Document Detail

Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats.
MedLine Citation:
PMID:  18285617     Owner:  NLM     Status:  MEDLINE    
Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 muL/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY ( approximately 40 bpm), while lowering MAP to a greater extent in SHR (-22+/-4 mm Hg) than WKY (-4+/-3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R.
Alexandre A da Silva; Jussara M do Carmo; Bela Kanyicska; John Dubinion; Elizabeth Brandon; John E Hall
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-02-19
Journal Detail:
Title:  Hypertension     Volume:  51     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-03-21     Completed Date:  2008-04-16     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  884-90     Citation Subset:  IM    
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MeSH Terms
Adrenergic alpha-Antagonists / pharmacology
Agouti-Related Protein / genetics
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects,  physiology*
Eating / drug effects,  physiology*
Heart Rate / drug effects,  physiology
Hypertension, Renal / drug therapy,  physiopathology*
Hypothalamus / physiology
Melanocortins / metabolism
Melanocyte-Stimulating Hormones / pharmacology
Neuropeptide Y / genetics
Prazosin / analogs & derivatives,  pharmacology
Pro-Opiomelanocortin / genetics
Propranolol / pharmacology
RNA, Messenger / metabolism
Rats, Inbred SHR
Rats, Inbred WKY
Receptor, Melanocortin, Type 3 / antagonists & inhibitors,  genetics*
Receptor, Melanocortin, Type 4 / antagonists & inhibitors,  genetics*
Receptors, Leptin / genetics
Sympathetic Nervous System / physiology*
Grant Support
Reg. No./Substance:
0/AGRP protein, rat; 0/Adrenergic alpha-Antagonists; 0/Agouti-Related Protein; 0/Antihypertensive Agents; 0/Melanocortins; 0/Neuropeptide Y; 0/RNA, Messenger; 0/Receptor, Melanocortin, Type 3; 0/Receptor, Melanocortin, Type 4; 0/Receptors, Leptin; 168482-23-3/SHU 9119; 66796-54-1/Pro-Opiomelanocortin; 8L5014XET7/Terazosin; 9002-79-3/Melanocyte-Stimulating Hormones; 9Y8NXQ24VQ/Propranolol; XM03YJ541D/Prazosin
Comment In:
Hypertension. 2008 Aug;52(2):e8; author reply e9   [PMID:  18559717 ]

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