Liu Shi J, Kennedy Richard H
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street, MS 522-3, Little Rock, AR 72205, USA.
Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H735-44. doi: 10.1152/ajpheart.01098.2002. Epub 2003 May 1.
Ceramide, a sphingolipid metabolite produced by activation of sphingomyelinase, has been previously shown to reduce L-type Ca2+ channel current (ICa,L) in adult rat ventricular myocytes; however, its effect on contractile function is unknown. In this study, we investigated the effects of ceramide on excitation-contraction coupling in adult ventricular myocytes and on left ventricular (LV) function in isolated hearts. Surprisingly, in patch-clamped myocytes, ceramide increased contraction concomitant with reductions in ICa,L. In intact myocytes, ceramide increased cell shortening (CS) concurrently with enhancing maximum rates of shortening and relaxation and the duration of contraction. Ceramide also increased the amplitudes of postrest potentiated (PRP) contraction. In fura-PE3-loaded myocytes, ceramide increased systolic Ca2+ and the magnitude and maximum rates of the rising and declining phases of Ca2+ transients. Ceramide-elicited decreases in magnitudes of PRP relative to steady-state contraction and the Ca2+ transient suggest an increased fractional Ca2+ release from the sarcoplasmic reticulum (SR). However, ceramide slightly reduced the caffeine-induced Ca2+ transient and had no significant effect on the amplitude of the PRP-elicited Ca2+ transient. Additionally, the ceramide-induced upward shift in the relationship of contraction and the Ca2+ transient and increase in the Ca2+ responsiveness of CS suggest an increase in myofilament Ca2+ sensitivity. In isolated hearts, ceramide increased LV developed pressure and maximum rates of contraction and relaxation at balloon volumes of 30-50 microl. In summary, regardless of decreasing ICa,L, ceramide elicits distinct positive inotropic and lusitropic effects, resulting probably from enhanced SR Ca2+ release and uptake, and increased Ca2+ sensitivity of ventricular myocytes.
神经酰胺是一种由鞘磷脂酶激活产生的鞘脂代谢产物，先前已证明其可降低成年大鼠心室肌细胞的L型钙通道电流（ICa,L）；然而，其对收缩功能的影响尚不清楚。在本研究中，我们研究了神经酰胺对成年心室肌细胞兴奋-收缩偶联及离体心脏左心室（LV）功能的影响。令人惊讶的是，在膜片钳记录的肌细胞中，神经酰胺在降低ICa,L的同时增加了收缩。在完整的肌细胞中，神经酰胺增加了细胞缩短（CS），同时提高了最大缩短和舒张速率以及收缩持续时间。神经酰胺还增加了静息后增强（PRP）收缩的幅度。在负载fura-PE3的肌细胞中，神经酰胺增加了收缩期Ca2+以及Ca2+瞬变上升和下降阶段的幅度和最大速率。相对于稳态收缩和Ca2+瞬变，神经酰胺引起的PRP幅度降低表明肌浆网（SR）的Ca2+释放分数增加。然而，神经酰胺略微降低了咖啡因诱导的Ca2+瞬变，并且对PRP诱导的Ca2+瞬变幅度没有显著影响。此外，神经酰胺引起的收缩与Ca2+瞬变关系的向上移位以及CS的Ca2+反应性增加表明肌丝Ca2+敏感性增加。在离体心脏中，在气球体积为30-50微升时，神经酰胺增加了左心室舒张末压以及最大收缩和舒张速率。总之，尽管神经酰胺降低了ICa,L，但它引发了明显的正性肌力和舒张期正性变时作用，这可能是由于SR Ca2+释放和摄取增强以及心室肌细胞Ca2+敏感性增加所致。
