Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function.
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.
Kuo
Jay J
JJ
Department of Physiology and Biophysics, Center of Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Silva
Alexandre A
AA
Hall
John E
JE
D000818:Animals; D001794:Blood Pressure; D004435:Eating; D006339:Heart Rate; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012964:Sodium / Q000652:urine; D013997:Time Factors; D014556:Urine; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
D006728:Hormones; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; D000521:alpha-MSH; D012964:Sodium