Journal
HYPERTENSION
Volume 41, Issue 3, Pages 768-774Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000048194.97428.1A
Keywords
hypertension, receptors, melanocortin; blood pressure; heart rate; hypertension, experimental; obesity; insulin
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Funding
- NHLBI NIH HHS [P01HL-51971] Funding Source: Medline
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This study examined control of cardiovascular and renal function during chronic melanocortin-3/4 receptor (MC3/4-R) activation or inhibition. Arterial and venous catheters were implanted in Sprague-Dawley rats for measurements of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and for intravenous infusions, and the lateral ventricle was cannulated for chronic intracerebroventricular (ICV) infusions. In experiment 1, after a 5-day control period, rats were administered the MC3/4-R agonist MTII (n=7, 10 ng/h ICV) or 0.9% saline (n=6, ICV) for 14 days, followed by a 5-day recovery period. In experiment 2, after a 5-day control period, rats were administered the MC3/4-R antagonist SHU-9119 (n=7, 1 nmol/h ICV) or 0.9% saline vehicle (n=7, ICV), or pair-fed during SHU-9119 infusion (n=5, 1 nmol/h ICV) for 12 days, followed by a 5-day recovery period. MC4-R activation transiently decreased food intake from 23+/-1 to 10+/-2 g/d. Despite the hypophagia, MC3/4-R activation increased MAP by 7+/-1 mm Hg. MC3/4-R inhibition for 12 days increased food intake from 21+/-1 to 35+/-4 g/d, decreased HR by 53+/-11 bpm, and caused no change in MAP despite the marked weight gain. In rats that were pair-fed to prevent increased food intake, MC3/4-R inhibition further decreased HR (-87+/-9 bpm), whereas MAP was unchanged. Thus, chronic hypothalamic MC3/4-R activation raises arterial pressure despite decreased food intake, whereas MC3/4-R inhibition causes marked weight gain without raising arterial pressure. These observations are consistent with the hypothesis that an intact hypothalamic MC3/4-R may be necessary for excess weight gain to raise arterial pressure.
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