Modulation of Blood Pressure by Central Melanocortinergic Pathways
Modulation of Blood Pressure by Central Melanocortinergic Pathways
复制标题
DOI：
10.1056/nejmoa0803085
复制
发表时间：
2009-01-01
影响因子：
158.5
通讯作者：
Farooqi, I. Sadaf
中科院分区：
文献类型：
--
作者：
Greenfield, Jerry R.;Miller, Jeffrey W.;Farooqi, I. Sadaf
背景体重增加和体重减轻与血压变化有关，其机制尚不清楚。中央黑皮质素信号的能量平衡和血压的啮齿动物的控制有牵连，但有没有这样的关联与血压在human.Methods我们评估了血压，心率和尿中的儿茶酚胺在超重或肥胖的主题与MC 4 R，黑皮质素4受体的基因编码的功能突变的损失，并在同样超重的对照组。我们还研究了MC 4 R激动剂给药7天在28超重或肥胖volunteers.Results高血压的患病率显着低于MC 4 R缺陷的主题比对照组（24%vs.53%，P = 0.009）。排除服用抗高血压药物的受试者后，MC 4 R缺陷受试者的血压水平显著低于对照受试者，平均（+/-SE）收缩压分别为123+/-14 mm Hg和131+/-12 mm Hg（P = 0.02），平均舒张压分别为73+/-10 mmHg和79+/-7 mmHg（P = 0.03）。与对照受试者相比，MC 4 R缺陷受试者清醒时心率增加较低（P = 0.007），血糖正常高胰岛素血症期间心率较低（P< 0.001），24小时尿去甲肾上腺素排泄较低（P = 0.04）。与安慰剂相比，MC 4 R激动剂的最大耐受日剂量1.0 mg导致24小时收缩压显著升高9.3+/-1.9 mmHg，舒张压显著升高6.6+/-1.1 mmHg（两种比较P< 0.001）。血压的差异不能解释胰岛素水平的变化，有没有显着的不良事件。结论我们的遗传和药理学研究结果牵连黑皮质素能信号在控制人体血压通过胰岛素非依赖性机制。
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.