Dept. of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Am J Physiol Cell Physiol. 2011 Dec;301(6):C1368-77. doi: 10.1152/ajpcell.00214.2011. Epub 2011 Sep 21.
Overactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is involved in diabetes-depressed excitability of aortic baroreceptor neurons in nodose ganglia. This involvement links to the autonomic dysfunction associated with high morbidity and mortality in diabetic patients. The present study examined the effects of an angiotensin II type I receptor (AT(1)R) antagonist (losartan), a NADPH oxidase inhibitor (apocynin), and a superoxide dismutase mimetic (tempol) on the enhanced HCN currents and attenuated cell excitability in diabetic nodose neurons. In sham and streptozotocin-induced type 1 diabetic rats, HCN currents and cell excitability of aortic baroreceptor neurons were recorded by the whole cell patch-clamp technique. The angiotensin II level in nodose ganglia from diabetic rats was higher than that from sham rats (101.6 ± 4.8 vs. 38.9 ± 4.2 pg/mg protein, P < 0.05). Single-cell RT-PCR, Western blot, immunofluorescence staining, and chemiluminescence data showed that mRNA and protein expression of AT(1)R, protein expression of NADPH oxidase components, and superoxide production in nodose neurons were increased in diabetic rats compared with those from sham rats. HCN current density was higher and cell excitability was lower in aortic baroreceptor neurons from diabetic rats than that from sham rats. Losartan (1 μM), apocynin (100 μM), and tempol (1 mM) normalized the enhanced HCN current density and increased the cell excitability in the aortic baroreceptor neurons of diabetic rats. These findings suggest that endogenous angiotensin II-NADPH oxidase-superoxide signaling contributes to the enhanced HCN currents and the depressed cell excitation in the aortic baroreceptor neurons of diabetic rats.
超极化激活环核苷酸门控 (HCN) 通道的过度激活与糖尿病患者自主神经功能障碍有关，而后者与糖尿病患者高发病率和高死亡率密切相关。本研究探讨了血管紧张素 II 型 1 型受体 (AT(1)R) 拮抗剂（氯沙坦）、NADPH 氧化酶抑制剂（apocynin）和超氧化物歧化酶模拟物（tempol）对糖尿病性迷走神经节主动脉压力感受器神经元增强的 HCN 电流和减弱的细胞兴奋性的影响。在假手术和链脲佐菌素诱导的 1 型糖尿病大鼠中，通过全细胞膜片钳技术记录主动脉压力感受器神经元的 HCN 电流和细胞兴奋性。糖尿病大鼠迷走神经节中的血管紧张素 II 水平高于假手术大鼠（101.6 ± 4.8 比 38.9 ± 4.2 pg/mg 蛋白，P < 0.05）。单细胞 RT-PCR、Western blot、免疫荧光染色和化学发光数据表明，与假手术大鼠相比，糖尿病大鼠迷走神经元中的 AT(1)R mRNA 和蛋白表达、NADPH 氧化酶成分的蛋白表达和超氧化物产生增加。糖尿病大鼠主动脉压力感受器神经元的 HCN 电流密度更高，细胞兴奋性更低。1 μM 氯沙坦、100 μM apocynin 和 1 mM tempol 可使糖尿病大鼠主动脉压力感受器神经元增强的 HCN 电流密度和增加的细胞兴奋性正常化。这些发现表明，内源性血管紧张素 II-NADPH 氧化酶-超氧化物信号参与了糖尿病大鼠主动脉压力感受器神经元中增强的 HCN 电流和抑制的细胞兴奋。
