Modulation of blood pressure by central melanocortinergic pathways.
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.
Greenfield
Jerry R
JR
University of Cambridge Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge, United Kingdom.
Miller
Jeffrey W
JW
Keogh
Julia M
JM
Henning
Elana
E
Satterwhite
Julie H
JH
Cameron
Gregory S
GS
Astruc
Beatrice
B
Mayer
John P
JP
Brage
Soren
S
See
Teik Choon
TC
Lomas
David J
DJ
O'Rahilly
Stephen
S
Farooqi
I Sadaf
IS
D000328:Adult; D001341:Autonomic Nervous System / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002395:Catecholamines / Q000652:urine; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D050177:Overweight / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015995:Prevalence; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012890:Sleep / Q000502:physiology
D002395:Catecholamines; D044105:Receptor, Melanocortin, Type 4