ANGIOTENSIN II RECEPTOR TYPE-1A KNOCKDOWN IN SUBFORNICAL ORGAN PREVENTS SUSTAINED INCREASE IN MEAN ARTERIAL PRESSURE ASSOCIATED WITH CHRONIC INTERMITTENT HYPOXIA

Purpose (a): Sleep apnea (SA) is associated with a sustained increase in mean arterial pressure (MAP) even during waking hours. Chronic intermittent hypoxia (CIH) models the hypoxemia associated with SA and produces elevated MAP during CIH and normoxia. Angiotensin II (Ang II) is implicated in the CIH associated increase in MAP. Subfornical organ (SFO), a forebrain circumventricular organ, lacks blood brain barrier and is a major site for the central effects of circulating Ang II. We investigated the effects of Ang II type 1a receptor knockdown (AT1aRKD) in the SFO on CIH hypertension in adult male rats. Methods (b): Adeno-associated viral vectors carrying GFP and either AT1aR shRNA or scrambled shRNA (SCM) were injected in SFO. Continuous measurements of mean arterial pressure, heart rate, respiratory rate, and activity were measured using radio-telemetry device implanted in abdominal aorta. Rats were exposed to cyclic hypoxia (3 min 21% O2 - 3 min 10% O2) for 8 hours/day for 7 days. Rats were sacrificed on Day 8. Results (c): Using laser-capture microdissection and qRT-PCR of amino-allyl RNA, AT1aRKD rats showed decreased SFO AT1aRmRNA in comparison with SCM rats. During intermittently-hypoxic light phase, the AT1aRKD rats exposed to CIH (3 min 10% O2 and 3 min room air cycles for 8 h during light phase for 7 d) exhibited significant increases in MAP vs. AT1aRKD-Normoxia group (p(p<0.05). During the normoxic dark phase, there was no difference in MAP between CIH and normoxic AT1aRKD rats (p=0.69). SCM-CIH group showed significant increase in MAP from SCM-Normoxia group during light phase CIH (p<0.001) and the normoxic dark phase (p<0.001). Conclusions (d): Our data indicate that AT1aRs in SFO may play a role in the sustained increases in MAP during normoxia associated with CIH.