Central AT1 receptor signaling by circulating angiotensin II is permissive to acute intermittent hypoxia-induced sympathetic neuroplasticity

Abstract

Acute intermittent hypoxia (AIH) triggers sympathetic long-term facilitation (sLTF), a progressive increase in sympathetic nerve activity (SNA) linked to central AT1 receptor (AT1R) activation by circulating angiotensin II (ANG II). Here, we investigated AIH activation of the peripheral renin-angiotensin system (RAS) and the extent to which the magnitude of RAS activation predicts the magnitude of AIH-induced sLTF. In anesthetized male Sprague-Dawley rats, plasma renin activity (PRA) increased in a linear fashion in response to 5 (P = 0.0342) and 10 (P < 0.0001) cycles of AIH, with PRA remaining at the 10th cycle level 1 h later, a period over which SNA progressively increased. On average, SNA ramping began at the AIH cycle 4.6 ± 0.9 (n = 12) and was similar in magnitude 1 h later whether AIH consisted of 5 or 10 cycles (n = 6/group). Necessity of central AT1R in post-AIH sLTF was affirmed by intracerebroventricular (icv) losartan (40 nmol, 2 µL; n = 5), which strongly attenuated both splanchnic (P = 0.0469) and renal (P = 0.0018) sLTF compared with vehicle [artificial cerebrospinal fluid (aCSF), 2 µL; n = 5]. Bilateral nephrectomy largely prevented sLTF, affirming the necessity of peripheral RAS activation. Sufficiency of central ANG II signaling was assessed in nephrectomized rats. Whereas ICV ANG II (0.5 ng/0.5 µL, 30 min) in nephrectomized rats exposed to sham AIH (n = 4) failed to cause SNA ramping, it rescued sLTF in nephrectomized rats exposed to five cycles of AIH [splanchnic SNA (SSNA), P = 0.0227; renal SNA (RSNA), P = 0.0390; n = 5]. Findings indicate that AIH causes progressive peripheral RAS activation, which stimulates an apparent threshold level of central AT1R signaling that plays a permissive role in triggering sLTF.NEW & NOTEWORTHY Acute intermittent hypoxia (AIH) triggers sympathetic long-term facilitation (sLTF) that relies on peripheral renin-angiotensin system (RAS) activation. Here, increasing AIH cycles from 5 to 10 proportionally increased RAS activity, but not the magnitude of post-AIH sLTF. Brain angiotensin II (ANG II) receptor blockade and nephrectomy each largely prevented sLTF, whereas central ANG II rescued it following nephrectomy. Peripheral RAS activation by AIH induces time-dependent neuroplasticity at an apparent central ANG II signaling threshold, triggering a stereotyped sLTF response.

Keywords: hypertension; sleep apnea; sympathetic nerve activity; synaptic plasticity.

Fig. 1.

Exposure to 5 and 10 cycles of acute intermittent hypoxia (AIH) elicits similar magnitude post-AIH sympathetic long-term facilitation (sLTF) responses. A and B: representative traces of arterial blood pressure (ABP) and splanchnic sympathetic nerve activity (SSNA) recorded from anesthetized rats exposed to 5 (A) and 10 cycles (B) of AIH. Vertical bars (gray) denote analyzed time points immediately before (pre-AIH) and after (post-AIH) AIH as well as 1 h post-AIH to quantify sLTF (LTF). C and D: summary data of mean arterial pressure (MAP) and SSNA responses at analyzed time points to 5 cycles (○; n = 6) and 10 cycles (□; n = 6) of AIH. Data are expressed as means ± SE and were compared by 2-way ANOVA with Tukey post hoc tests for pairwise comparisons. MAP was similar at all quantified time points before and after 5 and 10 cycles of AIH. By contrast, SSNA at LTF time points were significantly and similarly increased by 5 (*P = 0.0454, q = 5.001, df = 10) and 10 (ϕP = 0.0114, q = 6.303, df = 10) cycles of AIH relative to their corresponding post-AIH levels. ns, not significant.

Fig. 2.

Blockade of central AT1 receptors (AT1Rs) nearly prevents acute intermittent hypoxia (AIH)-induced sympathetic long-term facilitation (sLTF). Representative arterial blood pressure (ABP; top), splanchnic sympathetic nerve activity (SSNA; middle), and renal sympathetic nerve activity (RSNA; bottom) responses to 5 cycles of AIH in anesthetized rats treated with either intracerebroventricular (icv) artificial cerebrospinal fluid (aCSF) vehicle (A) or the angiotensin II (ANG II) AT1 receptor (AT1R) antagonist losartan (B). Robust AIH-induced sLTF observed with vehicle treatment was largely absent in the rat treated with losartan. C: summary data comparing MAP (left), SSNA (middle), and RSNA (right) responses to AIH in rats treated with icv aCSF (○) or icv losartan (□). Data are expressed as means ± SE and were compared by 2-way ANOVA. SSNA: *P = 0.0062 (q = 9.259, df = 4) vs. within group post-AIH value; ϕP = 0.0469 (t = 2.949, df = 7.6704) vs. between-group LTF value. RSNA: *P = 0.0032 (q = 11.06, df = 4) vs. within group post-AIH value; ϕP = 0.0018 (t = 6.567, df = 6) vs. between-group LTF value.

Fig. 3.

Post-acute intermittent hypoxia (AIH) sympathetic long-term facilitation (sLTF) is prevented by bilateral nephrectomy and rescued by central angiotensin II (ANG II). A–C: representative arterial blood pressure (ABP; top), splanchnic sympathetic nerve activity (SSNA; middle), and renal sympathetic nerve activity (RSNA; bottom) traces recorded in anesthetized bilateral nephrectomized rats during exposure to 5 cycles of AIH (A and B) or sham AIH consisting of continuous normoxia (C). Rats were treated either with continuous intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF; A) or ANG II (B and C). D: summary data show mean arterial pressure (MAP; left), SSNA (middle), and RSNA (right) responses at quantified time points before (pre-AIH), immediately after (post-AIH), and 1 h after (LTF) AIH/normoxia in rats that received icv vehicle + AIH (○; n = 5), icv ANG II + AIH (□; n = 5), and icv ANG II + normoxia (△; n = 4). Note: lack of SNA response to icv ANG II among normoxic rats suggests that the sLTF-like ramping of SNA among AIH-exposed rats that received icv ANG II was not a direct reflection of central ANG II actions but of central ANG II actions rescuing the sLTF response to AIH. Data are expressed as means ± SE and were compared by 2-way ANOVA. MAP: *P = 0.0315 (q = 5.623, df = 4.278); ϕP = 0.0092 (q = 6.117, df = 6.727). SSNA: *P = 0.0227 (q =5.761, df = 4.882), ϕP = 0.0059 (q = 8.621, df = 4.427). RSNA: *P = 0.0390 (q = 4.335, df = 7.582); ϕP = 0.0124 (q = 6.341, df = 5.433).