AT(1) antisense distinguishes receptors mediating angiotensin II actions in solitary tract nucleus.
Angiotensin (Ang) II receptors in the solitary tract nucleus (nTS) are located on vagal sensory-afferent fiber terminals as well as on neuronal cell bodies. Results from in vitro slice preparations indicate that approximately 50% of the neuronal excitatory actions of Ang II result from actions at presynaptic receptors. The differential contribution of actions on fiber terminals versus neuronal cell soma to the cardiovascular effects of Ang II in the nTS is not known. We used antisense oligonucleotides to the angiotensin 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 14+/-1 mm Hg and heart rate by 13+/-1 bpm (n=8) in male Sprague-Dawley rats anesthetized with chloralose/urethane. Although there was still a significant fall in pressure that was induced by Ang II at 90 and 150 minutes after 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 alter Ang II responses at any time. There was a 40% reduction in (125)I[Sar(1)Thr8]-Ang II binding when antisense-injected and noninjected sides of the nTS were compared with receptor autoradiography. This finding is consistent with the continued presence of AT(1) receptors on afferent fibers. This unique strategy illustrates that both presynaptic fiber terminals and nTS neurons 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.
Diz
D I
DI
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1032, USA. ddiz@wfubmc.edu
Westwood
B
B
Averill
D B
DB
D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000803:Angiotensin I