Müller-Ehmsen J, Brixius K, Schwinger R H
Laboratory of Muscle Research and Molecular Cardiology, Klinik III für Innere Medizin, der Universität zu Köln, Germany.
J Cardiovasc Pharmacol. 1998 May;31(5):684-9. doi: 10.1097/00005344-199805000-00006.
The aim of this study was to investigate the inotropic properties of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium. For comparison the Na+-channel modulator BDF 9148, the beta-adrenoceptor-agonist isoprenaline, and calcium were studied. Concentration-response curves for BDF 9198 (0.01-30 microM), BDF 9148 (0.01-30 microM), isoprenaline (0.001-1 microM), and calcium (1.8-15 mM) were obtained in electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilated cardiomyopathy, NYHA IV, heart transplantation; nonfailing, donor hearts). Whereas isoprenaline was significantly less effective and less potent in increasing the force of contraction in failing human myocardium than in nonfailing myocardium (p < 0.01), BDF 9198 and BDF 9148 were (in NYHA IV) as effective as in nonfailing human tissue. In both tissues, BDF 9198 and BDF 9148 exerted similar positive inotropic effects as calcium, with the novel Na+-channel modulator BDF 9198 being more potent in increasing force of contraction than was the preceding agent BDF 9148. The potencies of both Na+-channel modulators, BDF 9198 and BDF 9148, were enhanced in human failing myocardium when compared with nonfailing myocardium. In summary, the novel Na+-channel modulator BDF 9198 increases force of contraction to the same extent as calcium and with a higher potency than BDF 9148. The sensitivity of failing human myocardium to Na+-channel modulators is increased when compared with nonfailing myocardium, which might be the result of an altered Na+ homeostasis in human heart failure.
本研究旨在探讨新型钠通道调节剂BDF 9198在人类非衰竭和衰竭心肌中的变力特性。为作比较，对钠通道调节剂BDF 9148、β肾上腺素能受体激动剂异丙肾上腺素和钙进行了研究。在电驱动的人类左心室乳头肌条带（1Hz，37℃；扩张型心肌病，纽约心脏协会IV级，心脏移植；非衰竭，供体心脏）中获得了BDF 9198（0.01 - 30μM）、BDF 9148（0.01 - 30μM）、异丙肾上腺素（0.001 - 1μM）和钙（1.8 - 15mM）的浓度 - 反应曲线。与非衰竭心肌相比，异丙肾上腺素在增加衰竭人类心肌收缩力方面的效果和效力显著降低（p < 0.01），而BDF 9198和BDF 9148（纽约心脏协会IV级）在衰竭人类组织中的效果与非衰竭组织相同。在两种组织中，BDF 9198和BDF 9148产生的正性变力作用与钙相似，新型钠通道调节剂BDF 9198在增加收缩力方面比前一种药物BDF 9148更有效。与非衰竭心肌相比，两种钠通道调节剂BDF 9198和BDF 9148在人类衰竭心肌中的效力均增强。总之，新型钠通道调节剂BDF 9198增加收缩力的程度与钙相同，且效力高于BDF 9148。与非衰竭心肌相比，衰竭人类心肌对钠通道调节剂的敏感性增加，这可能是人类心力衰竭中钠稳态改变的结果。
