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.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Eur J Pharmacol. 2017 Feb 15;797:143-152. doi: 10.1016/j.ejphar.2017.01.023. Epub 2017 Jan 20.
The immunosuppressant drug cyclosporine A (CSA) improves survivability in endotoxemia and offsets associated loss in vascular reactivity and hypotension. We tested the hypothesis that central phosphoinositide-3-kinase (PI3K)/soluble guanylate cyclase (sGC)/mitogen activated protein kinases (MAPKs) cascade modulates the CSA counteraction of endotoxic hypotension and cardiac autonomic dysfunction. The effects of pharmacologic inhibition of these molecular substrates in central pools on CSA interaction with cardiovascular responses evoked by lipopolysaccharide (LPS) were evaluated in conscious rats. CSA (10mg/kg) reversed the LPS-evoked (i) hypotension and tachycardia, (ii) decreases in time and spectral measures of heart rate variability (HRV), and (iii) increases in serum TNFα and IL-6. These CSA effects disappeared after intracisternal (i.c.) administration of ODQ (sGC inhibitor) but not wortmannin (PI3K inhibitor). When used alone, ODQ or wortmannin abolished the LPS-evoked hypotension and tachycardia, but had no effect on the concomitant reductions in HRV. We also report that the reversal by CSA of LPS hypotension disappeared after treatment with i.c SB203580 (MAPK inhibitor) or PD98059 (MAPK inhibitor), in contrast to little effect for SP600125 (MAPK inhibitor). Alternatively, the CSA amelioration of LPS-evoked reductions in HRV was abolished in presence of SP600125 or PD98059, but not SB203580. The single exposure to SP600125 reduced the decreases in blood pressure, but not HRV, caused by LPS whereas SB203580 produced the exact opposite effects. Together, while central sGC/MAPKs circuits modulate the CSA counteraction of endotoxic manifestations, the recruitment of individual MAPKs into this interaction depends on the nature of the cardiovascular response.
免疫抑制剂环孢素A（CSA）可提高内毒素血症的生存率，并抵消相关的血管反应性丧失和低血压。我们检验了以下假设：中枢磷酸肌醇-3-激酶（PI3K）/可溶性鸟苷酸环化酶（sGC）/丝裂原活化蛋白激酶（MAPK）级联反应调节CSA对内毒素性低血压和心脏自主神经功能障碍的对抗作用。在清醒大鼠中评估了对这些中枢分子底物进行药理抑制对CSA与脂多糖（LPS）诱发的心血管反应相互作用的影响。CSA（10mg/kg）可逆转LPS诱发的（i）低血压和心动过速，（ii）心率变异性（HRV）的时间和频谱测量值降低，以及（iii）血清TNFα和IL-6升高。脑池内（i.c.）给予ODQ（sGC抑制剂）后，这些CSA效应消失，但给予渥曼青霉素（PI3K抑制剂）后未消失。单独使用时，ODQ或渥曼青霉素可消除LPS诱发的低血压和心动过速，但对同时出现的HRV降低无影响。我们还报告称，与SP600125（MAPK抑制剂）作用甚微不同，脑池内给予SB203580（MAPK抑制剂）或PD98059（MAPK抑制剂）后，CSA对LPS低血压的逆转作用消失。另外，在存在SP600125或PD98059的情况下，CSA对LPS诱发的HRV降低的改善作用消失，但在存在SB203580时未消失。单次暴露于SP600125可减轻LPS引起的血压降低，但对HRV无影响，而SB203580则产生相反的效果。总之，虽然中枢sGC/MAPK回路调节CSA对内毒素表现的对抗作用，但单个MAPK参与这种相互作用取决于心血管反应的性质。
