Salameh Aida, Zöbisch Helena, Schröder Bianca, Vigelahn Jonas, Jahn Mandy, Abraham Getu, Seeger Johannes, Dähnert Ingo, Dhein Stefan
Heart Centre Clinic for Paediatric Cardiology, University of Leipzig, Leipzig, Germany.
Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, Leipzig, Germany.
Front Physiol. 2020 Mar 19;11:224. doi: 10.3389/fphys.2020.00224. eCollection 2020.
Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1 in a Langendorff-perfused heart model. To discriminate a potentially different impact of extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided into 8 experimental groups: control group (pH = 7.4, O = 100%) without or with cariporide (1 μM), acidosis group (pH = 7.0, O = 100%) without or with cariporide (1 μM), hypoxia group (pH = 7.4, O = 40%) without or with cariporide (1 μM) and hypoxia+acidosis group (pH = 7.0, O = 40%) without or with cariporide (1 μM). Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis). Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600 mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from -1,500 mmHg/s to about -600 mmHg/s. During reperfusion hearts subjected to hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2 fold increase in both dispersion of activation-recovery interval and in total activation time in the hypoxia ± acidosis group. Cariporide application significantly improved LV hemodynamics and electrophysiology in the hypoxia group but not in the group subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase 3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again, cariporide mitigated these processes only in the hypoxia alone group, but not in the group with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and that NHE-inhibition improved only hypoxia-induced cardiac dysfunction.
缺氧常导致严重的心脏功能障碍。据推测，细胞内钙超载是导致左心室（LV）功能恶化的原因之一。抑制钠-氢交换体（NHE）最终可抑制/减缓钙超载，可能改善心脏功能。我们的目的是在Langendorff灌注心脏模型中评估NHE1抑制剂卡里波罗德。为了区分细胞外酸中毒和缺氧可能产生的不同影响，我们将48只杂种龙猫兔分为8个实验组：对照组（pH = 7.4，O = 100%），不使用或使用卡里波罗德（1 μM）；酸中毒组（pH = 7.0，O = 100%），不使用或使用卡里波罗德（1 μM）；缺氧组（pH = 7.4，O = 40%），不使用或使用卡里波罗德（1 μM）；缺氧+酸中毒组（pH = 7.0，O = 40%），不使用或使用卡里波罗德（1 μM）。心脏在酸中毒/缺氧条件下处理90分钟，随后再灌注60分钟。缺氧和缺氧+酸中毒导致左心室功能严重恶化，左心室压力下降约70%，舒张末期压力从6.7±0.6升高至36.8±5.4（缺氧）或从7.0±0.2升高至18.�±4.1（缺氧+酸中毒）。此外，在缺氧±酸中毒期间，最大收缩速度从约1800 mmHg/s降至600 mmHg/s，最大舒张速度从-1500 mmHg/s恶化至约-600 mmHg/s。在再灌注期间，缺氧+酸中毒处理的心脏比单纯缺氧处理的心脏恢复得更快，再灌注5分钟后达到对照水平。电生理分析显示，缺氧±酸中毒组的激活-恢复间期离散度和总激活时间均增加了1.2倍。应用卡里波罗德可显著改善缺氧组的左心室血流动力学和电生理，但对缺氧+酸中毒组无效。对心脏标本的免疫组织学分析显示，缺氧±酸中毒后左心室中涉及缺氧/再灌注损伤的因子如硝基酪氨酸和聚ADP-核糖以及凋亡诱导因子如AIF或裂解的半胱天冬酶3显著增加。缺氧会降低ATP，但酸中毒不会。同样，卡里波罗德仅在单纯缺氧组减轻了这些过程，而在伴有酸中毒的组中无效。无缺氧的酸中毒仅轻微干扰左心室功能和电生理，且不受卡里波罗德影响。因此，我们的研究表明酸中毒减轻或消除了缺氧的几种有害影响，且抑制NHE仅改善缺氧诱导的心脏功能障碍。
