Angiotensin II-NADPH oxidase-derived superoxide mediates diabetes-attenuated cell excitability of aortic baroreceptor neurons

Abstract

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.

Cardiovascular Autonomic Dysfunction in Diabetes as a Complication: Cellular and Molecular Mechanisms

“…More importantly, angiotensin II concentration and protein expression of AT 1 receptors are increased in the nodose neuronal cells from STZ-induced diabetic rats (Li & Zheng, 2011). At the same time, mRNA expression of AT 1 receptors measured by single cell real-time PCR technique is enhanced in the aortic baroreceptor neuron cells from the STZ-induced diabetic rats (Li & Zheng, 2011). In addition, AT 1 receptor antagonist (losartan) significantly normalizes the enhanced HCN currents and the attenuated cell excitability (including depolarization of the resting membrane potential, fall in the input resistance, and decrease in the action potential number) in the aortic baroreceptor neurons induced by diabetes (Li & Zheng, 2011) or exogenous angiotensin II .…”

“…Inhibition of HCN channels has been shown to hyperpolarize the nodose neurons (increasing the resting membrane potential) and to reduce action potential threshold in response to a depolarizing current stimulation, which suggests that HCN channels are involved in the cell excitability of the nodose neurons (Doan et al, 2004;Li et al, 2008a). Results from our recent studies (Li et al, 2008a;Li & Zheng, 2011;Tu et al, 2010) confirm that the HCN current density in A-and C-type aortic baroreceptor neurons from STZinduced diabetic rats is larger than that from the sham rats (Fig. 3).…”

“…This is via NADPH oxidase-derived superoxide because a specific HCN channel blocker blunts the inhibitory effect of the exogenous angiotensin II on action potentials . More importantly, angiotensin II concentration and protein expression of AT 1 receptors are increased in the nodose neuronal cells from STZ-induced diabetic rats (Li & Zheng, 2011). At the same time, mRNA expression of AT 1 receptors measured by single cell real-time PCR technique is enhanced in the aortic baroreceptor neuron cells from the STZ-induced diabetic rats (Li & Zheng, 2011).…”

“…3). In addition, the resting membrane potential is depolarized and the current threshold induced the action potentials was elevated in the A-/C-type aortic baroreceptor neurons from STZ-induced diabetic rats, compared with that in sham rats (Li et al, 2008a;Li & Zheng, 2011). Furthermore, HCN channel blockers (CsCl and ZD-7288) lowered the HCN current density, hyperpolarized the resting membrane potential, and raised the cell membrane excitability in A-/C-type aortic baroreceptor neurons from sham and STZ-induced diabetic rats (Li et al, 2008a;Zhang et al, 2010).…”

“…1). Simultaneously, AT 1 receptor antagonist also normalized the depressed cell excitability in the aortic baroreceptor neurons of STZ-induced diabetic rats (Li & Zheng, 2011). The fact is that nodose neurons are found to influence the conduction and frequency of the electrical impulses in the baroreceptor central axons projecting to the central nervous system when electrical signals in the baroreceptor peripheral axons reach the nodose neurons (Ducreux et al, 1993).…”