Adenoviral inhibition of AT1a receptors in the paraventricular nucleus inhibits acute increases in mean arterial blood pressure in the rat.
Brain and peripheral renin-angiotensin systems are important in blood pressure maintenance. Circulating ANG II stimulates brain RAS to contribute to the increase mean arterial pressure (MAP). This mechanism has not been fully clarified, so it was hypothesized that reducing angiotensin type 1a (AT(1a)) receptors (AT(1a)Rs) in the paraventricular nucleus (PVN) would diminish intravenous ANG II-induced increases in MAP. Adenoviruses (Ad) encoding AT(1a) small hairpin RNA (shRNA) or Ad-LacZ (marker gene) were injected into the PVN [1 × 10(9) plaque-forming units/ml, bilateral (200 nl/site)] of male Sprague-Dawley rats instrumented with radiotelemetry transmitters for MAP and heart rate measurements and with venous catheters for drug administration. No differences in weight gain or basal MAP were observed. ANG II (30 ng·kg(-1)·min(-1) iv, 15 μl/min for 60 min) was administered 3, 7, 10, and 14 days after PVN Ad injection to increase blood pressure. ANG II-induced elevations in MAP were significantly reduced in PVN Ad-AT(1a) shRNA rats compared with Ad-LacZ rats (32 ± 6 vs. 8 ± 9 mmHg at 7 days, 35 ± 6 vs. 10 ± 6 mmHg at 10 days, and 32 ± 2 vs. 1 ± 5 mmHg at 14 days; P < 0.05). These observations were confirmed by acute administration of losartan (20 nmol/l, 100 nl/site) in the PVN prior to short-term infusion of ANG II; the ANG II-pressor response was attenuated by 69%. In contrast, PVN Ad-AT(1a) shRNA treatment did not influence phenylephrine-induced increases in blood pressure (30 μg·kg(-1)·min(-1) iv, 15 μl/min for 30 min). Importantly, PVN Ad-AT(1a) shRNA did not alter superior mesenteric arterial contractility to ANG II or norepinephrine; ACh-induced arterial relaxation was also unaltered. β-Galactosidase staining revealed PVN Ad transduction, and Western blot analyses revealed significant reductions of PVN AT(1) protein. In conclusion, PVN-localized AT(1)Rs are critical for short-term circulating ANG II-mediated elevations of blood pressure. A sustained suppression of AT(1a)R expression by single administration of shRNA can interfere with short-term actions of ANG II.
Northcott
Carrie A
CA
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. taetscar@msu.edu
Watts
Stephanie
S
Chen
Yanfang
Y
Morris
Mariana
M
Chen
Alex
A
Haywood
Joseph R
JR
D000256:Adenoviridae / Q000235:genetics*; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006339:Heart Rate; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008845:Microinjections; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010656:Phenylephrine; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
C544067:Agtr1a protein, rat; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D010656:Phenylephrine