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

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 ( = 0.0342) and 10 ( < 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 ( = 12) and was similar in magnitude 1 h later whether AIH consisted of 5 or 10 cycles ( = 6/group). Necessity of central AT1R in post-AIH sLTF was affirmed by intracerebroventricular (icv) losartan (40 nmol, 2 µL; = 5), which strongly attenuated both splanchnic ( = 0.0469) and renal ( = 0.0018) sLTF compared with vehicle [artificial cerebrospinal fluid (aCSF), 2 µL; = 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 ( = 4) failed to cause SNA ramping, it rescued sLTF in nephrectomized rats exposed to five cycles of AIH [splanchnic SNA (SSNA), = 0.0227; renal SNA (RSNA), = 0.0390; = 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. 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.