Leineweber Kirsten, Aker Stephanie, Beilfuss Anja, Rekasi Heike, Konietzka Ina, Martin Claus, Heusch Gerd, Schulz Rainer
Institute of Pathophysiology, University of Essen School of Medicine, D-45122 Essen, Germany.
Br J Pharmacol. 2006 May;148(2):137-46. doi: 10.1038/sj.bjp.0706714.
Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial beta-adrenoceptor (betaAR)-adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton-exchanger (NHE)-1 attenuates LV remodeling and improves LV function. The mechanism(s) involved in these cardioprotective effects remain(s) unclear, but might involve effects on the impaired betaAR-AC system. Therefore, we investigated whether NHE-1 inhibition with sabiporide (SABI; 30 mg kg(-1) day(-1) p.o.) might affect myocardial betaAR density and AC activity in relation to changes in LV end-diastolic diameter (LVEDD) and LV systolic fractional shortening (LVS-FS) after 3 weeks of rapid LV pacing in rabbits. After 3 weeks of rapid LV pacing LVEDD was significantly increased (Shams 17+/-0.2 mm, n=9 vs 3 wksHF 20+/-0.5 mm, n=8; P<0.05) and LVS-FS decreased (Shams 31+/-1%, n=9 vs 3 wksHF 10+/-1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3 wksHF+2 wksSABI (n=7): LVEDD 18+/-1 mm; LVS-FS 16+/-4%) or before pacing (3 wksHF+3wksSABI (n=9): LVEDD 18+/-1 mm; LVS-FS 18+/-6%). After 3 weeks of rapid LV pacing, SABI treatment significantly attenuated increases in serum NA content (Shams 0.83+/-0.19, 3 wksHF 2.68+/-0.38, 3 wksHF+2 wksSABI 1.22+/-0.32, 3 wksHF+3wksSABI 1.38+/-0.33 ng ml(-1)). Moreover, betaAR density (Shams 64+/-5, 3 wksHF 38+/-3, 3 wksHF+2 wksSABI 48+/-4, 3 wksHF+3 wksSABI 55+/-3 fmol mg(-1) protein) and responsiveness (isoprenaline-stimulated AC activity. (Shams 57.6+/-4.9, 3 wksHF 36.3+/-6.0, 3 wksHF+2 wksSABI 56.9+/-6.0, 3 wksHF+3 wksSABI 54.5+/-4.8 pmol cyclic AMP mg(-1) protein(-1) min(-1)) were significantly improved in SABI-treated rabbits. From the present data we cannot address whether the improved betaAR-AC system permitted improved LV function and/or whether the improved LV function resulted in less activation of the sympathetic nervous system and by this in a reduced stimulation of the betaAR-AC system. Accordingly, additional studies are needed to fully establish the cause-and-effect relationship between NHE-1 inhibition and the restoration of the myocardial betaAR system.
慢性心力衰竭（HF）的特征是左心室（LV）结构重塑、功能受损、循环去甲肾上腺素（NA）水平升高以及心肌β-肾上腺素能受体（βAR）-腺苷酸环化酶（AC）系统反应性受损。在衰竭心脏中，抑制钠/质子交换体（NHE）-1可减轻左心室重塑并改善左心室功能。这些心脏保护作用所涉及的机制尚不清楚，但可能涉及对受损的βAR-AC系统的影响。因此，我们研究了用沙比必利（SABI；30mg·kg⁻¹·d⁻¹口服）抑制NHE-1是否会影响兔快速左心室起搏3周后心肌βAR密度和AC活性，以及左心室舒张末期直径（LVEDD）和左心室收缩期缩短分数（LVS-FS）的变化。快速左心室起搏3周后，LVEDD显著增加（假手术组17±0.2mm，n=9 vs 3周HF组20±0.5mm，n=8；P<0.0），LVS-FS降低（假手术组31±1%），n=9 vs 3周HF组10±1%，n=8；P<0.05）。SABI治疗显著改善了左心室功能，无论兔子是在起搏1周后（3周HF+2周SABI（n=7）：LVEDD 18±1mm；LVS-FS 16±4%）还是起搏前（3周HF+3周SABI（n=9）：LVEDD 18±1mm；LVS-FS 18±6%）接受治疗。快速左心室起搏3周后，SABI治疗显著减轻了血清NA含量的增加（假手术组0.83±0.19，3周HF组2.68±0.38，3周HF+2周SABI组1.22±0.32，3周HF+3周SABI组1.38±0.33ng·ml⁻¹）。此外，SABI治疗的兔子的βAR密度（假手术组64±5，3周HF组38±3，3周HF+2周SABI组48±4，3周HF+3周SABI组55±3fmol·mg⁻¹蛋白）和反应性（异丙肾上腺素刺激的AC活性，假手术组57.6±4.9，3周HF组36.3±6.0，3周HF+2周SABI组56.9±6.0，3周HF+3周SABI组54.5±4.8pmol环磷酸腺苷·mg⁻¹蛋白⁻¹·min⁻¹）均显著改善。根据目前的数据，我们无法确定改善的βAR-AC系统是否允许改善左心室功能和/或改善的左心室功能是否导致交感神经系统激活减少，从而减少对βAR-AC系统的刺激。因此，需要进一步的研究来充分确立NHE-1抑制与心肌βAR系统恢复之间的因果关系
