Sallam Marwa Y, El-Gowilly Sahar M, Abdel-Galil Abdel-Galil A, El-Mas Mahmoud M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
J Cardiovasc Pharmacol. 2016 Aug;68(2):171-81. doi: 10.1097/FJC.0000000000000400.
Reduced blood pressure (BP) and cardiac autonomic activity are early manifestations of endotoxemia. We investigated whether these effects are modulated by central mitogen-activated protein kinases (MAPKs) and related phosphoinositide-3-kinase (PI3K)/soluble guanylate cyclase (sGC) signaling in conscious rats. The effect of pharmacologic inhibition of these molecular substrates on BP, heart rate (HR), and heart rate variability (HRV) responses evoked by intravascular lipopolysaccharide (LPS) (10 mg/kg) were assessed. LPS (1) lowered BP (2) increased HR, (3) reduced time [SD of beat-to-beat intervals (SDNN), and root mean square of successive differences in R-R intervals (rMSSD)], and frequency domain indices of HRV (total power and spectral bands of low and high-frequency), and (4) elevated serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels. The inhibition of TNF-α (pentoxifylline) or inducible nitric oxide synthase (iNOS, aminoguanidine) abolished hemodynamic, HRV, and inflammatory actions of LPS. Intracisternal (i.c.) injection of ODQ (sGC inhibitor), wortmannin (PI3K inhibitor), and SP600125 (MAPKJNK inhibitor) mitigated the hypotensive and tachycardic actions of LPS but failed to affect associated decreases in HRV. MAPKp38 inhibition by i.c. SB203580 produced exactly opposite effects. None of the LPS effects was altered after i.c. PD98059 (MAPKERK1/2 inhibitor). Overall, central MAPKs/PI3K/sGC pathways variably contribute to the TNF-α/iNOS-dependent reductions in BP and HRV seen during endotoxic shock.
血压（BP）降低和心脏自主神经活动是内毒素血症的早期表现。我们研究了在清醒大鼠中，这些效应是否受中枢丝裂原活化蛋白激酶（MAPK）及相关的磷酸肌醇-3-激酶（PI3K）/可溶性鸟苷酸环化酶（sGC）信号传导的调节。评估了对这些分子底物进行药理抑制对血管内注射脂多糖（LPS，10 mg/kg）所诱发的血压、心率（HR）和心率变异性（HRV）反应的影响。LPS（1）降低血压，（2）增加心率，（3）缩短时间[逐搏间期标准差（SDNN）和R-R间期连续差值的均方根（rMSSD）]以及HRV的频域指标（总功率和低频及高频谱带），并且（4）升高血清肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平。抑制TNF-α（己酮可可碱）或诱导型一氧化氮合酶（iNOS，氨基胍）可消除LPS的血流动力学、HRV和炎症作用。脑池内（i.c.）注射ODQ（sGC抑制剂）、渥曼青霉素（PI3K抑制剂）和SP600125（MAPK JNK抑制剂）可减轻LPS的降压和心动过速作用，但未能影响HRV的相关降低。脑池内注射SB203580抑制MAPK p38产生了完全相反的效果。脑池内注射PD98059（MAPK ERK1/2抑制剂）后，LPS的所有效应均未改变。总体而言，中枢MAPK/PI3K/sGC途径对在内毒素休克期间所见的TNF-α/iNOS依赖性血压降低和HRV降低有不同程度的作用。
