Effect of angiotensin II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats

Abstract

Background: Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex.

Method: In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats.

Results: Using Ang II I radioimmunoassay, real-time reverse transcription-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor in nodose ganglia from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the nodose ganglia decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an angiotension II type 1 receptor antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nmol/l) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μmol/l) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons.

Conclusion: These results suggest that elevation of endogenous Ang II in the nodose ganglia contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels.

Fig.1

Angiotension II (Ang II) concentration (A) and Ang II type-1 receptor (AT₁R) mRNA and protein expression (B–D) in the nodose ganglia (NG) from sham and CHF rats. Data are means ± SE, n=6 rats in each group. *p<0.05 vs. sham.

Fig.2

Arterial baroreflex sensitivity in all experimental groups under anesthesia. Representative recordings (A) and logistic regression curves (B) for reflex changes of heart rate (HR) in response to changes in mean arterial pressure (MAP) from sham, sham +Ang II, CHF, and CHF + losartan rats. C, Quantitative data for maximum gains of HR calculated from logistic regression curves. Phenylephrine (10 μg) was intravenously injected, and Ang II (50 nl, 0.2 nmol) or losartan (50 nl, 1 nmol) was simultaneously microinjected into the NG on both sides. Data are mean ± SE, n=5 rats in each group. *P<0.05 vs. sham; ^#p<0.05 vs. CHF; ^† P<0.05 vs. sham + Ang II.

Fig.3

Effect of Ang II on the voltage-gated sodium (Na_v) currents in the aortic baroreceptor neurons identified with DiI labeling from sham and CHF rats. A: original Na_v currents recording in A-type aortic baroreceptor neurons from sham and CHF rats, with or without Ang II treatment. B and C: Na_v currents density-voltage (I–V) curves in A-type (B) and C-type (C) aortic baroreceptor neurons from sham and CHF rats, with or without Ang II treatment; *p<0.05 vs. sham control, #p<0.05 vs. CHF control. D: quantitative data in all groups; *p<0.05 vs. respective control in sham and CHF, #p<0.05 vs. respective Ang II treatment in sham and CHF. E: percentage of Ang II-decreased Na_v currents; *P<0.05 vs. sham. Data are mean ± SE; n=4–11 cells from 4–7 rats.

Fig.4

A, representative recordings for steady-state inactivation of the voltage-gated sodium (Na_v) channel in A-type aortic baroreceptor neurons from sham and CHF rats. B and C, summary data for steady-state activation and inactivation of the Na_v channel in A- and C-type aortic baroreceptor neurons from sham and CHF rats. Data are means ± SE; n= 6–11 cells from 5–7 rats.