Aker Stephanie, Snabaitis Andrew K, Konietzka Ina, Van De Sand Anita, Böngler Kerstin, Avkiran Metin, Heusch Gerd, Schulz Rainer
Institute of Pathophysiology, University of Essen Medical School, Hufelandstrasse 55, Essen 45122, Germany.
Cardiovasc Res. 2004 Aug 1;63(2):273-82. doi: 10.1016/j.cardiores.2004.04.014.
Inhibition of the Na+/H+-exchanger (NHE) preserves myocardial morphology and function in rat and mouse models of hypertrophy and failure. The mechanism(s) involved in such cardioprotective effects remain(s) unclear, but might involve blockade of increased protein kinase activity as observed in untreated hearts.
We investigated the functional, morphological and biochemical consequences of NHE-inhibition with BIIB722 in rabbits with pacing-induced heart failure (HF). In sham rabbits treated with placebo (n = 9) or BIIB722 (30 mg/kg/day po, n = 9), LV end-diastolic diameter (LVEDD) and systolic fractional shortening (FS, %) remained unchanged. In HF rabbits (n = 9), LVEDD increased and FS decreased from 31.5 +/- 1.4 to 8.1 +/- 0.9 (p < 0.05) at 3 weeks of LV pacing (400 bpm). Apoptosis, fibrosis and myocyte cross-sectional area as well as p38MAPK phosphorylation and iNOS protein expression were significantly increased in HF compared to sham rabbits. The activity of the 90 kDa NHE-kinase was greater in HF than in sham rabbits. In HF rabbits receiving BIIB722 prior to (18.1 +/- 2.2, n = 9) or following 1 week (15.5 +/- 1.6, n = 7) of pacing, FS at 3 weeks was better preserved than in untreated HF rabbits (p < 0.05). Apoptosis, fibrosis, myocyte cross-sectional area, p38MAPK phosphorylation and iNOS protein expression were significantly reduced in HF rabbits receiving BIIB722.
NHE-inhibition attenuates the functional, morphological and biochemical derangements of pacing-induced HF in rabbits.
在大鼠和小鼠的肥大及衰竭模型中，抑制钠氢交换体（NHE）可维持心肌形态和功能。这种心脏保护作用所涉及的机制尚不清楚，但可能与阻断未治疗心脏中观察到的蛋白激酶活性增加有关。
我们研究了用BIIB722抑制NHE对伴有起搏诱导性心力衰竭（HF）的家兔的功能、形态和生化影响。在用安慰剂治疗的假手术家兔（n = 9）或用BIIB722治疗的假手术家兔（口服30 mg/kg/天，n = 9）中，左心室舒张末期直径（LVEDD）和收缩期缩短分数（FS，%）保持不变。在HF家兔（n = 9）中，在左心室起搏（400次/分钟）3周时，LVEDD增加，FS从31.5±1.4降至8.1±0.9（p < 0.05）。与假手术家兔相比，HF家兔的凋亡、纤维化、心肌细胞横截面积以及p38丝裂原活化蛋白激酶（p38MAPK）磷酸化和诱导型一氧化氮合酶（iNOS）蛋白表达显著增加。HF家兔中90 kDa NHE激酶的活性高于假手术家兔。在起搏前（18.1±2.2，n = 9）或起搏1周后（15.5±1.6，n = 7）接受BIIB722治疗的HF家兔中，3周时的FS比未治疗的HF家兔得到更好的保留（p < 0.05）。接受BIIB722治疗的HF家兔的凋亡、纤维化、心肌细胞横截面积、p38MAPK磷酸化和iNOS蛋白表达显著降低。
NHE抑制可减轻家兔起搏诱导性HF的功能、形态和生化紊乱。
