Document Detail

Modulation of blood pressure by central melanocortinergic pathways.
MedLine Citation:
PMID:  19092146     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans.
METHODS: We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.
RESULTS: The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.
CONCLUSIONS: Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.
Jerry R Greenfield; Jeffrey W Miller; Julia M Keogh; Elana Henning; Julie H Satterwhite; Gregory S Cameron; Beatrice Astruc; John P Mayer; Soren Brage; Teik Choon See; David J Lomas; Stephen O'Rahilly; I Sadaf Farooqi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-17
Journal Detail:
Title:  The New England journal of medicine     Volume:  360     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-01     Completed Date:  2009-01-16     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  44-52     Citation Subset:  AIM; IM    
Copyright Information:
2009 Massachusetts Medical Society
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MeSH Terms
Autonomic Nervous System / physiology
Blood Pressure / drug effects,  genetics,  physiology*
Catecholamines / urine
Cross-Over Studies
Dose-Response Relationship, Drug
Double-Blind Method
Heart Rate / genetics,  physiology
Hypertension / complications,  genetics,  metabolism*
Obesity / complications,  genetics,  metabolism
Overweight / complications,  genetics,  metabolism*
Receptor, Melanocortin, Type 4 / agonists,  deficiency,  genetics,  metabolism*
Signal Transduction*
Sleep / physiology
Grant Support
082390//Wellcome Trust; G9824984//Medical Research Council; MC_U106179473//Medical Research Council; //Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/Catecholamines; 0/Receptor, Melanocortin, Type 4

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