Document Detail

Adenoviral inhibition of AT1a receptors in the paraventricular nucleus inhibits acute increases in mean arterial blood pressure in the rat.
MedLine Citation:
PMID:  20702798     Owner:  NLM     Status:  MEDLINE    
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.
Carrie A Northcott; Stephanie Watts; Yanfang Chen; Mariana Morris; Alex Chen; Joseph R Haywood
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Publication Detail:
Type:  Journal Article     Date:  2010-08-11
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  299     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-03     Completed Date:  2010-12-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R1202-11     Citation Subset:  IM    
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.
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MeSH Terms
Adenoviridae / genetics*
Angiotensin II
Angiotensin II Type 1 Receptor Blockers / pharmacology
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects,  genetics*
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Transfer Techniques*
Genetic Vectors*
Heart Rate
Hypertension / chemically induced,  genetics,  metabolism,  physiopathology,  prevention & control*
Muscle, Smooth, Vascular / physiopathology
Paraventricular Hypothalamic Nucleus / drug effects,  metabolism*,  physiopathology
RNA Interference*
RNA, Small Interfering / biosynthesis
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 / drug effects,  genetics*,  metabolism
Time Factors
Vasoconstrictor Agents / pharmacology
Vasodilator Agents / pharmacology
Reg. No./Substance:
0/Agtr1a protein, rat; 0/Angiotensin II Type 1 Receptor Blockers; 0/Antihypertensive Agents; 0/RNA, Small Interfering; 0/Receptor, Angiotensin, Type 1; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 11128-99-7/Angiotensin II; 59-42-7/Phenylephrine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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