Giordano Roberta, Grottoli Silvia, Brossa PierClaudio, Pellegrino Micaela, Destefanis Silvia, Lanfranco Fabio, Gianotti Laura, Ghigo Ezio, Arvat Emanuela
Divisions of Endocrinology and Nuclear Medicine, Department of Internal Medicine, University of Turin, Italy.
Clin Endocrinol (Oxf). 2003 Sep;59(3):314-20. doi: 10.1046/j.1365-2265.2003.01847.x.
Alprazolam (ALP), a benzodiazepine-activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH- and/or AVP-secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects.
In eight normal subjects [four women and four men, 22-34 years old, body mass index (BMI) 20-25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin-induced hypoglycaemia [ITT, 0.1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0.02 mg/kg orally at -90 min) were studied in two sessions at least 10 days apart.
Blood samples were taken basely at -90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions.
All subjects experienced hypoglycaemia (plasma glucose levels below 2.2 mmol/l). After placebo ITT induced clear-cut increases in ACTH (peak vs. baseline, mean +/- SEM: 27.9 +/- 3.9 vs. 7.1 +/- 1.5 pmol/l), cortisol (438.1 +/- 32.0 vs. 237.7 +/- 19.3 nmol/l) and GH (38.1 +/- 9.7 vs. 5.7 +/- 2.0 micro g/l) levels (P < 0.05). Marked increase in A (6627.2 +/- 116.7 vs. 263.7 +/- 71.4 pmol/l) and NA (3.8 +/- 1.5 vs. 1.6 +/- 1.0 nmol/l) levels were also recorded (P < 0.05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17.8 +/- 5.0 pmol/l, P < 0.05), while the cortisol response showed a non significant reduction (342.1 +/- 38.7 nmol/l). ALP also significantly reduced the GH (21.7 +/- 4.7 micro g/l, P < 0.02) and A (3828.0 +/- 1400.7 pmol/l, P < 0.02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0.05) but did not significantly affect its response to ITT (2.2 +/- 1.2 nmol/l). Glucose changes induced by ITT were not modified by ALP.
This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.
阿普唑仑（ALP）是一种激活GABA能受体的苯二氮䓬类药物，对促肾上腺皮质激素（ACTH）和皮质醇分泌具有明显的中枢介导抑制作用，这可能反映了对促肾上腺皮质激素释放激素（CRH）和/或精氨酸加压素（AVP）分泌神经元的抑制影响。ALP对儿茶酚胺释放也有抑制作用，但其对生长激素（GH）分泌的影响尚不清楚。为进一步阐明ALP的神经内分泌作用，我们研究了一组正常受试者中ALP对低血糖神经激素反应的影响。
在8名正常受试者[4名女性和4名男性，年龄22 - 34岁，体重指数（BMI）20 - 25 kg/m²]中，在至少间隔10天的两个时间段内，研究了在安慰剂或ALP（-90分钟时口服0.02 mg/kg）预处理后，对胰岛素诱导的低血糖[胰岛素耐量试验（ITT），0分钟时静脉注射（i.v.）0.1 UI/kg普通胰岛素]的ACTH、皮质醇、GH、肾上腺素（A）和去甲肾上腺素（NA）反应。
在-90分钟和0分钟时采集基础血样，并在直至+120分钟期间每隔15分钟采集一次。在两个时间段的每个时间点测定ACTH、皮质醇、GH、A和NA水平。
所有受试者均出现低血糖（血浆葡萄糖水平低于2.2 mmol/l）。安慰剂ITT后，ACTH（峰值与基线相比，均值±标准误：27.9±3.9 vs. 7.1±1.5 pmol/l）、皮质醇（438.1±32.0 vs. 237.7±19.3 nmol/l）和GH（38.1±9.7 vs. 5.7±2.0 μg/l）水平明显升高（P < 0.05）。A（6627.2±116.7 vs. 263.7±71.4 pmol/l）和NA（3.8±1.5 vs. 1.6±1.0 nmol/l）水平也显著升高（P < 0.05）。ALP预处理显著抑制了ITT引起的ACTH峰值反应（17.8±5.0 pmol/l，P < 0.05），而皮质醇反应有非显著性降低（342.1±38.7 nmol/l）。ALP还显著降低了ITT引起的GH（21.7±4.7 μg/l，P < 0.02）和A（3828.0±1400.7 pmol/l，P < 0.02）反应。相反，ALP降低了基础NA水平（P < 0.05），但对其对ITT的反应无显著影响（2.2±1.2 nmol/l）。ITT诱导的血糖变化未被ALP改变。
本研究表明，阿普唑仑激活GABA能可显著抑制对低血糖的神经内分泌和肾上腺髓质反应。
