Document Detail

Receptor activity-modifying protein 1 increases baroreflex sensitivity and attenuates Angiotensin-induced hypertension.
MedLine Citation:
PMID:  20100989     Owner:  NLM     Status:  MEDLINE    
Calcitonin gene-related peptide (CGRP) is a powerful vasodilator that interacts with the autonomic nervous system. A subunit of the CGRP receptor complex, receptor activity-modifying protein 1 (RAMP1), is required for trafficking of the receptor to the cell surface and high-affinity binding to CGRP. We hypothesized that upregulation of RAMP1 would favorably enhance autonomic regulation and attenuate hypertension. Blood pressure, heart rate, and locomotor activity were measured by radiotelemetry in transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1) and littermate controls. Compared with control mice, hRAMP1 mice exhibited similar mean arterial pressure, a lower mean heart rate, increased heart rate variability, reduced blood pressure variability, and increased baroreflex sensitivity (2.83+/-0.20 versus 1.49+/-0.10 ms/mm Hg in controls; P<0.05). In control mice, infusion of angiotensin II (Ang-II) increased mean arterial pressure from 118+/-2 mm Hg to 153+/-4 and 174+/-6 mm Hg after 7 and 14 days of infusion, respectively (P<0.05). In contrast, Ang-II hypertension was markedly attenuated in hRAMP1 mice with corresponding values of mean arterial pressure of 111+/-2, 119+/-2, and 132+/-3 mm Hg. Ang-II induced decreases in baroreflex sensitivity and heart rate variability, and increases in blood pressure variability observed in control mice were also abrogated or reversed in hRAMP1 mice (P<0.05). Moreover, during the Ang-II infusion, the pressor response to the CGRP receptor antagonist CGRP(8-37) was significantly greater (P<0.05) in hRAMP1 mice (+30+/-2 mm Hg) than in control mice (+19+/-2 mm Hg), confirming a significantly greater antihypertensive action of endogenous CGRP in hRAMP1 mice. We conclude that RAMP1 overexpression attenuates Ang-II-induced hypertension and induces a protective change in cardiovascular autonomic regulation.
Rasna Sabharwal; Zhongming Zhang; Yongjun Lu; Francois M Abboud; Andrew F Russo; Mark W Chapleau
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-01-25
Journal Detail:
Title:  Hypertension     Volume:  55     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-19     Completed Date:  2010-03-18     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  627-35     Citation Subset:  IM    
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MeSH Terms
Angiotensin II / pharmacology
Angiotensin II Type 1 Receptor Blockers / pharmacology
Autonomic Nervous System Diseases / physiopathology
Baroreflex / physiology*
Blood Pressure / physiology*
Calcitonin Gene-Related Peptide / genetics
Gene Expression / physiology
Heart Rate / physiology
Hypertension / chemically induced,  drug therapy,  physiopathology*
Intracellular Signaling Peptides and Proteins / genetics*,  metabolism*
Losartan / pharmacology
Membrane Proteins / genetics*,  metabolism*
Mice, Transgenic
Parasympathetic Nervous System / physiology
Receptor Activity-Modifying Protein 1
Receptor Activity-Modifying Proteins
Receptor, Angiotensin, Type 1 / genetics
Vasoconstrictor Agents / pharmacology
Grant Support
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/RAMP1 protein, human; 0/Ramp1 protein, mouse; 0/Receptor Activity-Modifying Protein 1; 0/Receptor Activity-Modifying Proteins; 0/Receptor, Angiotensin, Type 1; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 83652-28-2/Calcitonin Gene-Related Peptide; JMS50MPO89/Losartan

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