Cardiovascular, Renal, and Metabolic Responses to Chronic Central Administration of Agouti-Related Peptide

Abstract

Although excess hypothalamic agouti-related peptide (AGRP), an endogenous antagonist of the melanocortin 3/4 receptor, causes hyperphagia and obesity, its role in regulating cardiovascular function is unclear. This study examined control of mean arterial pressure (MAP), heart rate (HR), and metabolism during chronic central administration of AGRP in rats. A cannula was placed in the lateral ventricle for intracerebroventricular infusion, and arterial and venous catheters were implanted for monitoring MAP and HR 24 hours per day, as well as intravenous infusions. After a 5-day control period, rats received AGRP (n=6; 0.02 nmol per hour ICV) or artificial cerebrospinal fluid (aCSF; n=9; 0.02 nmol per hour ICV) for 12 days, followed by a 5-day recovery period. A third group was infused intracerebroventricularly with AGRP and pair-fed to match food intake of control rats (n=7). AGRP produced a peak decrease in MAP and HR of -7+/-2 mm Hg and -68+/-7 bpm, respectively, despite increased food intake (from 23+/-0.5 to 36+/-3 g per day) and weight gain (from 350+/-8 to 454+/-5 g). AGRP also increased glomerular filtration rate, plasma insulin, glucose, and leptin. AGRP infusion in pair-fed rats produced a peak decrease in HR of -70+/-8 bpm but did not alter MAP or other variables. The metabolic effects of AGRP may be secondary to hyperphagia because they were abolished in pair-fed rats. aCSF infusion did not change any of the variables studied. These results demonstrate that increased central nervous system AGRP levels produce chronic reductions in MAP and HR despite marked increases in food intake and weight gain that normally tend to raise arterial pressure.