靶向去肾交感神经术对犬肾脏局部交感活性和肾素血管紧张素系统的影响

Effects of targeted renal denervation guided by renal nerve stimulation on intrarenal renin-angiotensin systems and sympathetic activity in canine

目的研究经肾神经刺激(RNS)引导下不同血压反应位点的靶向去肾交感神经术(RDN)后肾脏局部交感及肾素血管紧张素系统(RAS)活性的变化。方法 21只无肾动脉解剖异常的昆明犬随机分为肾神经刺激组(假手术组,Sham组,n=7),刺激弱反应位点消融组(WRA,n=7),刺激强反应位点消融组(SRA,n=7)。WRA组及SRA组分别在弱反应位点和强反应位点行射频消融治疗,Sham组仅予以刺激处理。记录基线及术后4周各组实验犬股动脉血压,检测RDN术后4周各组实验犬肾脏局部去甲肾上腺素(NE)水平、酪氨酸羟化酶(TH)以及RAS组分的表达。结果术中WRA组和SRA组刺激和消融位点的数目差异无统计学意义(P=0.535);3组实验犬基线血压差异无统计学意义(收缩压:P=0.188,舒张压:P=0.304)。RDN术后4周,与Sham组相比,WRA组收缩压和舒张压分别降低(14.74±6.09)和(13.12±8.78)mm Hg(P=0.004和0.042),SRA组收缩压和舒张压分别降低(28.64±6.71)和(20.45±10.80)mm Hg(P<0.001和P=0.001)。与WRA组相比,SRA组收缩压降幅更大(P=0.002),舒张压降幅也更明显,但未达到统计学差异(P=0.131)。相比于Sham组,WRA组及SRA组肾脏局部NE水平、TH和肾素的表达均有不同程度的降低,并且在SRA组更为显著。局部RAS组分的变化表明:与Sham组相比,两消融组中血管紧张素转换酶(ACE)、血管紧张素原(AGT)、血管紧张素Ⅱ1型受体(AT1R)的表达均有不同程度的降低,而血管紧张素转换酶2(ACE2)的表达上调,两种变化同样均以SRA组更为明显。结论RNS引导下两类不同血压反应位点的靶向RDN治疗均能不同程度地通过降低肾脏局部交感及RAS活性而实现降低血压,其中选择性对强反应位点的消融治疗靶向性更好,降压幅度也更大。

Objective To investigate the changes and differences of intrarenal renin-angiotensin systems(RAS) and sympathetic activity after targeted renal denervation(RDN) at sites with different blood pressure(BP) responses to renal nerve stimulation(RNS). Methods Twenty-one dogs anatomically eligible for performing RNS and RDN were randomly assigned into 3 groups: sham group(n=7), weak BP-response to RNS ablation group(WRA, n=7) and strong BP-response to RNS ablation group(SRA, n=7). Radiofrequency ablation was performed at the sites with weak or strong responses in WRA or SRA group, respectively. Invasive femoral artery BP was recorded at baseline and 4 weeks after RDN. The levels of norepinephrine(NE), expression of tyrosine hydroxylase(TH) and RAS components in kidney were measured by Western blot and immunohistochemistry. Results There was no significant difference in the number of stimulation or ablation sites between WRA and SRA group. No significant differences at baseline among groups in systolic BP(SBP,P=0.188) and diastolic BP(DBP, P=0.304). The SBP/DBP decreased by(14.74±6.09)/(13.12±8.78) mm Hg(P=0.004 and 0.042) in the WRA group and(28.64±6.71)/(20.45±10.80) mm Hg(P<0.001 and P=0.001) in SRA group, respectively, compared with the sham group at 4 weeks after RDN. In addition, the reduction of SBP was greater in SRA group than in WRA group(P=0.002);in contrast, although the reduction trend of DBP was more pronounced in SRA group, there was no statistical difference compared with WRA group(P=0.131). Compared with the sham group, the NE concentration, TH and renin protein expression were significantly reduced in both groups, and all these reductions were more significant in the SRA group. The expression of angiotensin converting enzyme(ACE), angiotensinogen(AGT), and angiotensin Ⅱ type 1 receptor(AT1R) were significantly attenuated in both ablation groups, compared with the sham group, while the ACE2 was significantly up-regulated. Both changes were more marked in the SRA group. Conclusion Targeted RDN at the sites with two different types of BP response can lower blood pressure by attenuating intrarenal sympathetic activity and RAS activity, and selective RDN at sites with strong BP-response to RNS is more effective.