AT(1) antisense distinguishes receptors mediating angiotensin II actions in solitary tract nucleus

Angiotensin (Ang) II receptors in the solitary tract nucleus (nTS) are loca ted on vagal sensory-efferent fiber terminals as well as on neuronal cell b odies. Results from in vitro slice preparations indicate that approximate t o 50% of the neuronal excitatory actions of Ang II result from actions at p resynaptic receptors. The differential contribution of actions on fiber ter minals versus neuronal cell soma to the cardiovascular effects of Ang II in the nTS is not known. We used antisense oligonucleotides to the angiotensi n type 1 (AT(1)) receptor, which should reduce receptors on neurons within the injection site but not those on fiber terminals projecting to the nTS. Ang II injections (250 fmol/30 nL) into the nTS reduced blood pressure by 1 4 +/-1 mm Hg and heart rate by 13 +/-1 bpm (n=8) in male Sprague-Dawley rat s anesthetized with chloralose/urethane. Although there was still a signifi cant fall in pressure that was induced by Ang II at 90 and 150 minutes afte r AT(1) antisense (164 pmol/120 nL) was injected into the nTS, the response was blunted 50% (P<0.01). Heart rate responses were completely blocked at the 150-minute time point. Scrambled sequence oligonucleotides did not alte r Ang II responses at any time. There was a 40% reduction in I-125[Sar(1)Th r(8)]-Ang II binding when antisense-injected and noninjected sides of the n TS were compared with receptor autoradiography. This finding is consistent with the continued presence of AT(1) receptors on afferent fibers. This uni que strategy illustrates that both presynaptic fiber terminals and nTS neur ons are involved in the blood pressure lowering actions of Ang II, whereas heart rate responses are largely due to actions directly on nTS neurons and activation of vagal efferent pathways.