Tallam Lakshmi S, Kuo Jay J, da Silva Alexandre A, Hall John E
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505, USA.
Hypertension. 2004 Dec;44(6):853-8. doi: 10.1161/01.HYP.0000148993.47498.b2. Epub 2004 Nov 15.
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.
尽管下丘脑过量分泌的刺鼠相关肽（AGRP）是黑皮质素3/4受体的内源性拮抗剂，可导致食欲亢进和肥胖，但其在调节心血管功能中的作用尚不清楚。本研究检测了大鼠长期脑室内注射AGRP期间平均动脉压（MAP）、心率（HR）和代谢的调控情况。将套管置于侧脑室用于脑室内输注，并植入动脉和静脉导管以每天24小时监测MAP和HR，以及进行静脉输注。在为期5天的对照期后，大鼠接受AGRP（n = 6；每小时0.02 nmol脑室内注射）或人工脑脊液（aCSF；n = 9；每小时0.02 nmol脑室内注射），持续12天，随后是为期5天的恢复期。第三组大鼠脑室内注射AGRP并进行配对喂养，使其食物摄入量与对照大鼠相匹配（n = 7）。尽管食物摄入量增加（从每天23±0.5克增加到36±3克）和体重增加（从350±8克增加到454±5克），AGRP分别使MAP和HR峰值降低了-7±2 mmHg和-68±7次/分钟。AGRP还增加了肾小球滤过率、血浆胰岛素、葡萄糖和瘦素。对配对喂养的大鼠输注AGRP使HR峰值降低了-70±8次/分钟，但未改变MAP或其他变量。AGRP的代谢作用可能继发于食欲亢进，因为在配对喂养的大鼠中这些作用被消除了。输注aCSF未改变所研究的任何变量。这些结果表明，尽管食物摄入量和体重显著增加通常会使动脉压升高，但中枢神经系统AGRP水平升高会导致MAP和HR长期降低。
