivity in developing rabbit hearts. Am J Physiol 263: H1506–H1513
Mahony L 1996 Regulation of intracellular calcium concentration in the developing heart. Cardiovasc Res 31: E61–E67
Neely JR, Liebermeister H, Battersby EJ, Morgan HE 1967 Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol 212: 804–814
Bünger R, Sommer O, Walter G, Stiegler H, Gerlach E 1979 Functional and metabolic features of an isolated perfused guinea pig heart performing pressure-volume work. Pflugers Arch 380: 259–266
Hoey A, Amos GJ, Ravens U 1994 Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium. J Mol Cell Cardiol 26: 985–994
Greenhouse SW, Geisser S 1958 On methods in the analysis of profile data. Psychometrika 32: 95–112
Colucci W, Braunwald E 1997 Pathophysiology of the heart failure. In: Braunwald E (ed) Heart Disease. WB Saunders, Philadelphia, pp 394–420.
Baumgart D, Ehring T, Krajcar M, Skyschally A, Heusch G 1994 Characterization of the inotropic and arrhythmogenic action of the sodium channel activator BDF 9148: in comparison to its S-enantiomer BDF 9196, to its congener DPI 201-106, to norepinephrine, and to ouabain. Basic Res Cardiol 89: 61–79
Raap A, Armah B, Mest HJ, Stenzel W, Schloos J, Blechacz W 1997 Investigations of the mechanism of the positive inotropic action of BDF 9148; comparison with DPI 201-106 and the enantiomers. J Cardiovasc Pharmacol 29: 164–173
Ravens U, Wettwer E, Pfeifer T, Himmel H, Armah B 1991 Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea-pig heart. Br J Pharmacol 104: 1019–1023
Flesch M, Schwinger RH, Pütz F, Frank K, Südkamp M, Kuhn-Regnier F, Arnold G, Böhm M 1996 Evidence for a functional relevance of an enhanced expression of the Na+-Ca2+-exchanger in the failing human myocardium. Circulation 94: 992–1002
Konishi T, Apstein CS 1991 Deleterious effects of digitalis on newborn rabbit myocardium after simulated cardiac surgery. J Thorac Cardiovasc Surg 101: 331–341
Lorell BH, Isoyama S, Grice WN, Weinberg EO, Apstein CS 1988 Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts. Circ Res 63: 457–467
Hasenfuβ G, Mulieri LA, Allen PD, Just H, Alpert NR 1996 Influence of isoproterenol and ouabain on excitation-contraction coupling, cross-bridge function, and energetics in failing human myocardium. Circulation 94: 3155–3160
Boerth RC 1975 Decreased sensitivity of newborn myocardium to the inotropic effects of ouabain. In: Morselli PL, Garatinni S, Sereni F (eds) Basic and Therapeutic Aspects of Perinatal Pharmacology. Raven Press, New York, pp 191–199.
Marsh JD, Allen PD 1989 Developmental regulation of cardiac calcium channels and contractile sensitivity to [Ca]o . Am J Physiol 256: H179–H185
Nakanishi T, Shimizu T, Uemura S, Jarmakani JM 1984 Ouabain effect on myocardial mechanical function and sodium pump in the fetus. Am J Physiol 246: H213–H221
Park MK 1981 Ouabain-induced inotropism of isolated newborn and adult rabbit myocardium. Dev Pharamcol Ther 2: 201–214
Driscoll DJ 1987 Use of inotropic and chronotropic agents in neonates. Clin Perinatol 14: 931–949
Pridjian AK, vanMeter CH, McFadden PM, Chung KC, Touchard CI, Ochsner JL 1996 Repletion of high energy phosphates in the postischemic neonatal heart. Am Surg 62: 494–498
Hasenfuβ G, Holubarsch CH, Heiss WH, Meinertz T, Bonzel T, Wais U, Lehmann M, Just H 1989 Myocardial energetics in patients with dilated cardiomyopathy. Influence of nitroprusside and enoximone. Circulation 80: 51–64
Schranz D, Huth R, Dahm M, Stein I, Hein E, Stopfkuchen H, Jüngst BK 1989 Acute hemodynamic response to intravenous enoximone: an animal study and preliminary report in infants after cardiac surgery. J Cardiovasc Pharmacol 14 ( suppl 1): 62–68
Hasenfuss G, Holubarsch C, Heiss WH, Bonzel T, Meinertz T, Just H 1987 Influence of phosphodiesterase inhibition on myocardial energetics in dilative cardiomyopathy. Basic Res Cardiol 82 ( suppl 2): 403–409
Heiss HW, Hasenfuβ G, Holubarsch C, Meinertz T, Just H 1987 Cardiac energetics after intravenous enoximone in idiopathic dilated cardiomyopathy. Am J Cardiol 60: 53C–56C
Martin AF, Ball K, Gao LZ, Kumar P, Solaro RJ 1991 Identification and functional significance of troponin I isoforms in neonatal rat heart myofibrils. Circ Res 69: 1244–1252
Viquerat CE, Kereiakes D, Morris L, Daly PA, Wexman M, Frank P, Parmley WW, Chatterjee K 1985 Alterations in left ventricular function, coronary hemodynamics and myocardial catecholamine balance with MDL 17043, a new inotropic vasodilator agent, in patients with severe heart failure. J Am Coll Cardiol 5: 326–332
Holubarsch C, Hasenfuβ G, Just H, Blanchard E, Mulieri LA, Alpert NR 1989 Influence of enoximone on mechanics and energetics of right ventricular guinea pig papillary muscles. J Cardiovasc Pharmacol 14 ( suppl 1): S24–S28
Ross-Ascuitto NT, Ascuitto RJ, Ramage D, McDonough KH 1991 The effects of milrinone in the neonatal pig heart. Cardiovasc Drugs Ther 5: 1011–1019
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Schiffmann, H., Rizouli, V., Lüers, F. et al. Na+-Channel Modulation, a New Principle of Inotropic Intervention: Effects on Hemodynamic and Myocardial Energetics in the Immature Rabbit Heart. Pediatr Res 54, 875–884 (2003). https://doi.org/10.1203/01.PDR.0000091286.21994.E5
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DOI: https://doi.org/10.1203/01.PDR.0000091286.21994.E5
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